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Kaletra (lopinavir / ritonavir) – Summary of product characteristics - J05AR10

Updated on site: 08-Oct-2017

Medication nameKaletra
ATC CodeJ05AR10
Substancelopinavir / ritonavir
ManufacturerAbbVie Ltd

1.NAME OF THE MEDICINAL PRODUCT

Kaletra (80 mg + 20 mg) / ml oral solution

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of Kaletra oral solution contains 80 mg of lopinavir co-formulated with 20 mg of ritonavir as a pharmacokinetic enhancer.

Excipients with known effect:

Each 1 ml contains 356.3 mg of alcohol (42.4% v/v), 168.6 mg of high fructose corn syrup, 152.7 mg of propylene glycol (15.3% w/v) (see section 4.3), 10.2 mg of polyoxyl 40 hydrogenated castor oil and 4.1 mg of acesulfame potassium (see section 4.4).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Oral solution

The solution is light yellow to golden.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 2 years.

The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

4.2Posology and method of administration

Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.

Posology

Adults and adolescents

The recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg) twice daily taken with food.

Paediatric population (2 years of age and above)

The recommended dosage of Kaletra is 230/57.5 mg/m2 twice daily taken with food, up to a maximum dose of 400/100 mg twice daily. The 230/57.5 mg/m2 dosage might be insufficient in some children when co-administered with nevirapine or efavirenz. An increase of the dose of Kaletra to

300/75 mg/m2 should be considered in these patients. If weight-based dosing is preferred, the dosage for patients greater than or equal to 15 kg to 40 kg is 10/2.5 mg/kg twice daily when Kaletra is not co- administered with nevirapine or efavirenz. Dose should be administered using a calibrated oral dosing syringe.

The oral solution is the recommended option for the most accurate dosing in children based on body surface area. However, if it judged necessary to resort to solid oral dosage form for children weighing

less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able to swallow tablets, Kaletra

100 mg/25 mg tablets may be used. The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or with a Body Surface Area (BSA)* greater than 1.4 m2. Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or crushed. Please refer to the Kaletra 100 mg/25 mg film-coated tablets Summary of Product Characteristics.

The following tables contain dosing guidelines for Kaletra oral solution based on body weight and BSA.

 

Paediatric dosing guidelines based on body weight*

 

 

 

 

Body weight (kg)

Twice daily oral solution dose

 

 

(dose in mg/kg)

 

 

 

 

≥ 15 to 40 kg

10/2.5 mg/kg

 

*weight based dosing recommendations are based on limited data

 

 

 

Paediatric dosing guidelines for the dose 230/57.5 mg/m2

 

Body Surface Area* (m2)

Twice daily oral solution dose (dose in mg)

 

0.25

0.7 ml (57.5/14.4 mg)

 

0.40

1.2 ml (96/24 mg)

 

0.50

1.4 ml (115/28.8 mg)

 

0.75

2.2 ml (172.5/43.1 mg)

 

0.80

2.3 ml (184/46 mg)

 

1.00

2.9 ml (230/57.5 mg)

 

1.25

3.6 ml (287.5/71.9 mg)

 

1.3

3.7 ml (299/74.8 mg)

 

1.4

4.0 ml (322/80.5 mg)

 

1.5

4.3 ml (345/86.3 mg)

 

1.7

5 ml (402.5/100.6 mg)

*Body surface area can be calculated with the following equation

BSA (m2) = √ (Height (cm) X Weight (kg) / 3600)

Children less than 2 years of age

The safety and efficacy of Kaletra in children aged less than 2 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on the posology can be made. Total amounts of alcohol and propylene glycol from all medicines, including Kaletra oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients (see section 4.4).

Hepatic impairment

In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra must not be given to these patients (see section 4.3).

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Method of administration

Kaletra is administered orally and should always be taken with food (see section 5.2)

4.3Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Severe hepatic insufficiency.

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include:

Medicinal product

Medicinal products

Rationale

class

within class

 

 

 

Concomitant medicinal product levels increased

 

 

 

 

Alpha1-adrenoreceptor

Alfuzosin

Increased plasma concentrations of alfuzosin

antagonist

 

which may lead to severe hypotension. The

 

 

concomitant administration with alfuzosin is

 

 

contraindicated (see section 4.5).

Antianginal

Ranolazine

Increased plasma concentrations of ranolazine

 

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section

 

 

4.5).

Antiarrhythmics

Amiodarone,

Increased plasma concentrations of amiodarone

 

dronedarone

and dronedarone. Thereby, increasing the risk of

 

 

arrhythmias or other serious adverse reactions.

Antibiotic

Fusidic Acid

Increased plasma concentrations of fusidic acid.

 

 

The concomitant administration with fusidic acid

 

 

is contraindicated in dermatological infections.

 

 

(see section 4.5).

Anti-gout

Colchicine

Increased plasma concentrations of colchicine.

 

 

Potential for serious and/or life-threatening

 

 

reactions in patients with renal and/or hepatic

 

 

impairment (see sections 4.4 and 4.5).

Antihistamines

Astemizole, terfenadine

Increased plasma concentrations of astemizole

 

 

and terfenadine. Thereby, increasing the risk of

 

 

serious arrhythmias from these agents.

Antipsychotics/

Lurasidone

Increased plasma concentrations of lurasidone

Neuroleptics

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section

 

 

4.5).

 

Pimozide

Increased plasma concentrations of pimozide.

 

 

Thereby, increasing the risk of serious

 

 

haematologic abnormalities, or other serious

 

 

adverse effects from this agent.

 

Quetiapine

Increased plasma concentrations of quetiapine

 

 

which may lead to coma. The concomitant

 

 

administration with quetiapine is contraindicated

 

 

(see section 4.5).

Ergot alkaloids

Dihydroergotamine,

Increased plasma concentrations of ergot

 

ergonovine,

derivatives leading to acute ergot toxicity,

 

ergotamine,

including vasospasm and ischaemia.

 

methylergonovine

 

GI motility agent

Cisapride

Increased plasma concentrations of cisapride.

 

 

Thereby, increasing the risk of serious

 

 

arrhythmias from this agent.

HMG Co-A Reductase

Lovastatin, simvastatin

Increased plasma concentrations of lovastatin

Inhibitors

 

and simvastatin; thereby, increasing the risk of

 

 

myopathy including rhabdomyolysis (see section

 

 

4.5).

Phosphodiesterase

Avanafil

Increased plasma concentrations of avanafil (see

(PDE5) inhibitors

 

sections 4.4 and 4.5)

 

Sildenafil

Contraindicated when used for the treatment of

 

 

pulmonary arterial hypertension (PAH) only.

 

 

Increased plasma concentrations of sildenafil.

 

 

Thereby, increasing the potential for sildenafil-

 

 

associated adverse events (which include

 

 

hypotension and syncope). See section 4.4 and

 

 

section 4.5 for co-administration of sildenafil in

 

 

patients with erectile dysfunction.

 

Vardenafil

Increased plasma concentrations of vardenafil

 

 

(see sections 4.4 and 4.5)

Sedatives/hypnotics

Oral midazolam,

Increased plasma concentrations of oral

 

triazolam

midazolam and triazolam. Thereby, increasing

 

 

the risk of extreme sedation and respiratory

 

 

depression from these agents.

 

 

For caution on parenterally administered

 

 

midazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

 

 

 

Herbal products

St. John’s wort

Herbal preparations containing St John’s wort

 

 

(Hypericum perforatum) due to the risk of

 

 

decreased plasma concentrations and reduced

clinical effects of lopinavir and ritonavir (see section 4.5).

Kaletra oral solution is contraindicated in children below the age of 2 years, pregnant women, patients with hepatic or renal failure and patients treated with disulfiram or metronidazole due to the potential risk of toxicity from the excipient propylene glycol (see section 4.4).

4.4Special warnings and precautions for use

Patients with coexisting conditions

Hepatic impairment

The safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction was serious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and close monitoring should be performed during treatment.

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Pancreatitis

Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see section 5.1).

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Interactions with medicinal products

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).

The combination of Kaletra with:

-tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended (see section 4.5);

-riociguat is not recommended (see section 4.5);

-vorapaxar is not recommended (see section 4.5);

-fusidic acid in osteo-articular infections is not recommended (see section 4.5);

-salmeterol is not recommended (see section 4.5);

-rivaroxaban is not recommended (see section 4.5).

The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these medicinal products

is expected to substantially increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra is contraindicated (see section 4.3).

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse reactions. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3).

Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).

Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).

Other

Patients taking the oral solution, particularly those with renal impairment or with decreased ability to metabolise propylene glycol (e.g. those of Asian origin), should be monitored for adverse reactions potentially related to propylene glycol toxicity (i.e. seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis) (see section 4.3).

Kaletra is not a cure for HIV infection or AIDS. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS.

Besides propylene glycol as described above, Kaletra oral solution contains alcohol (42% v/v) which is potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. It may modify or increase the effects of other medicines. Kaletra oral solution contains up to 0.8 g of fructose per dose when taken according to the dosage recommendations. This may be unsuitable in hereditary fructose intolerance. Kaletra oral solution contains up to 0.3 g of glycerol per dose. Only at high inadvertent doses, it can cause headache and gastrointestinal upset. Furthermore, polyoxol 40 hydrogenated castor oil and potassium present in Kaletra oral solution may cause only at high inadvertent doses gastrointestinal upset. Patients on a low potassium diet should be cautioned.

Particular risk of toxicity in relation to the amount of alcohol and propylene glycol contained in Kaletra oral solution

Healthcare professionals should be aware that Kaletra oral solution is highly concentrated and contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v). Each 1 ml of Kaletra oral solution contains 356.3 mg of alcohol and 152.7 mg of propylene glycol.

Special attention should be given to accurate calculation of the dose of Kaletra, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose. This is especially important for infants and young children.

Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. Infants should be monitored closely for toxicity related to Kaletra oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, central nervous system (CNS) depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Postmarketing life-threatening cases of cardiac toxicity (including complete atrioventricular (AV) block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra oral solution (see sections 4.3 and 4.9).

4.5Interaction with other medicinal products and other forms of interaction

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A

in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).

Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products.

Medicinal products that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in section 4.3.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below.

Interaction table

Interactions between Kaletra and co-administered medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as

“BID” and three times daily as "TID").

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of lopinavir/ritonavir (i.e. 400/100 mg twice daily).

Co-administered drug

Effects on drug levels

 

Clinical recommendation

by therapeutic area

 

 

concerning co-administration

 

Geometric Mean Change (%) in

 

with Kaletra

 

AUC, Cmax, Cmin

 

 

 

Mechanism of interaction

 

 

Antiretroviral Agents

 

 

 

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

 

Stavudine, Lamivudine

Lopinavir: ↔

 

No dose adjustment necessary.

 

 

 

 

Abacavir, Zidovudine

Abacavir, Zidovudine:

 

The clinical significance of

 

Concentrations may be reduced

 

reduced abacavir and zidovudine

 

due to increased glucuronidation

 

concentrations is unknown.

 

by Kaletra.

 

 

Tenofovir, 300 mg QD

Tenofovir:

 

No dose adjustment necessary.

 

AUC: ↑ 32%

 

Higher tenofovir concentrations

 

Cmax: ↔

 

could potentiate tenofovir

 

Cmin: ↑ 51%

 

associated adverse events,

 

Lopinavir: ↔

 

including renal disorders.

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

Efavirenz, 600 mg QD

Lopinavir:

 

The Kaletra tablets dosage should

 

AUC: ↓ 20%

 

be increased to 500/125 mg twice

 

Cmax: ↓ 13%

 

daily when co-administered with

 

Cmin: ↓ 42%

 

efavirenz.

Efavirenz, 600 mg QD

Lopinavir: ↔

 

 

 

 

 

(Lopinavir/ritonavir

(Relative to 400/100 mg BID

 

 

500/125 mg BID)

administered alone)

 

 

Nevirapine, 200 mg

Lopinavir:

 

The Kaletra tablets dosage should

BID

AUC: ↓ 27%

 

be increased to 500/125 mg twice

 

Cmax: ↓ 19%

 

daily when co-administered with

 

Cmin: ↓ 51%

 

nevirapine.

Etravirine

Etravirine :

 

No dose adjustment necessary

 

AUC: ↓ 35%

 

 

(Lopinavir/ritonavir

Cmin: ↓ 45%

 

 

tablet 400/100 mg BID)

Cmax: ↓ 30%

 

 

 

Lopinavir :

 

 

 

AUC: ↔

 

 

 

Cmin: ↓ 20%

 

 

 

Cmax: ↔

 

 

Rilpivirine

Rilpivirine:

 

Concomitant use of Kaletra with

 

AUC: ↑ 52%

 

rilpivirine causes an increase in

(Lopinavir/ritonavir

Cmin: ↑ 74%

 

the plasma concentrations of

capsule 400/100 mg

Cmax: ↑ 29%

 

rilpivirine, but no dose adjustment

BID)

Lopinavir:

 

is required.

 

 

 

 

AUC: ↔

 

 

 

Cmin: ↓ 11%

 

 

 

Cmax: ↔

 

 

 

(inhibition of CYP3A enzymes)

 

 

HIV CCR5 – antagonist

Maraviroc

Maraviroc:

The dose of maraviroc should be

 

AUC: ↑ 295%

decreased to 150 mg twice daily

 

Cmax: ↑ 97%

during co-administration with

 

Due to CYP3A inhibition by

Kaletra 400/100 mg twice daily.

 

lopinavir/ritonavir.

 

Integrase inhibitor

 

 

Raltegravir

Raltegravir:

No dose adjustment necessary

 

AUC: ↔

 

 

Cmax: ↔

 

 

C12: ↓ 30%

 

 

Lopinavir: ↔

 

Co-administration with other HIV protease inhibitors (PIs)

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Fosamprenavir/

Fosamprenavir:

Co-administration of increased

ritonavir (700/100 mg

Amprenavir concentrations are

doses of fosamprenavir (1400 mg

BID)

significantly reduced.

BID) with lopinavir/ritonavir

 

 

(533/133 mg BID) to protease

(Lopinavir/ritonavir

 

inhibitor-experienced patients

400/100 mg BID)

 

resulted in a higher incidence of

 

 

gastrointestinal adverse events and

or

 

elevations in triglycerides with the

 

 

combination regimen without

Fosamprenavir

 

increases in virological efficacy,

(1400 mg BID)

 

when compared with standard

 

 

doses of fosamprenavir/ritonavir.

(Lopinavir/ritonavir

 

Concomitant administration of

533/133 mg BID)

 

these medicinal products is not

 

 

recommended.

 

 

 

Indinavir, 600 mg BID

Indinavir:

The appropriate doses for this

 

AUC: ↔

combination, with respect to

 

Cmin: ↑ 3.5-fold

efficacy and safety, have not been

 

Cmax: ↓

established.

 

(relative to indinavir 800 mg TID

 

 

alone)

 

 

Lopinavir: ↔

 

 

(relative to historical comparison)

 

Saquinavir

Saquinavir: ↔

No dose adjustment necessary.

1000 mg BID

 

 

Tipranavir/ritonavir

Lopinavir:

Concomitant administration of

(500/100 mg BID)

AUC: ↓ 55%

these medicinal products is not

 

Cmin: ↓ 70%

recommended.

 

Cmax: ↓ 47%

 

Acid reducing agents

 

 

Omeprazole (40 mg

Omeprazole: ↔

No dose adjustment necessary

QD)

Lopinavir: ↔

 

 

 

Ranitidine (150 mg

Ranitidine: ↔

No dose adjustment necessary

single dose)

 

 

Alpha1 adrenoreceptor antagonist

Alfuzosin

Alfuzosin:

Concomitant administration of

 

Due to CYP3A inhibition by

Kaletra and alfuzosin is contra-

 

lopinavir/ritonavir, concentrations

indicated (see section 4.3) as

 

of alfuzosin are expected to

alfuzosin-related toxicity,

 

increase.

including hypotension, may be

 

 

increased.

Analgesics

 

 

Fentanyl

Fentanyl:

Careful monitoring of adverse

 

Increased risk of side-effects

effects (notably respiratory

 

(respiratory depression, sedation)

depression but also sedation) is

 

due to higher plasma

recommended when fentanyl is

 

concentrations because of

concomitantly administered with

 

CYP3A4 inhibition by Kaletra

Kaletra.

Antianginal

 

 

Ranolazine

Due to CYP3A inhibition by

The concomitant administration of

 

lopinavir/ritonavir, concentrations

Kaletra and ranolazine is

 

of ranolazine are expected to

contraindicated (see section 4.3).

 

increase.

 

Antiarrhythmics

 

 

Amiodarone,

Amiodarone, Dronedarone:

Concomitant administration of

Dronedarone

Concentrations may be increased

Kaletra and amiodarone or

 

due to CYP3A4 inhibition by

dronedarone is contraindicated

 

Kaletra.

(see section 4.3) as the risk of

 

 

arrhythmias or other serious

 

 

adverse reactions may be

 

 

increased.

Digoxin

Digoxin:

Caution is warranted and

 

Plasma concentrations may be

therapeutic drug monitoring of

 

increased due to P-glycoprotein

digoxin concentrations, if

 

inhibition by Kaletra. The

available, is recommended in case

 

increased digoxin level may

of co-administration of Kaletra

 

lessen over time as Pgp induction

and digoxin. Particular caution

 

develops.

should be used when prescribing

 

 

Kaletra in patients taking digoxin

 

 

as the acute inhibitory effect of

 

 

ritonavir on Pgp is expected to

 

 

significantly increase digoxin

 

 

levels. Initiation of digoxin in

 

 

patients already taking Kaletra is

 

 

likely to result in lower than

 

 

expected increases of digoxin

 

 

concentrations.

Bepridil, Systemic

Bepridil, Systemic Lidocaine,

Caution is warranted and

Lidocaine, and

Quinidine:

therapeutic drug concentration

Quinidine

Concentrations may be increased

monitoring is recommended when

 

when co-administered with

available.

 

Kaletra.

 

Antibiotics

Clarithromycin

Clarithromycin:

For patients with renal impairment

 

Moderate increases in

(CrCL < 30 ml/min) dose

 

clarithromycin AUC are expected

reduction of clarithromycin should

 

due to CYP3A inhibition by

be considered (see section 4.4).

 

Kaletra.

Caution should be exercised in

 

 

administering clarithromycin with

 

 

Kaletra to patients with impaired

 

 

hepatic or renal function.

Anticancer agents

 

 

Afatinib

Afatinib:

Caution should be exercised in

 

AUC: ↑

administering afatinib with

(Ritonavir 200 mg twice

Cmax: ↑

Kaletra. Refer to the afatinib

daily)

 

SmPC for dosage adjustment

 

The extent of increase depends on

recommendations. Monitor for

 

the timing of ritonavir

ADRs related to afatinib.

 

administration.

 

 

Due to BCRP (breast cancer

 

 

resistance protein/ABCG2) and

 

 

acute P-gp inhibition by Kaletra

 

Ceritinib

Serum concentrations may be

Caution should be exercised in

 

increased due to CYP3A and

administering ceritinib with

 

P-gp inhibition by Kaletra.

Kaletra. Refer to the ceritinib

 

 

SmPC for dosage adjustment

 

 

recommendations. Monitor for

 

 

ADRs related to ceritinib.

Most tyrosine kinase

Most tyrosine kinase inhibitors

Careful monitoring of the

inhibitors such as

such as dasatinib and nilotinib,

tolerance of these anticancer

dasatinib and nilotinib,

also vincristine and vinblastine:

agents.

vincristine, vinblastine

Risk of increased adverse events

 

 

due to higher serum

 

 

concentrations because of

 

 

CYP3A4 inhibition by Kaletra.

 

Anticoagulants

 

 

Warfarin

Warfarin:

It is recommended that INR

 

Concentrations may be affected

(international normalised ratio) be

 

when co-administered with

monitored.

 

Kaletra due to CYP2C9

 

 

induction.

 

Rivaroxaban

Rivaroxaban:

Co-administration of rivaroxaban

 

AUC: ↑ 153%

and Kaletra may increase

(Ritonavir 600 mg twice

Cmax: ↑ 55%

rivaroxaban exposure which may

daily)

Due to CYP3A and P-gp

increase the risk of bleeding.

 

inhibition by lopinavir/ritonavir.

The use of rivaroxaban is not

 

 

recommended in patients

 

 

receiving concomitant treatment

 

 

with Kaletra (see section 4.4).

Vorapaxar

Serum concentrations may be

The coadministration of vorapaxar

 

increased due to CYP3A

with Kaletra is not recommended

 

inhibition by Kaletra.

(see section 4.4 and refer to the

 

 

vorapaxar SmPC).

Anticonvulsants

Phenytoin

Phenytoin:

Caution should be exercised in

 

Steady-state concentrations was

administering phenytoin with

 

moderately decreased due to

Kaletra.

 

CYP2C9 and CYP2C19 induction

 

 

by Kaletra.

Phenytoin levels should be

 

 

monitored when co-administering

 

Lopinavir:

with lopinavir/ritonavir.

 

Concentrations are decreased due

 

 

to CYP3A induction by

When co-administered with

 

phenytoin.

phenytoin, an increase of Kaletra

 

 

dosage may be envisaged. Dose

 

 

adjustment has not been evaluated

 

 

in clinical practice.

Carbamazepine and

Carbamazepine:

Caution should be exercised in

Phenobarbital

Serum concentrations may be

administering carbamazepine or

 

increased due to CYP3A

phenobarbital with Kaletra.

 

inhibition by Kaletra.

Carbamazepine and phenobarbital

 

 

 

Lopinavir:

levels should be monitored when

 

Concentrations may be decreased

co-administering with

 

due to CYP3A induction by

lopinavir/ritonavir.

 

carbamazepine and phenobarbital.

When co-administered with

 

 

 

 

carbamazepine or phenobarbital,

 

 

an increase of Kaletra dosage may

 

 

be envisaged. Dose adjustment

 

 

has not been evaluated in clinical

 

 

practice

Lamotrigine and

Lamotrigine:

Patients should be monitored

Valproate

AUC: ↓ 50%

closely for a decreased VPA effect

 

Cmax: ↓ 46%

when Kaletra and valproic acid or

 

Cmin: ↓ 56%

valproate are given concomitantly.

 

Due to induction of lamotrigine

In patients starting or stopping

 

glucuronidation

Kaletra while currently taking

 

Valproate: ↓

maintenance dose of lamotrigine:

 

lamotrigine dose may need to be

 

 

increased if Kaletra is added, or

 

 

decreased if Kaletra is

 

 

discontinued; therefore plasma

 

 

lamotrigine monitoring should be

 

 

conducted, particularly before and

 

 

during 2 weeks after starting or

 

 

stopping Kaletra, in order to see if

 

 

lamotrigine dose adjustment is

 

 

needed.

 

 

In patients currently taking

 

 

Kaletra and starting lamotrigine:

 

 

no dose adjustments to the

 

 

recommended dose escalation of

 

 

lamotrigine should be necessary.

Antidepressants and Anxiolytics

Trazodone single dose

Trazodone:

It is unknown whether the

 

AUC: ↑ 2.4-fold

combination of lopinavir/ritonavir

(Ritonavir, 200 mg

 

causes a similar increase in

BID)

Adverse events of nausea,

trazodone exposure. The

 

dizziness, hypotension and

combination should be used with

 

syncope were observed following

caution and a lower dose of

 

co-administration of trazodone

trazodone should be considered.

 

and ritonavir.

 

Antifungals

 

 

Ketoconazole and

Ketoconazole, Itraconazole:

High doses of ketoconazole and

Itraconazole

Serum concentrations may be

itraconazole (> 200 mg/day) are

 

increased due to CYP3A

not recommended.

 

inhibition by Kaletra.

 

Voriconazole

Voriconazole:

Co-administration of voriconazole

 

Concentrations may be decreased.

and low dose ritonavir (100 mg

 

 

BID) as contained in Kaletra

 

 

should be avoided unless an

 

 

assessment of the benefit/risk to

 

 

patient justifies the use of

 

 

voriconazole.

Anti-gout agents

 

 

Colchicine single dose

Colchicine:

Concomitant administration of

 

AUC: ↑ 3-fold

Kaletra with colchicine in patients

(Ritonavir 200 mg twice

Cmax: ↑ 1.8-fold

with renal and/or hepatic

daily)

Due to P-gp and/or CYP3A4

impairment is contraindicated due

 

inhibition by ritonavir.

to a potential increase of

 

 

colchicine-related serious and/or

 

 

life-threatening reactions such as

 

 

neuromuscular toxicity (including

 

 

rhabdomyolysis) (see sections 4.3

 

 

and 4.4). A reduction in

 

 

colchicine dosage or an

 

 

interruption of colchicine

 

 

treatment is recommended in

 

 

patients with normal renal or

 

 

hepatic function if treatment with

 

 

Kaletra is required. Refer to

 

 

colchicine prescribing

 

 

information.

Anti-infectives

 

 

Fusidic acid

Fusidic acid:

Concomitant administration of

 

Concentrations may be increased

Kaletra with fusidic acid is contra-

 

due to CYP3A inhibition by

indicated in dermatological

 

lopinavir/ritonavir.

indications due to the increased

 

 

risk of adverse events related to

 

 

fusidic acid, notably

 

 

rhabdomyolysis (see section 4.3).

 

 

When used for osteo-articular

 

 

infections, where the co-

 

 

administration is unavoidable,

 

 

close clinical monitoring for

 

 

muscular adverse events is

 

 

strongly recommended (see

 

 

section 4.4).

Antimycobacterials

Bedaquiline

Bedaquiline:

Due to the risk of bedaquiline

(single dose)

AUC: ↑ 22%

related adverse events, the

(Lopinavir/ritonavir

Cmax: ↔

combination of bedaquiline and

 

lopinavir/ritonavir should be

400/100 mg BID,

A more pronounced effect on

avoided. If the benefit outweighs

multiple dose)

bedaquiline plasma exposures

the risk, co-administration of

 

may be observed during

bedaquiline with

 

prolonged co-administration with

lopinavir/ritonavir must be done

 

lopinavir/ritonavir.

with caution. More frequent

 

 

electrocardiogram monitoring and

 

CYP3A4 inhibition likely due to

monitoring of transaminases is

 

lopinavir/ritonavir.

recommended (see section 4.4 and

 

 

refer to the bedaquiline SmPC).

Delamanid (100 mg

Delamanid:

Due to the risk of QTc

BID)

AUC: ↑ 22%

prolongation associated with

 

 

DM-6705, if co-administration of

(Lopinavir/ritonavir

DM-6705 (delamanid active

delamanid with lopinavir/ritonavir

400/100 mg BID)

metabolite):

is considered necessary, very

 

AUC: ↑ 30%

frequent ECG monitoring

 

 

throughout the full delamanid

 

A more pronounced effect on

treatment period is recommended

 

DM-6705 exposure may be

(see section 4.4 and refer to the

 

observed during prolonged co-

delamanid SmPC).

 

administration with

 

 

lopinavir/ritonavir.

 

Rifabutin, 150 mg QD

Rifabutin (parent drug and active

When given with Kaletra the

 

25-O-desacetyl metabolite):

recommended dose of rifabutin is

 

AUC: ↑ 5.7-fold

150 mg 3 times per week on set

 

Cmax: ↑ 3.5-fold

days (for example Monday-

 

 

Wednesday-Friday). Increased

 

 

monitoring for rifabutin-

 

 

associated adverse reactions

 

 

including neutropenia and uveitis

 

 

is warranted due to an expected

 

 

increase in exposure to rifabutin.

 

 

Further dosage reduction of

 

 

rifabutin to 150 mg twice weekly

 

 

on set days is recommended for

 

 

patients in whom the 150 mg dose

 

 

3 times per week is not tolerated.

 

 

It should be kept in mind that the

 

 

twice weekly dosage of 150 mg

 

 

may not provide an optimal

 

 

exposure to rifabutin thus leading

 

 

to a risk of rifamycin resistance

 

 

and a treatment failure. No dose

 

 

adjustment is needed for Kaletra.

Rifampicin

Lopinavir:

Co-administration of Kaletra with

 

Large decreases in lopinavir

rifampicin is not recommended as

 

concentrations may be observed

the decrease in lopinavir

 

due to CYP3A induction by

concentrations may in turn

 

rifampicin.

significantly decrease the lopinavir

 

 

therapeutic effect. A dose

 

 

adjustment of Kaletra

 

 

400 mg/400 mg (i.e. Kaletra

 

 

400/100 mg + ritonavir 300 mg)

 

 

twice daily has allowed

 

 

compensating for the CYP 3A4

 

 

inducer effect of rifampicin.

 

 

However, such a dose adjustment

 

 

might be associated with ALT/AST

 

 

elevations and with increase in

 

 

gastrointestinal disorders.

 

 

Therefore, this co-administration

 

 

should be avoided unless judged

 

 

strictly necessary. If this

 

 

co-administration is judged

 

 

unavoidable, increased dose of

 

 

Kaletra at 400 mg/400 mg twice

 

 

daily may be administered with

 

 

rifampicin under close safety and

 

 

therapeutic drug monitoring. The

 

 

Kaletra dose should be titrated

 

 

upward only after rifampicin has

 

 

been initiated (see section 4.4).

Antipsychotics

 

 

Lurasidone

Due to CYP3A inhibition by

The concomitant administration

 

lopinavir/ritonavir,

with lurasidone is contraindicated

 

concentrations of lurasidone are

(see section 4.3).

 

expected to increase.

 

Quetiapine

Due to CYP3A inhibition by

Concomitant administration of

 

lopinavir/ritonavir,

Kaletra and quetiapine is

 

concentrations of quetiapine are

contraindicated as it may increase

 

expected to increase.

quetiapine-related toxicity.

Benzodiazepines

 

 

Midazolam

Oral Midazolam:

Kaletra must not be

 

AUC: ↑ 13-fold

co-administered with oral

 

Parenteral Midazolam:

midazolam (see section 4.3),

 

AUC: ↑ 4-fold

whereas caution should be used

 

Due to CYP3A inhibition by

with co-administration of Kaletra

 

Kaletra

and parenteral midazolam. If

 

 

Kaletra is co-administered with

 

 

parenteral midazolam, it should be

 

 

done in an intensive care unit (ICU)

 

 

or similar setting which ensures

 

 

close clinical monitoring and

 

 

appropriate medical management in

 

 

case of respiratory depression

 

 

and/or prolonged sedation. Dosage

 

 

adjustment for midazolam should

 

 

be considered especially if more

 

 

than a single dose of midazolam is

 

 

administered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol

 

Salmeterol:

The combination may result in

 

 

Concentrations are expected to

increased risk of cardiovascular

 

 

increase due to CYP3A inhibition

adverse events associated with

 

 

by lopinavir/ritonavir.

salmeterol, including QT

 

 

 

prolongation, palpitations and

 

 

 

sinus tachycardia.

 

 

 

Therefore, concomitant

 

 

 

administration of Kaletra with

 

 

 

salmeterol is not recommended

 

 

 

(see section 4.4).

Calcium channel blockers

 

 

Felodipine, Nifedipine,

 

Felodipine, Nifedipine,

Clinical monitoring of therapeutic

and Nicardipine

 

Nicardipine:

and adverse effects is

 

 

Concentrations may be increased

recommended when these

 

 

due to CYP3A inhibition by

medicines are concomitantly

 

 

Kaletra.

administered with Kaletra.

Corticosteroids

 

 

Dexamethasone

 

Lopinavir:

Clinical monitoring of antiviral

 

 

Concentrations may be decreased

efficacy is recommended when

 

 

due to CYP3A induction by

these medicines are concomitantly

 

 

dexamethasone.

administered with Kaletra.

 

 

 

 

Inhaled, injectable or

 

Fluticasone propionate, 50 g

Greater effects may be expected

intranasal fluticasone

 

intranasal 4 times daily:

when fluticasone propionate is

propionate, budesonide,

 

Plasma concentrations ↑

inhaled. Systemic corticosteroid

triamcinolone

 

Cortisol levels ↓ 86%

effects including Cushing's

 

 

 

syndrome and adrenal suppression

 

 

 

have been reported in patients

 

 

 

receiving ritonavir and inhaled or

 

 

 

intranasally administered

 

 

 

fluticasone propionate; this could

 

 

 

also occur with other

 

 

 

corticosteroids metabolised via the

 

 

 

P450 3A pathway e.g. budesonide

 

 

 

and triamcinolone. Consequently,

 

 

 

concomitant administration of

 

 

 

Kaletra and these glucocorticoids

 

 

 

is not recommended unless the

 

 

 

potential benefit of treatment

 

 

 

outweighs the risk of systemic

 

 

 

corticosteroid effects (see section

 

 

 

4.4). A dose reduction of the

 

 

 

glucocorticoid should be

 

 

 

considered with close monitoring

 

 

 

of local and systemic effects or a

 

 

 

switch to a glucocorticoid, which

 

 

 

is not a substrate for CYP3A4

 

 

 

(e.g. beclomethasone). Moreover,

 

 

 

in case of withdrawal of

 

 

 

glucocorticoids progressive dose

 

 

 

reduction may have to be

 

 

 

performed over a longer period.

Phosphodiesterase(PDE5) inhibitors

Avanafil

Avanafil:

The use of avanafil with Kaletra is

(ritonavir 600 mg BID)

AUC: ↑ 13-fold

contraindicated (see section 4.3).

 

Due to CYP3A inhibition by

 

 

lopinavir/ritonavir.

 

 

 

 

Tadalafil

Tadalafil:

For the treatment of pulmonary

 

AUC: ↑ 2-fold

arterial hypertension:

 

Due to CYP3A4 inhibition by

Co-administration of Kaletra with

 

lopinavir/ritonavir.

sildenafil is contraindicated (see

 

 

section 4.3). Co-administration of

Sildenafil

Sildenafil:

Kaletra with tadalafil is not

 

AUC: ↑ 11-fold

recommended.

 

Due to CYP3A inhibition by

For erectile dysfunction:

 

lopinavir/ritonavir.

 

 

Particular caution must be used

 

 

when prescribing sildenafil or

 

 

tadalafil in patients receiving

 

 

Kaletra with increased monitoring

 

 

for adverse events including

 

 

hypotension, syncope, visual

 

 

changes and prolonged erection

 

 

(see section 4.4).

 

 

When co-administered with

 

 

Kaletra, sildenafil doses must not

 

 

exceed 25 mg in 48 hours and

 

 

tadalafil doses must not exceed

 

 

10 mg every 72 hours

 

 

 

Vardenafil

Vardenafil:

The use of vardenafil with Kaletra

 

AUC: ↑ 49-fold

is contraindicated (see section

 

Due to CYP3A inhibition by

4.3).

 

Kaletra.

 

HCV Protease Inhibitors

 

 

Boceprevir 800 mg

Boceprevir:

It is not recommended to

three times daily

AUC: ↓ 45%

co-administer Kaletra and

 

Cmax: ↓ 50%

boceprevir.

 

Cmin: ↓ 57%

 

 

Lopinavir:

 

 

AUC: ↓ 34%

 

 

Cmax: ↓ 30%

 

 

Cmin: ↓ 43%

 

Simeprevir 200 mg

Simeprevir:

It is not recommended to

daily (ritonavir 100 mg

AUC: ↑ 7.2-fold

co-administer Kaletra and

BID)

Cmax: ↑ 4.7-fold

simeprevir.

 

Cmin: ↑ 14.4-fold

 

Telaprevir 750 mg

Telaprevir:

It is not recommended to

three times daily

AUC: ↓ 54%

co-administer Kaletra and

 

Cmax: ↓ 53%

telaprevir.

 

Cmin: ↓ 52%

 

 

Lopinavir: ↔

 

Herbal products

St John’s wort

Lopinavir:

Herbal preparations containing St

(Hypericum perforatum)

Concentrations may be reduced

John’s wort must not be combined

 

due to induction of CYP3A by the

with lopinavir and ritonavir. If a

 

herbal preparation St John’s wort.

patient is already taking St John’s

 

 

wort, stop St John’s wort and if

 

 

possible check viral levels.

 

 

Lopinavir and ritonavir levels may

 

 

increase on stopping

 

 

St John’s wort. The dose of

 

 

Kaletra may need adjusting. The

 

 

inducing effect may persist for at

 

 

least 2 weeks after cessation of

 

 

treatment with St John’s wort (see

 

 

section 4.3). Therefore, Kaletra

 

 

can be started safely 2 weeks after

 

 

cessation of St John's wort.

Immunosuppressants

 

 

Cyclosporin, Sirolimus

Cyclosporin, Sirolimus

More frequent therapeutic

(rapamycin), and

(rapamycin), Tacrolimus:

concentration monitoring is

Tacrolimus

Concentrations may be increased

recommended until plasma levels

 

due to CYP3A inhibition by

of these products have been

 

Kaletra.

stabilised.

Lipid lowering agents

 

 

Lovastatin and

Lovastatin, Simvastatin:

Since increased concentrations of

Simvastatin

Markedly increased plasma

HMG-CoA reductase inhibitors

 

concentrations due to CYP3A

may cause myopathy, including

 

inhibition by Kaletra.

rhabdomyolysis, the combination

 

 

of these agents with Kaletra is

 

 

contraindicated (see section 4.3).

Atorvastatin

Atorvastatin:

The combination of Kaletra with

 

AUC: ↑ 5.9-fold

atorvastatin is not recommended.

 

Cmax: ↑ 4.7-fold

If the use of atorvastatin is

 

Due to CYP3A inhibition by

considered strictly necessary, the

 

Kaletra.

lowest possible dose of

 

 

atorvastatin should be

 

 

administered with careful safety

 

 

monitoring (see section 4.4).

Rosuvastatin, 20 mg QD

Rosuvastatin:

Caution should be exercised and

 

AUC: ↑ 2-fold

reduced doses should be

 

Cmax: ↑ 5-fold

considered when Kaletra is

 

While rosuvastatin is poorly

co-administered with rosuvastatin

 

metabolised by CYP3A4, an

(see section 4.4).

 

increase of its plasma

 

 

concentrations was observed.

 

 

The mechanism of this interaction

 

 

may result from inhibition of

 

 

transport proteins.

 

Fluvastatin or

Fluvastatin, Pravastatin:

If treatment with an HMG-CoA

Pravastatin

No clinical relevant interaction

reductase inhibitor is indicated,

 

expected.

fluvastatin or pravastatin is

 

Pravastatin is not metabolised by

recommended.

 

CYP450.

 

 

Fluvastatin is partially

 

 

metabolised by CYP2C9.

 

Opioids

Buprenorphine, 16 mg

Buprenorphine: ↔

No dose adjustment necessary.

QD

 

 

Methadone

Methadone: ↓

Monitoring plasma concentrations

 

 

of methadone is recommended.

Oral Contraceptives

 

 

Ethinyl Oestradiol

Ethinyl Oestradiol: ↓

In case of co-administration of

 

 

Kaletra with contraceptives

 

 

containing ethinyl oestradiol

 

 

(whatever the contraceptive

 

 

formulation e.g. oral or patch),

 

 

additional methods of

 

 

contraception must be used.

Smoking cessation aids

 

 

Bupropion

Buproprion and its active

If the co-administration of

 

metabolite, hydroxybupropion:

lopinavir/ritonavir with bupropion

 

AUC and Cmax ↓ ~50%

is judged unavoidable, this should

 

 

be done under close clinical

 

This effect may be due to

monitoring for bupropion efficacy,

 

induction of bupropion

without exceeding the

 

metabolism.

recommended dosage, despite the

 

 

observed induction.

Vasodilating agents

 

 

Bosentan

Lopinavir - ritonavir:

Caution should be exercised in

 

Lopinavir/ritonavir plasma

administering Kaletra with

 

concentrations may decrease due

bosentan.

 

to CYP3A4 induction by

When Kaletra is administered

 

bosentan.

concomitantly with bosentan, the

 

 

efficacy of the HIV therapy should

 

Bosentan:

be monitored and patients should

 

AUC: ↑ 5-fold

be closely observed for bosentan

 

Cmax: ↑ 6-fold

toxicity, especially during the first

 

Initially, bosentan Cmin: ↑ by

week of co-administration.

 

approximately 48-fold.

 

 

Due to CYP3A4 inhibition by

 

 

lopinavir/ritonavir.

 

Riociguat

Serum concentrations may be

The coadministration of riociguat

 

increased due to CYP3A and

with Kaletra is not recommended

 

P-gp inhibition by Kaletra.

(see section 4.4 and refer to

 

 

riociguat SmPC).

Other medicinal products

 

 

Based on known metabolic profiles, clinically significant interactions are not expected between

Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

4.6Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed.

Breastfeeding

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that mothers infected by HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.

Fertility

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.

4.7Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).

Kaletra oral solution contains approximately 42% v/v alcohol.

4.8Undesirable effects

a. Summary of the safety profile

The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, of which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.

It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4).

b. Tabulated list of adverse reactions

Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:

The following events have been identified as adverse reactions. The frequency category includes all reported events of moderate to severe intensity, regardless of the individual causality assessment. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥1/10), common (≥ 1/100

to < 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the available data).

Events noted as having frequency “Not known” were identified via post-marketing surveillance.

Undesirable effects in clinical studies and post-marketing in adult patients

System organ class

Frequency

Adverse reaction

 

 

 

Infections and infestations

Very common

Upper respiratory tract infection

 

Common

Lower respiratory tract infection, skin infections

 

 

including cellulitis, folliculitis and furuncle

Blood and lymphatic system

Common

Anaemia, leucopenia, neutropenia,

disorders

 

lymphadenopathy

 

 

 

Immune system disorders

Common

Hypersensitivity including urticaria and

 

 

angioedema

 

Uncommon

Immune reconstitution inflammatory syndrome

Endocrine disorders

Uncommon

Hypogonadism

Metabolism and nutrition

Common

Blood glucose disorders including diabetes

disorders

 

mellitus, hypertriglyceridaemia,

 

 

hypercholesterolemia, weight decreased,

 

 

decreased appetite

 

Uncommon

Weight increased, increased appetite

Psychiatric disorders

Common

Anxiety

 

Uncommon

Abnormal dreams, libido decreased

Nervous system disorders

Common

Headache (including migraine), neuropathy

 

 

(including peripheral neuropathy), dizziness,

 

 

insomnia

 

Uncommon

Cerebrovascular accident, convulsion,

 

 

dysgeusia, ageusia, tremor

Eye disorders

Uncommon

Visual impairment

Ear and labyrinth disorders

Uncommon

Tinnitus, vertigo

 

 

 

Cardiac disorders

Uncommon

Atherosclerosis such as myocardial infarction1,

 

 

atrioventricular block, tricuspid valve

 

 

incompetence

Vascular disorders

Common

Hypertension

 

Uncommon

Deep vein thrombosis

Gastrointestinal disorders

Very common

Diarrhoea, nausea

 

Common

Pancreatitis1, vomiting, gastrooesophageal

 

 

reflux disease, gastroenteritis and colitis,

 

 

abdominal pain (upper and lower), abdominal

 

 

distension, dyspepsia, haemorrhoids, flatulence

 

Uncommon

Gastrointestinal haemorrhage including

 

 

gastrointestinal ulcer, duodenitis, gastritis and

 

 

rectal haemorrhage, stomatitis and oral ulcers,

 

 

faecal incontinence, constipation, dry mouth

Hepatobiliary disorders

Common

Hepatitis including AST, ALT and GGT

 

 

increases

 

Uncommon

Hepatic steatosis, hepatomegaly, cholangitis,

 

 

hyperbilirubinemia

 

Not known

Jaundice

Skin and subcutaneous tissue

Common

Rash including maculopapular rash,

disorders

 

dermatitis/rash including eczema and seborrheic

 

 

dermatitis, night sweats, pruritus

 

Uncommon

Alopecia, capillaritis, vasculitis

 

Not known

Steven-Johnson syndrome, erythema

 

 

multiforme

Musculoskeletal and connective

Common

Myalgia, musculoskeletal pain including

tissue disorders

 

arthralgia and back pain, muscle disorders such

 

 

as weakness and spasms

 

Uncommon

Rhabdomyolysis, osteonecrosis

Renal and urinary disorders

Uncommon

Creatinine clearance decreased, nephritis,

 

 

haematuria

Reproductive system and breast

Common

Erectile dysfunction, menstrual disorders -

disorders

 

amenorrhoea, menorrhagia

General disorders and

Common

Fatigue including asthenia

administration site conditions

 

 

1 See section 4.4: pancreatitis and lipids

c. Description of selected adverse reactions

Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

d. Paediatric populations

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see Table in section b).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9Overdose

To date, there is limited human experience of acute overdose with Kaletra.

Overdoses with Kaletra oral solution have been reported (including fatal outcome). The following events have been reported in association with unintended overdoses in preterm neonates: complete atrioventricular block, cardiomyopathy, lactic acidosis, and acute renal failure.

The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.

There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

However, dialysis can remove both alcohol and propylene glycol in the case of overdose with Kaletra oral solution.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, combinations, ATC code: J05AR10

Mechanism of action

Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Effects on the electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/r doses at steady state. No subject experienced an

increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose. Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).

Antiviral activity in vitro

The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir against

HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.

Resistance

In vitro selection of resistanceHIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Analysis of resistance in ARV-naïve patients

In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has not been observed in naïve patients without significant protease inhibitor resistance at baseline. See further the detailed description of the clinical studies.

Analysis of resistance in PI-experienced patients

The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of

3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from patients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Antiviral activity of Kaletra in patients failing protease inhibitor therapy

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma

HIV RNA ≤ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold, 10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced

in vitro susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of patients not receiving Kaletra.

Cross-resistance

Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor- experienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.

Clinical results

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of 48 to 360 weeks duration.

Adult Use

Patients without prior antiretroviral therapy

Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm3 (range: 2 to

949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml).

Table 1

Outcomes at Week 48: Study M98-863

 

Kaletra (N=326)

Nelfinavir (N=327)

HIV RNA < 400 copies/ml*

75%

63%

HIV RNA < 50 copies/ml*†

67%

52%

Mean increase from baseline in

CD4+ T-cell count (cells/mm3)

 

 

* intent to treat analysis where patients with missing values are considered virologic failures

† p < 0.001

One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack of resistance to lopinavir was confirmed by phenotypic analysis.

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study).

Table 2

Outcomes at Week 360: Study M97-720

 

Kaletra (N=100)

HIV RNA < 400 copies/ml

61%

HIV RNA < 50 copies/ml

59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.

Patients with prior antiretroviral therapy

M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and 400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Median baseline CD4 cell count was 349 cells/mm3 (range 72 to 807 cells/mm3) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ml (range

2.9 to 5.8 log10 copies/ml).

Table 3

Outcomes at Week 24: Study M97-765

 

Kaletra 400/100 mg

 

(N=36)

HIV RNA < 400 copies/ml (ITT)*

75%

HIV RNA < 50 copies/ml (ITT)*

58%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

* intent to treat analysis where patients with missing values are considered virologic failures

M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels (400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of 400/100 mg were converted to a dose of 533/133 mg. Median baseline CD4 cell count was

220 cells/mm3 (range13 to 1030 cells/mm3).

Table 4

Outcomes at Week 48: Study M98-957

 

Kaletra 400/100 mg

 

(N=57)

HIV RNA < 400 copies/ml*

65%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

* intent to treat analysis where patients with missing values are considered virologic failures

Paediatric Use

M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or

300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptase inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m2 dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml.

Table 5

Outcomes at Week 48: Study M98-940

 

 

Antiretroviral Naïve

Antiretroviral

 

 

(N=44)

Experienced (N=56)

 

HIV RNA < 400 copies/ml

84%

75%

 

Mean increase from baseline in

 

CD4+ T-cell count (cells/mm3)

 

 

5.2 Pharmacokinetic properties

 

 

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The

in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.

Absorption

Multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 ± 5.4 g/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7 g/ml. Lopinavir AUC over a 12 hour dosing interval averaged

113.2 ± 60.5 g•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.

Effects of food on oral absorption

Kaletra soft capsules and liquid have been shown to be bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single 400/100 mg dose of Kaletra soft capsules with a moderate fat meal (500 – 682 kcal, 22.7 –25.1% from fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively. Administration of Kaletra with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax by 96% and 43%, respectively, for soft capsules, and 130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability Kaletra is to be taken with food.

Distribution

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients.

Biotransformation

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

Elimination

After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged

5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.

Special Populations

Paediatrics

There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of Kaletra 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC,

Cmax, and Cmin were 72.6 ± 31.1 g•h/ml, 8.2 ± 2.9 g/ml and 3.4 ± 2.1 g/ml, respectively after Kaletra 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ± 36.9 g•h/ml,

10.0 ± 3.3 g/ml and 3.6 ± 3.5 g/ml, respectively after 300/75 mg/m2 twice daily with nevirapine (n=12). The 230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine.

Gender, Race and Age

Kaletra pharmacokinetics have not been studied in older people. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified.

Renal Insufficiency

Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Insufficiency

The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).

5.3Preclinical safety data

Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.

During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.

In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance.

The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8).

In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights, increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.

Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk. Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Oral solution contains: alcohol (42.4% v/v), high fructose corn syrup,

propylene glycol (15.3% w/v), purified water,

glycerol,

povidone,

magnasweet-110 flavour (mixture of monoammonium glycyrrhizinate and glycerol),

vanilla flavour (containing p-hydroxybenzoic acid, p-hydroxybenzaldehyde, vanillic acid, vanillin, heliotropin, ethyl vanillin),

polyoxyl 40 hydrogenated castor oil,

cotton candy flavour (containing ethyl maltol, ethyl vanillin, acetoin, dihydrocoumarin, propylene glycol),

acesulfame potassium, saccharin sodium, sodium chloride, peppermint oil, sodium citrate,

citric acid, levomenthol.

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

Store in a refrigerator (2°C - 8°C).

In use storage: If kept outside of the refrigerator, do not store above 25°C and discard any unused contents after 42 days (6 weeks). It is advised to write the date of removal from the refrigerator on the package.

Avoid exposure to excessive heat.

6.5Nature and contents of container

Amber coloured multiple-dose polyethylene terephthalate (PET) bottles in a 60 ml size. Multipacks containing 300 ml (5 bottles of 60 ml) oral solution. The pack also contains 5 x 5 ml syringes with 0.1 ml graduations from 0 to 5 ml (400/100 mg).

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

AbbVie Ltd

Maidenhead

SL6 4UB

United Kingdom

8.MARKETING AUTHORISATION NUMBER

EU/1/01/172/003

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 March 2001

Date of latest renewal: 20 March 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

1. NAME OF THE MEDICINAL PRODUCT

Kaletra 200 mg/50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a pharmacokinetic enhancer.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Yellow debossed with [Abbott logo] and “KA”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 2 years.

The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.

Kaletra tablets must be swallowed whole and not chewed, broken or crushed.

Posology

Adults and adolescents

The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twice daily taken with or without food. In adult patients, in cases where once-daily dosing is considered necessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four 200/50 mg tablets) once daily with or without food. The use of a once-daily dosing should be limited to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than 3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the population) and should take into account the risk of a lesser sustainability of the virologic suppression (see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standard twice-daily dosing. An oral solution is available to patients who have difficulty swallowing. Refer to the Summary of Product Characteristics for Kaletra oral solution for dosing instructions.

Paediatric population (2 years of age and above)

The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or with a Body Surface Area (BSA)* greater than 1.4 m2. For children weighing less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able to swallow tablets, please refer to the Kaletra 100 mg/25 mg tablets Summary of Product Characteristics. For children unable to swallow tablets, please refer to the Kaletra oral solution Summary of Product Characteristics. Based on the current data available, Kaletra should not be administered once daily in paediatric patients (see section 5.1).

* Body surface area can be calculated with the following equation:

BSA (m2) = √ (Height (cm) X Weight (kg) / 3600)

Children less than 2 years of age

The safety and efficacy of Kaletra in children aged less than 2 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Concomitant Therapy: Efavirenz or nevirapine

The following table contains dosing guidelines for Kaletra tablets based on BSA when used in combination with efavirenz or nevirapine in children.

Paediatric dosing guidelines with concomitant efavirenz or nevirapine

Body Surface Area (m2)

Recommended lopinavir/ritonavir dosing

 

(mg) twice daily.

 

The adequate dosing may be achieved with

 

the two available strengths of Kaletra

 

tablets: 100/25 mg and 200/50 mg.*

 

 

≥ 0.5 to < 0.8

200/50 mg

≥ 0.8 to < 1.2

300/75 mg

≥ 1.2 to < 1.4

400/100 mg

≥ 1.4

500/125 mg

* Kaletra tablets must not be chewed, broken or crushed.

Hepatic impairment

In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra must not be given to these patients (see section 4.3).

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Pregnancy and postpartum

No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum.

Once-daily administration of lopinavir/ritonavir is not recommended for pregnant women due to the lack of pharmacokinetic and clinical data.

Method of administration

Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or crushed. Kaletra tablets can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Severe hepatic insufficiency.

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include:

Medicinal product

Medicinal products

Rationale

class

within class

 

 

 

 

 

Concomitant medicinal product levels increased

 

 

 

 

 

 

Alpha1-adrenoreceptor

Alfuzosin

Increased plasma concentrations of alfuzosin

antagonist

 

which may lead to severe hypotension. The

 

 

concomitant administration with alfuzosin is

 

 

contraindicated (see section 4.5).

Antianginal

Ranolazine

Increased plasma concentrations of ranolazine

 

 

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section

 

 

4.5).

 

Antiarrhythmics

Amiodarone,

Increased plasma concentrations of amiodarone

 

 

dronedarone

and dronedarone. Thereby, increasing the risk of

 

 

arrhythmias or other serious adverse reactions.

Antibiotic

Fusidic Acid

Increased plasma concentrations of fusidic acid.

 

 

The concomitant administration with fusidic acid

 

 

is contraindicated in dermatological infections.

 

 

(see section 4.5).

Anti-gout

Colchicine

Increased plasma concentrations of colchicine.

 

 

Potential for serious and/or life-threatening

 

 

reactions in patients with renal and/or hepatic

 

 

impairment (see sections 4.4 and 4.5).

Antihistamines

Astemizole, terfenadine

Increased plasma concentrations of astemizole

 

 

and terfenadine. Thereby, increasing the risk of

 

 

serious arrhythmias from these agents.

Antipsychotics/

Lurasidone

Increased plasma concentrations of lurasidone

Neuroleptics

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section 4.5).

 

Pimozide

Increased plasma concentrations of pimozide.

 

 

Thereby, increasing the risk of serious

 

 

haematologic abnormalities, or other serious

 

 

adverse effects from this agent.

 

Quetiapine

Increased plasma concentrations of quetiapine

 

 

which may lead to coma. The concomitant

 

 

administration with quetiapine is contraindicated

 

 

(see section 4.5).

Ergot alkaloids

Dihydroergotamine,

Increased plasma concentrations of ergot

 

ergonovine,

derivatives leading to acute ergot toxicity,

 

ergotamine,

including vasospasm and ischaemia.

 

methylergonovine

 

 

GI motility agent

Cisapride

Increased plasma concentrations of cisapride.

 

 

Thereby, increasing the risk of serious

 

 

arrhythmias from this agent.

 

 

 

HMG Co-A Reductase

Lovastatin, simvastatin

Increased plasma concentrations of lovastatin and

Inhibitors

 

simvastatin; thereby, increasing the risk of

 

 

myopathy including rhabdomyolysis (see section

 

 

4.5).

Phosphodiesterase

Avanafil

Increased plasma concentrations of avanafil (see

(PDE5) inhibitors

 

sections 4.4 and 4.5)

 

Sildenafil

Contraindicated when used for the treatment of

 

 

pulmonary arterial hypertension (PAH) only.

 

 

Increased plasma concentrations of sildenafil.

 

 

Thereby, increasing the potential for sildenafil-

 

 

associated adverse events (which include

 

 

hypotension and syncope). See section 4.4 and

 

 

section 4.5 for co-administration of sildenafil in

 

 

patients with erectile dysfunction.

 

Vardenafil

Increased plasma concentrations of vardenafil

 

 

(see sections 4.4 and 4.5)

Sedatives/hypnotics

Oral midazolam,

Increased plasma concentrations of oral

 

triazolam

midazolam and triazolam. Thereby, increasing

 

 

the risk of extreme sedation and respiratory

 

 

depression from these agents.

 

 

For caution on parenterally administered

 

 

midazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

 

 

 

Herbal products

St. John’s wort

Herbal preparations containing St John’s wort

 

 

(Hypericum perforatum) due to the risk of

decreased plasma concentrations and reduced clinical effects of lopinavir and ritonavir (see section 4.5).

4.4 Special warnings and precautions for use

Patients with coexisting conditions

Hepatic impairment:

The safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction was serious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and close monitoring should be performed during treatment.

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Pancreatitis

Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see section 5.1).

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Interactions with medicinal products

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).

The combination of Kaletra with:

-tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended (see section 4.5);

-riociguat is not recommended (see section 4.5);

-vorapaxar is not recommended (see section 4.5);

-fusidic acid in osteo-articular infections is not recommended (see section 4.5);

-salmeterol is not recommended (see section 4.5);

-rivaroxaban is not recommended (see section 4.5).

The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these medicinal products is expected to substantially increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra is contraindicated (see section 4.3).

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse reactions. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3).

Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).

Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).

Other

Kaletra is not a cure for HIV infection or AIDS. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS.

4.5 Interaction with other medicinal products and other forms of interaction

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A

in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).

Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products.

Medicinal products that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in section 4.3.

All interaction studies, when otherwise not stated, were performed using Kaletra capsules, which gives an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below.

Interaction table

Interactions between Kaletra and co-administered medicinal products are listed in the table below

(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as

“BID” and three times daily as "TID").

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of lopinavir/ritonavir (i.e. 400/100 mg twice daily).

Co-administered drug

Effects on drug levels

 

Clinical recommendation

by therapeutic area

 

 

concerning co-administration with

 

Geometric Mean Change (%) in

 

Kaletra

 

AUC, Cmax, Cmin

 

 

 

Mechanism of interaction

 

 

Antiretroviral Agents

 

 

 

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

 

Stavudine, Lamivudine

Lopinavir: ↔

 

No dose adjustment necessary.

 

 

 

 

Abacavir, Zidovudine

Abacavir, Zidovudine:

 

The clinical significance of reduced

 

Concentrations may be reduced

 

abacavir and zidovudine

 

due to increased glucuronidation

 

concentrations is unknown.

 

by Kaletra.

 

 

Tenofovir, 300 mg QD

Tenofovir:

 

No dose adjustment necessary.

 

AUC: ↑ 32%

 

Higher tenofovir concentrations could

 

Cmax: ↔

 

potentiate tenofovir associated

 

Cmin: ↑ 51%

 

adverse events, including renal

 

Lopinavir: ↔

 

disorders.

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

Efavirenz, 600 mg QD

Lopinavir:

 

The Kaletra tablets dosage should be

 

AUC: ↓ 20%

 

increased to 500/125 mg twice daily

 

Cmax: ↓ 13%

 

when co-administered with efavirenz.

 

Cmin: ↓ 42%

 

Kaletra must not be administered

Efavirenz, 600 mg QD

 

 

once daily in combination with

 

Lopinavir: ↔

 

efavirenz.

(Lopinavir/ritonavir

(Relative to 400/100 mg BID

 

 

500/125 mg BID)

administered alone)

 

 

Nevirapine, 200 mg

Lopinavir:

 

The Kaletra tablets dosage should be

BID

AUC: ↓ 27%

 

increased to 500/125 mg twice daily

 

Cmax: ↓ 19%

 

when co-administered with

 

Cmin: ↓ 51%

 

nevirapine.

 

 

 

Kaletra must not be administered

 

 

 

once daily in combination with

 

 

 

nevirapine.

Etravirine

Etravirine :

 

No dose adjustment necessary

 

AUC: ↓ 35%

 

 

(Lopinavir/ritonavir

Cmin: ↓ 45%

 

 

tablet 400/100 mg BID)

Cmax: ↓ 30%

 

 

 

Lopinavir :

 

 

 

AUC: ↔

 

 

 

Cmin: ↓ 20%

 

 

 

Cmax: ↔

 

 

Rilpivirine

Rilpivirine:

 

Concomitant use of Kaletra with

 

AUC: ↑ 52%

 

rilpivirine causes an increase in the

(Lopinavir/ritonavir

Cmin: ↑ 74%

 

plasma concentrations of rilpivirine,

capsule 400/100 mg

Cmax: ↑ 29%

 

but no dose adjustment is required.

BID)

Lopinavir:

 

 

 

 

 

 

AUC: ↔

 

 

 

Cmin: ↓ 11%

 

 

 

Cmax: ↔

 

 

 

(inhibition of CYP3A enzymes)

 

 

HIV CCR5 – antagonist

Maraviroc

Maraviroc:

The dose of maraviroc should be

 

AUC: ↑ 295%

decreased to 150 mg twice daily

 

Cmax: ↑ 97%

during co-administration with Kaletra

 

Due to CYP3A inhibition by

400/100 mg twice daily.

 

lopinavir/ritonavir.

 

Integrase inhibitor

 

 

Raltegravir

Raltegravir:

No dose adjustment necessary

 

AUC: ↔

 

 

Cmax: ↔

 

 

C12: ↓ 30%

 

 

Lopinavir: ↔

 

Co-administration with other HIV protease inhibitors (PIs)

 

According to current treatment guidelines, dual therapy with protease inhibitors is generally not

recommended.

 

 

Fosamprenavir/

Fosamprenavir:

Co-administration of increased doses

ritonavir (700/100 mg

Amprenavir concentrations are

of fosamprenavir (1400 mg BID)

BID)

significantly reduced.

with lopinavir/ritonavir (533/133 mg

 

 

BID) to protease

(Lopinavir/ritonavir

 

inhibitor-experienced patients

400/100 mg BID)

 

resulted in a higher incidence of

 

 

gastrointestinal adverse events and

or

 

elevations in triglycerides with the

 

 

combination regimen without

Fosamprenavir

 

increases in virological efficacy,

(1400 mg BID)

 

when compared with standard doses

 

 

of fosamprenavir/ritonavir.

(Lopinavir/ritonavir

 

Concomitant administration of these

533/133 mg BID)

 

medicinal products is not

 

 

recommended.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

amprenavir.

Indinavir, 600 mg BID

Indinavir:

The appropriate doses for this

 

AUC: ↔

combination, with respect to efficacy

 

Cmin: ↑ 3.5-fold

and safety, have not been established.

 

Cmax: ↓

 

 

(relative to indinavir 800 mg TID

 

 

alone)

 

 

Lopinavir: ↔

 

 

(relative to historical comparison)

 

Saquinavir

Saquinavir: ↔

No dose adjustment necessary.

1000 mg BID

 

 

Tipranavir/ritonavir

Lopinavir:

Concomitant administration of these

(500/100 mg BID)

AUC: ↓ 55%

medicinal products is not

 

Cmin: ↓ 70%

recommended.

 

Cmax: ↓ 47%

 

Acid reducing agents

 

 

Omeprazole (40 mg

Omeprazole: ↔

No dose adjustment necessary

QD)

Lopinavir: ↔

 

 

 

Ranitidine (150 mg

Ranitidine: ↔

No dose adjustment necessary

single dose)

 

 

Alpha1 adrenoreceptor antagonist

Alfuzosin

Alfuzosin:

Concomitant administration of

 

Due to CYP3A inhibition by

Kaletra and alfuzosin is contra-

 

lopinavir/ritonavir, concentrations

indicated (see section 4.3) as

 

of alfuzosin are expected to

alfuzosin-related toxicity, including

 

increase.

hypotension, may be increased.

Analgesics

 

 

Fentanyl

Fentanyl:

Careful monitoring of adverse effects

 

Increased risk of side-effects

(notably respiratory depression but

 

(respiratory depression, sedation)

also sedation) is recommended when

 

due to higher plasma

fentanyl is concomitantly

 

concentrations because of

administered with Kaletra.

 

CYP3A4 inhibition by Kaletra

 

Antianginal

 

 

Ranolazine

Due to CYP3A inhibition by

The concomitant administration of

 

lopinavir/ritonavir, concentrations

Kaletra and ranolazine is

 

of ranolazine are expected to

contraindicated (see section 4.3).

 

increase.

 

Antiarrhythmics

 

 

Amiodarone,

Amiodarone, Dronedarone:

Concomitant administration of

Dronedarone

Concentrations may be increased

Kaletra and amiodarone or

 

due to CYP3A4 inhibition by

dronedarone is contraindicated (see

 

Kaletra.

section 4.3) as the risk of arrhythmias

 

 

or other serious adverse reactions

 

 

may be increased.

Digoxin

Digoxin:

Caution is warranted and therapeutic

 

Plasma concentrations may be

drug monitoring of digoxin

 

increased due to P-glycoprotein

concentrations, if available, is

 

inhibition by Kaletra. The

recommended in case of

 

increased digoxin level may

co-administration of Kaletra and

 

lessen over time as Pgp induction

digoxin. Particular caution should be

 

develops.

used when prescribing Kaletra in

 

 

patients taking digoxin as the acute

 

 

inhibitory effect of ritonavir on Pgp is

 

 

expected to significantly increase

 

 

digoxin levels. Initiation of digoxin

 

 

in patients already taking Kaletra is

 

 

likely to result in lower than expected

 

 

increases of digoxin concentrations.

Bepridil, Systemic

Bepridil, Systemic Lidocaine,

Caution is warranted and therapeutic

Lidocaine, and

Quinidine:

drug concentration monitoring is

Quinidine

Concentrations may be increased

recommended when available.

 

when co-administered with

 

 

Kaletra.

 

Antibiotics

 

 

Clarithromycin

Clarithromycin:

For patients with renal impairment

 

Moderate increases in

(CrCL < 30 ml/min) dose reduction

 

clarithromycin AUC are expected

of clarithromycin should be

 

due to CYP3A inhibition by

considered (see section 4.4). Caution

 

Kaletra.

should be exercised in administering

 

 

clarithromycin with Kaletra to

 

 

patients with impaired hepatic or

 

 

renal function.

Anticancer agents

 

 

Afatinib

Afatinib:

Caution should be exercised in

 

AUC: ↑

administering afatinib with Kaletra.

(Ritonavir 200 mg twice

Cmax: ↑

Refer to the afatinib SmPC for

daily)

 

dosage adjustment recommendations.

 

The extent of increase depends on

Monitor for ADRs related to afatinib.

 

the timing of ritonavir

 

 

administration.

 

 

Due to BCRP (breast cancer

 

 

resistance protein/ABCG2) and

 

 

acute P-gp inhibition by Kaletra

 

Ceritinib

Serum concentrations may be

Caution should be exercised in

 

increased due to CYP3A and

administering ceritinib with Kaletra.

 

P-gp inhibition by Kaletra.

Refer to the ceritinib SmPC for

 

 

dosage adjustment recommendations.

 

 

Monitor for ADRs related to

 

 

ceritinib.

Most tyrosine kinase

Most tyrosine kinase inhibitors

Careful monitoring of the tolerance of

inhibitors such as

such as dasatinib and nilotinib,

these anticancer agents.

dasatinib and nilotinib,

also vincristine and vinblastine:

 

vincristine, vinblastine

Risk of increased adverse events

 

 

due to higher serum

 

 

concentrations because of

 

 

CYP3A4 inhibition by Kaletra.

 

Anticoagulants

 

 

Warfarin

Warfarin:

It is recommended that INR

 

Concentrations may be affected

(international normalised ratio) be

 

when co-administered with

monitored.

 

Kaletra due to CYP2C9

 

 

induction.

 

Rivaroxaban

Rivaroxaban:

Co-administration of rivaroxaban and

 

AUC: ↑ 153%

Kaletra may increase rivaroxaban

(Ritonavir 600 mg twice

Cmax: ↑ 55%

exposure which may increase the risk

daily)

Due to CYP3A and P-gp

of bleeding.

 

inhibition by lopinavir/ritonavir.

The use of rivaroxaban is not

 

 

recommended in patients receiving

 

 

concomitant treatment with Kaletra

 

 

(see section 4.4).

Vorapaxar

Serum concentrations may be

The coadministration of vorapaxar

 

increased due to CYP3A

with Kaletra is not recommended (see

 

inhibition by Kaletra.

section 4.4 and refer to the vorapaxar

 

 

SmPC).

Anticonvulsants

Phenytoin

Phenytoin:

Caution should be exercised in

 

Steady-state concentrations was

administering phenytoin with Kaletra.

 

moderately decreased due to

Phenytoin levels should be monitored

 

CYP2C9 and CYP2C19 induction

when co-administering with

 

by Kaletra.

lopinavir/ritonavir.

 

 

When co-administered with

 

Lopinavir:

phenytoin, an increase of Kaletra

 

Concentrations are decreased due

dosage may be envisaged. Dose

 

to CYP3A induction by

adjustment has not been evaluated in

 

phenytoin.

clinical practice.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

phenytoin.

Carbamazepine and

Carbamazepine:

Caution should be exercised in

Phenobarbital

Serum concentrations may be

administering carbamazepine or

 

increased due to CYP3A

phenobarbital with Kaletra.

 

inhibition by Kaletra.

Carbamazepine and phenobarbital

 

 

levels should be monitored when

 

Lopinavir:

co-administering with

 

Concentrations may be decreased

lopinavir/ritonavir.

 

due to CYP3A induction by

When co-administered with

 

carbamazepine and phenobarbital.

carbamazepine or phenobarbital, an

 

 

increase of Kaletra dosage may be

 

 

envisaged. Dose adjustment has not

 

 

been evaluated in clinical practice.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

carbamazepine and phenobarbital.

Lamotrigine and

Lamotrigine:

Patients should be monitored closely

Valproate

AUC: ↓ 50%

for a decreased VPA effect when

 

Cmax: ↓ 46%

Kaletra and valproic acid or valproate

 

Cmin: ↓ 56%

are given concomitantly.

 

Due to induction of lamotrigine

In patients starting or stopping

 

glucuronidation

Kaletra while currently taking

 

Valproate: ↓

maintenance dose of lamotrigine:

 

lamotrigine dose may need to be

 

 

increased if Kaletra is added, or

 

 

decreased if Kaletra is discontinued;

 

 

therefore plasma lamotrigine

 

 

monitoring should be conducted,

 

 

particularly before and during 2

 

 

weeks after starting or stopping

 

 

Kaletra, in order to see if lamotrigine

 

 

dose adjustment is needed.

 

 

In patients currently taking Kaletra

 

 

and starting lamotrigine: no dose

 

 

adjustments to the recommended

 

 

dose escalation of lamotrigine should

 

 

be necessary.

Antidepressants and Anxiolytics

Trazodone single dose

Trazodone:

It is unknown whether the

 

AUC: ↑ 2.4-fold

combination of lopinavir/ritonavir

(Ritonavir, 200 mg

 

causes a similar increase in trazodone

BID)

Adverse events of nausea,

exposure. The combination should

 

dizziness, hypotension and

be used with caution and a lower dose

 

syncope were observed following

of trazodone should be considered.

 

co-administration of trazodone

 

 

and ritonavir.

 

Antifungals

 

 

Ketoconazole and

Ketoconazole, Itraconazole:

High doses of ketoconazole and

Itraconazole

Serum concentrations may be

itraconazole (> 200 mg/day) are not

 

increased due to CYP3A

recommended.

 

inhibition by Kaletra.

 

Voriconazole

Voriconazole:

Co-administration of voriconazole

 

Concentrations may be decreased.

and low dose ritonavir (100 mg BID)

 

 

as contained in Kaletra should be

 

 

avoided unless an assessment of the

 

 

benefit/risk to patient justifies the use

 

 

of voriconazole.

Anti-gout agents

 

 

Colchicine single dose

Colchicine:

Concomitant administration of

 

AUC: ↑ 3-fold

Kaletra with colchicine in patients

(Ritonavir 200 mg

Cmax: ↑ 1.8-fold

with renal and/or hepatic impairment

twice-daily)

Due to P-gp and/or CYP3A4

is contraindicated due to a potential

 

inhibition by ritonavir.

increase of colchicine-related serious

 

 

and/or life-threatening reactions such

 

 

as neuromuscular toxicity (including

 

 

rhabdomyolysis) (see sections 4.3 and

 

 

4.4). A reduction in colchicine

 

 

dosage or an interruption of

 

 

colchicine treatment is recommended

 

 

in patients with normal renal or

 

 

hepatic function if treatment with

 

 

Kaletra is required. Refer to

 

 

colchicine prescribing information.

Anti-infectives

 

 

Fusidic acid

Fusidic acid:

Concomitant administration of

 

Concentrations may be increased

Kaletra with fusidic acid is contra-

 

due to CYP3A inhibition by

indicated in dermatological

 

lopinavir/ritonavir.

indications due to the increased risk

 

 

of adverse events related to fusidic

 

 

acid, notably rhabdomyolysis (see

 

 

section 4.3). When used for osteo-

 

 

articular infections, where the co-

 

 

administration is unavoidable, close

 

 

clinical monitoring for muscular

 

 

adverse events is strongly

 

 

recommended (see section 4.4).

Antimycobacterials

Bedaquiline

Bedaquiline:

Due to the risk of bedaquiline related

(single dose)

AUC: ↑ 22%

adverse events, the combination of

(Lopinavir/ritonavir

Cmax: ↔

bedaquiline and lopinavir/ritonavir

 

should be avoided. If the benefit

400/100 mg BID,

A more pronounced effect on

outweighs the risk, co-administration

multiple dose)

bedaquiline plasma exposures

of bedaquiline with

 

may be observed during

lopinavir/ritonavir must be done with

 

prolonged co-administration with

caution. More frequent

 

lopinavir/ritonavir.

electrocardiogram monitoring and

 

 

monitoring of transaminases is

 

CYP3A4 inhibition likely due to

recommended (see section 4.4 and

 

lopinavir/ritonavir.

refer to the bedaquiline SmPC).

 

 

 

Delamanid (100 mg

Delamanid:

Due to the risk of QTc prolongation

BID)

AUC: ↑ 22%

associated with DM-6705, if

 

 

co-administration of delamanid with

(Lopinavir/ritonavir

DM-6705 (delamanid active

lopinavir/ritonavir is considered

400/100 mg BID)

metabolite):

necessary, very frequent ECG

 

AUC: ↑ 30%

monitoring throughout the full

 

 

delamanid treatment period is

 

A more pronounced effect on

recommended (see section 4.4 and

 

DM-6705 exposure may be

refer to the delamanid SmPC).

 

observed during prolonged co-

 

 

administration with

 

 

lopinavir/ritonavir.

 

Rifabutin, 150 mg QD

Rifabutin (parent drug and active

When given with Kaletra the

 

25-O-desacetyl metabolite):

recommended dose of rifabutin is

 

AUC: ↑ 5.7-fold

150 mg 3 times per week on set days

 

Cmax: ↑ 3.5-fold

(for example Monday-Wednesday-

 

 

Friday). Increased monitoring for

 

 

rifabutin-associated adverse reactions

 

 

including neutropenia and uveitis is

 

 

warranted due to an expected increase

 

 

in exposure to rifabutin. Further

 

 

dosage reduction of rifabutin to

 

 

150 mg twice weekly on set days is

 

 

recommended for patients in whom

 

 

the 150 mg dose 3 times per week is

 

 

not tolerated. It should be kept in

 

 

mind that the twice weekly dosage of

 

 

150 mg may not provide an optimal

 

 

exposure to rifabutin thus leading to a

 

 

risk of rifamycin resistance and a

 

 

treatment failure. No dose

 

 

adjustment is needed for Kaletra.

Rifampicin

Lopinavir:

Co-administration of Kaletra with

 

Large decreases in lopinavir

rifampicin is not recommended as

 

concentrations may be observed

the decrease in lopinavir

 

due to CYP3A induction by

concentrations may in turn

 

rifampicin.

significantly decrease the lopinavir

 

 

therapeutic effect. A dose adjustment

 

 

of Kaletra 400 mg/400 mg (i.e.

 

 

Kaletra 400/100 mg + ritonavir

 

 

300 mg) twice daily has allowed

 

 

compensating for the CYP 3A4

 

 

inducer effect of rifampicin.

 

 

However, such a dose adjustment

 

 

might be associated with ALT/AST

 

 

elevations and with increase in

 

 

gastrointestinal disorders. Therefore,

 

 

this co-administration should be

 

 

avoided unless judged strictly

 

 

necessary. If this co-administration is

 

 

judged unavoidable, increased dose

 

 

of Kaletra at 400 mg/400 mg twice

 

 

daily may be administered with

 

 

rifampicin under close safety and

 

 

therapeutic drug monitoring. The

 

 

Kaletra dose should be titrated

 

 

upward only after rifampicin has been

 

 

initiated (see section 4.4).

Antipsychotics

 

 

Lurasidone

Due to CYP3A inhibition by

The concomitant administration with

 

lopinavir/ritonavir, concentrations

lurasidone is contraindicated (see

 

of lurasidone are expected to

section 4.3).

 

increase.

 

Quetiapine

Due to CYP3A inhibition by

Concomitant administration of

 

lopinavir/ritonavir, concentrations

Kaletra and quetiapine is

 

of quetiapine are expected to

contraindicated as it may increase

 

increase.

quetiapine-related toxicity.

Benzodiazepines

 

 

Midazolam

Oral Midazolam:

Kaletra must not be co-administered

 

AUC: ↑ 13-fold

with oral midazolam (see section

 

Parenteral Midazolam:

4.3), whereas caution should be used

 

AUC: ↑ 4-fold

with co-administration of Kaletra and

 

Due to CYP3A inhibition by

parenteral midazolam. If Kaletra is

 

Kaletra

co-administered with parenteral

 

 

midazolam, it should be done in an

 

 

intensive care unit (ICU) or similar

 

 

setting which ensures close clinical

 

 

monitoring and appropriate medical

 

 

management in case of respiratory

 

 

depression and/or prolonged sedation.

 

 

Dosage adjustment for midazolam

 

 

should be considered especially if

 

 

more than a single dose of midazolam

 

 

is administered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol

 

Salmeterol:

The combination may result in

 

 

Concentrations are expected to

increased risk of cardiovascular

 

 

increase due to CYP3A inhibition

adverse events associated with

 

 

by lopinavir/ritonavir.

salmeterol, including QT

 

 

 

prolongation, palpitations and sinus

 

 

 

tachycardia.

 

 

 

Therefore, concomitant

 

 

 

administration of Kaletra with

 

 

 

salmeterol is not recommended (see

 

 

 

section 4.4).

Calcium channel blockers

 

 

Felodipine, Nifedipine,

 

Felodipine, Nifedipine,

Clinical monitoring of therapeutic

and Nicardipine

 

Nicardipine:

and adverse effects is recommended

 

 

Concentrations may be increased

when these medicines are

 

 

due to CYP3A inhibition by

concomitantly administered with

 

 

Kaletra.

Kaletra.

Corticosteroids

 

 

Dexamethasone

 

Lopinavir:

Clinical monitoring of antiviral

 

 

Concentrations may be decreased

efficacy is recommended when these

 

 

due to CYP3A induction by

medicines are concomitantly

 

 

dexamethasone.

administered with Kaletra.

Inhaled, injectable or

 

Fluticasone propionate, 50 g

Greater effects may be expected

intranasal fluticasone

 

intranasal 4 times daily:

when fluticasone propionate is

propionate, budesonide,

 

Plasma concentrations ↑

inhaled. Systemic corticosteroid

triamcinolone

 

Cortisol levels ↓ 86%

effects including Cushing's syndrome

 

 

 

and adrenal suppression have been

 

 

 

reported in patients receiving

 

 

 

ritonavir and inhaled or intranasally

 

 

 

administered fluticasone propionate;

 

 

 

this could also occur with other

 

 

 

corticosteroids metabolised via the

 

 

 

P450 3A pathway e.g. budesonide

 

 

 

and triamcinolone. Consequently,

 

 

 

concomitant administration of Kaletra

 

 

 

and these glucocorticoids is not

 

 

 

recommended unless the potential

 

 

 

benefit of treatment outweighs the

 

 

 

risk of systemic corticosteroid effects

 

 

 

(see section 4.4). A dose reduction of

 

 

 

the glucocorticoid should be

 

 

 

considered with close monitoring of

 

 

 

local and systemic effects or a switch

 

 

 

to a glucocorticoid, which is not a

 

 

 

substrate for CYP3A4 (e.g.

 

 

 

beclomethasone). Moreover, in case

 

 

 

of withdrawal of glucocorticoids

 

 

 

progressive dose reduction may have

 

 

 

to be performed over a longer period.

Phosphodiesterase(PDE5) inhibitors

Avanafil

Avanafil:

The use of avanafil with Kaletra is

(ritonavir 600 mg BID)

AUC: ↑ 13-fold

contraindicated (see section 4.3).

 

Due to CYP3A inhibition by

 

 

lopinavir/ritonavir.

 

Tadalafil

Tadalafil:

For the treatment of pulmonary

 

AUC: ↑ 2-fold

arterial hypertension:

 

Due to CYP3A4 inhibition by

Co-administration of Kaletra with

 

lopinavir/ritonavir.

sildenafil is contraindicated (see

Sildenafil

Sildenafil:

section 4.3). Co-administration of

 

AUC: ↑ 11-fold

Kaletra with tadalafil is not

 

Due to CYP3A inhibition by

recommended.

 

lopinavir/ritonavir.

For erectile dysfunction:

 

 

 

 

Particular caution must be used when

 

 

prescribing sildenafil or tadalafil in

 

 

patients receiving Kaletra with

 

 

increased monitoring for adverse

 

 

events including hypotension,

 

 

syncope, visual changes and

 

 

prolonged erection (see section 4.4).

 

 

When co-administered with Kaletra,

 

 

sildenafil doses must not exceed

 

 

25 mg in 48 hours and tadalafil doses

 

 

must not exceed 10 mg every 72

 

 

hours.

Vardenafil

Vardenafil:

The use of vardenafil with Kaletra is

 

AUC: ↑ 49-fold

contraindicated (see section 4.3).

 

Due to CYP3A inhibition by

 

 

Kaletra.

 

HCV Protease Inhibitors

 

 

Boceprevir 800 mg

Boceprevir:

It is not recommended to

three times daily

AUC: ↓ 45%

co-administer Kaletra and boceprevir.

 

Cmax: ↓ 50%

 

 

Cmin: ↓ 57%

 

 

Lopinavir:

 

 

AUC: ↓ 34%

 

 

Cmax: ↓ 30%

 

 

Cmin: ↓ 43%

 

Simeprevir 200 mg

Simeprevir:

It is not recommended to

daily (ritonavir 100 mg

AUC: ↑ 7.2-fold

co-administer Kaletra and simeprevir.

BID)

Cmax: ↑ 4.7-fold

 

 

Cmin: ↑ 14.4-fold

 

Telaprevir 750 mg

Telaprevir:

It is not recommended to

three times daily

AUC: ↓ 54%

co-administer Kaletra and telaprevir.

 

Cmax: ↓ 53%

 

 

Cmin: ↓ 52%

 

 

Lopinavir: ↔

 

Herbal products

St John’s wort

Lopinavir:

Herbal preparations containing St

(Hypericum perforatum)

Concentrations may be reduced

John’s wort must not be combined

 

due to induction of CYP3A by the

with lopinavir and ritonavir. If a

 

herbal preparation St John’s wort.

patient is already taking St John’s

 

 

wort, stop St John’s wort and if

 

 

possible check viral levels. Lopinavir

 

 

and ritonavir levels may increase on

 

 

stopping St John’s wort. The dose of

 

 

Kaletra may need adjusting. The

 

 

inducing effect may persist for at

 

 

least 2 weeks after cessation of

 

 

treatment with St John’s wort (see

 

 

section 4.3). Therefore, Kaletra can

 

 

be started safely 2 weeks after

 

 

cessation of St John's wort.

Immunosuppressants

 

 

Cyclosporin, Sirolimus

Cyclosporin, Sirolimus

More frequent therapeutic

(rapamycin), and

(rapamycin), Tacrolimus:

concentration monitoring is

Tacrolimus

Concentrations may be increased

recommended until plasma levels of

 

due to CYP3A inhibition by

these products have been stabilised.

 

Kaletra.

 

Lipid lowering agents

 

 

Lovastatin and

Lovastatin, Simvastatin:

Since increased concentrations of

Simvastatin

Markedly increased plasma

HMG-CoA reductase inhibitors may

 

concentrations due to CYP3A

cause myopathy, including

 

inhibition by Kaletra.

rhabdomyolysis, the combination of

 

 

these agents with Kaletra is

 

 

contraindicated (see section 4.3).

Atorvastatin

Atorvastatin:

The combination of Kaletra with

 

AUC: ↑ 5.9-fold

atorvastatin is not recommended. If

 

Cmax: ↑ 4.7-fold

the use of atorvastatin is considered

 

Due to CYP3A inhibition by

strictly necessary, the lowest possible

 

Kaletra.

dose of atorvastatin should be

 

 

administered with careful safety

 

 

monitoring (see section 4.4).

Rosuvastatin, 20 mg QD

Rosuvastatin:

Caution should be exercised and

 

AUC: ↑ 2-fold

reduced doses should be considered

 

Cmax: ↑ 5-fold

when Kaletra is co-administered with

 

While rosuvastatin is poorly

rosuvastatin (see section 4.4).

 

metabolised by CYP3A4, an

 

 

increase of its plasma

 

 

concentrations was observed.

 

 

The mechanism of this interaction

 

 

may result from inhibition of

 

 

transport proteins.

 

Fluvastatin or

Fluvastatin, Pravastatin:

If treatment with an HMG-CoA

Pravastatin

No clinical relevant interaction

reductase inhibitor is indicated,

 

expected.

fluvastatin or pravastatin is

 

Pravastatin is not metabolised by

recommended.

 

CYP450.

 

 

Fluvastatin is partially

 

 

metabolised by CYP2C9.

 

Opioids

Buprenorphine, 16 mg

Buprenorphine: ↔

No dose adjustment necessary.

QD

 

 

Methadone

Methadone: ↓

Monitoring plasma concentrations of

 

 

methadone is recommended.

Oral Contraceptives

 

 

Ethinyl Oestradiol

Ethinyl Oestradiol: ↓

In case of co-administration of

 

 

Kaletra with contraceptives

 

 

containing ethinyl oestradiol

 

 

(whatever the contraceptive

 

 

formulation e.g. oral or patch),

 

 

additional methods of contraception

 

 

must be used.

Smoking cessation aids

 

 

Bupropion

Buproprion and its active

If the co-administration of

 

metabolite, hydroxybupropion:

lopinavir/ritonavir with bupropion is

 

AUC and Cmax ↓ ~50%

judged unavoidable, this should be

 

 

done under close clinical monitoring

 

This effect may be due to

for bupropion efficacy, without

 

induction of bupropion

exceeding the recommended dosage,

 

metabolism.

despite the observed induction.

 

 

 

Vasodilating agents

 

 

Bosentan

Lopinavir - ritonavir:

Caution should be exercised in

 

Lopinavir/ritonavir plasma

administering Kaletra with bosentan.

 

concentrations may decrease due

When Kaletra is administered

 

to CYP3A4 induction by

concomitantly with bosentan, the

 

bosentan.

efficacy of the HIV therapy should be

 

 

monitored and patients should be

 

Bosentan:

closely observed for bosentan

 

AUC: ↑ 5-fold

toxicity, especially during the first

 

Cmax: ↑ 6-fold

week of co-administration.

 

Initially, bosentan Cmin :↑ by

 

 

approximately 48-fold.

 

 

Due to CYP3A4 inhibition by

 

 

lopinavir/ritonavir.

 

Riociguat

Serum concentrations may be

The coadministration of riociguat

 

increased due to CYP3A and

with Kaletra is not recommended (see

 

P-gp inhibition by Kaletra.

section 4.4 and refer to riociguat

 

 

SmPC).

Other medicinal products

Based on known metabolic profiles, clinically significant interactions are not expected between

Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

4.6 Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed.

Breastfeeding

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that mothers infected by HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.

Fertility

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).

4.8 Undesirable effects

a. Summary of the safety profile

The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, of which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may be greater with once-daily dosing of Kaletra. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.

It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4).

b. Tabulated list of adverse reactions

Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:

The following events have been identified as adverse reactions. The frequency category includes all reported events of moderate to severe intensity, regardless of the individual causality assessment. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥ 1/10), common (≥ 1/100

to < 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the available data).

Events noted as having frequency “Not known” were identified via post-marketing surveillance.

Undesirable effects in clinical studies and post-marketing in adult patients

System organ class

Frequency

Adverse reaction

 

 

 

Infections and infestations

Very common

Upper respiratory tract infection

 

Common

Lower respiratory tract infection, skin infections

 

 

including cellulitis, folliculitis and furuncle

Blood and lymphatic system

Common

Anaemia, leucopenia, neutropenia,

disorders

 

lymphadenopathy

Immune system disorders

Common

Hypersensitivity including urticaria and

 

 

angioedema

 

Uncommon

Immune reconstitution inflammatory syndrome

Endocrine disorders

Uncommon

Hypogonadism

Metabolism and nutrition

Common

Blood glucose disorders including diabetes

disorders

 

mellitus, hypertriglyceridaemia,

 

 

hypercholesterolemia, weight decreased,

 

 

decreased appetite

 

Uncommon

Weight increased, increased appetite

Psychiatric disorders

Common

Anxiety

 

Uncommon

Abnormal dreams, libido decreased

Nervous system disorders

Common

Headache (including migraine), neuropathy

 

 

(including peripheral neuropathy), dizziness,

 

 

insomnia

 

Uncommon

Cerebrovascular accident, convulsion,

 

 

dysgeusia, ageusia, tremor

 

 

 

Eye disorders

Uncommon

Visual impairment

Ear and labyrinth disorders

Uncommon

Tinnitus, vertigo

Cardiac disorders

Uncommon

Atherosclerosis such as myocardial infarction,

 

 

atrioventricular block, tricuspid valve

 

 

incompetence

Vascular disorders

Common

Hypertension

 

Uncommon

Deep vein thrombosis

Gastrointestinal disorders

Very common

Diarrhoea, nausea

 

Common

Pancreatitis1, vomiting, gastrooesophageal

 

 

reflux disease, gastroenteritis and colitis,

 

 

abdominal pain (upper and lower), abdominal

 

 

distension, dyspepsia, haemorrhoids, flatulence

 

Uncommon

Gastrointestinal haemorrhage including

 

 

gastrointestinal ulcer, duodenitis, gastritis and

 

 

rectal haemorrhage, stomatitis and oral ulcers,

 

 

faecal incontinence, constipation, dry mouth

Hepatobiliary disorders

Common

Hepatitis including AST, ALT and GGT

 

 

increases

 

Uncommon

Hepatic steatosis, hepatomegaly, cholangitis,

 

 

hyperbilirubinemia

 

Not known

Jaundice

Skin and subcutaneous tissue

Common

Rash including maculopapular rash,

disorders

 

dermatitis/rash including eczema and seborrheic

 

 

dermatitis, night sweats, pruritus

 

Uncommon

Alopecia, capillaritis, vasculitis

 

Not known

Stevens-Johnson syndrome, erythema

 

 

multiforme

Musculoskeletal and connective

Common

Myalgia, musculoskeletal pain including

tissue disorders

 

arthralgia and back pain, muscle disorders such

 

 

as weakness and spasms

 

Uncommon

Rhabdomyolysis, osteonecrosis

Renal and urinary disorders

Uncommon

Creatinine clearance decreased, nephritis,

 

 

haematuria

Reproductive system and breast

Common

Erectile dysfunction, menstrual disorders -

disorders

 

amenorrhoea, menorrhagia

General disorders and

Common

Fatigue including asthenia

administration site conditions

 

 

1 See section 4.4: pancreatitis and lipids

c. Description of selected adverse reactions

Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

d. Paediatric populations

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see Table in section b).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

To date, there is limited human experience of acute overdose with Kaletra.

The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.

There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, combinations, ATC code: J05AR10

Mechanism of action

Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Effects on the electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once-daily or twice-daily LPV/r doses at steady state. No subject experienced an

increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose. Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).

Antiviral activity in vitro

The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir against

HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.

Resistance

In vitro selection of resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Analysis of resistance in ARV-naïve patients

In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has not been observed in naïve patients without significant protease inhibitor resistance at baseline. See further the detailed description of the clinical studies.

Analysis of resistance in PI-experienced patients

The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from patients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Antiviral activity of Kaletra in patients failing protease inhibitor therapy

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma

HIV RNA ≤ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold, 10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively. In

addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz,

particularly in patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of patients not receiving Kaletra.

Cross-resistance

Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor- experienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.

Clinical results

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of 48 to 360 weeks duration.

Adult Use

Patients without prior antiretroviral therapy

Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm3 (range: 2 to

949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml).

Table 1

Outcomes at Week 48: Study M98-863

 

Kaletra (N=326)

Nelfinavir (N=327)

HIV RNA < 400 copies/ml*

75%

63%

HIV RNA < 50 copies/ml*†

67%

52%

Mean increase from baseline in

CD4+ T-cell count (cells/mm3)

 

 

* intent to treat analysis where patients with missing values are considered virologic failures

† p < 0.001

One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack of resistance to lopinavir was confirmed by phenotypic analysis.

Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Given the pharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this study might not be strictly extrapolable when other backbone regimens are used with Kaletra. Patients were randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 400/100 mg twice daily (n = 331). Further stratification within each group was 1:1 (tablet versus soft capsule). Patients were administered either the tablet or the soft capsule formulation for 8 weeks, after which all patients were administered the tablet formulation once daily or twice daily for the remainder of the study. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Protocol defined non-inferiority of once-daily dosing compared with twice-daily dosing was demonstrated if the lower bound of the 95% confidence interval for the difference in proportion of subjects responding (once daily minus twice daily) excluded -12% at Week 48. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to 7.0 log10 copies/ml).

Table 2

Virologic Response of Study Subjects at Week 48 and Week 96

 

 

Week 48

 

 

Week 96

 

 

QD

BID

 

Difference

QD

BID

 

Difference

 

 

 

 

[95% CI]

 

 

 

[95% CI]

NC= Failure

257/333

251/331

 

1.3 %

216/333

229/331

 

-4.3%

 

(77.2%)

(75.8%)

 

[-5.1, 7.8]

(64.9%)

(69.2%)

 

[-11.5, 2.8]

Observed data

257/295

250/280

 

-2.2%

216/247

229/248

 

-4.9%

 

(87.1%)

(89.3%)

 

[-7.4, 3.1]

(87.4%)

(92.3%)

 

[-10.2, 0.4]

Mean increase from

 

 

 

 

baseline in CD4+ T-cell

 

 

 

 

 

 

 

 

count (cells/mm3)

 

 

 

 

 

 

 

 

Through Week 96, genotypic resistance testing results were available from 25 patients in the QD group and 26 patients in the BID group who had incomplete virologic response. In the QD group, no patient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease inhibitor resistance at baseline demonstrated additional lopinavir resistance on study.

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice-daily dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one patients completed the study (35 patients received the recommended 400/100 mg twice-daily dose throughout the study).

Table 3

Outcomes at Week 360: Study M97-720

 

Kaletra (N=100)

HIV RNA < 400 copies/ml

61%

HIV RNA < 50 copies/ml

59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.

Patients with prior antiretroviral therapy

M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of once-daily and twice-daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Patients had not been on prior lopinavir/ritonavir therapy. They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. The enrolled population was moderately PI-experienced with more than half of patients having never received prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% were male. Mean baseline CD4+ T-cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/ml (range: 1.7 to 6.6 log10 copies/ml). Around 85% of patients had a viral load of < 100,000 copies/ml.

Table 4

Virologic Response of Study Subjects at Week 48 Study 802

 

QD

BID

Difference

 

 

 

[95% CI]

NC= Failure

171/300

161/299

3.2%

 

(57%)

(53.8%)

[-4.8%, 11.1%]

 

 

 

 

Observed data

171/225

161/223

3.8%

 

(76.0%)

(72.2%)

[-4.3%, 11.9%]

Mean increase from baseline in

 

CD4+ T-cell count (cells/mm3)

 

 

 

Through Week 48, genotypic resistance testing results were available from 75 patients in the QD group and 75 patients in the BID group who had incomplete virologic response. In the QD group, 6/75 (8%) patients demonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 84, 90), as did 12/77 (16%) patients in the BID group.

Paediatric Use

M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or

300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptase inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m2 dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml.

Table 5

Outcomes at Week 48: Study M98-940

 

Antiretroviral Naïve

Antiretroviral

 

(N=44)

Experienced (N=56)

HIV RNA < 400 copies/ml

84%

75%

Mean increase from baseline in

CD4+ T-cell count (cells/mm3)

 

 

KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated the pharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing of lopinavir/ritonavir 100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged <18 years, ≥15 kg in weight, receiving cART that included lopinavir/ritonavir, HIV-1 ribonucleic acid (RNA) <50 copies/ml for at least 24 weeks and able to swallow tablets. At week 48, the efficacy and safety with twice-daily dosing (n=87) in the paediatric population given lopinavir/ritonavir 100 mg/25 mg tablets was consistent with the efficacy and safety findings in previous adult and paediatric studies using lopinavir/ritonavir twice daily. The percentage of patients with confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatric patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-daily dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group. The efficacy data favouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameters significantly favouring the twice-daily regimen (see section 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The

in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.

Absorption

Multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal restriction

produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 ± 5.4 g/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the

morning dose was 8.1 ± 5.7 g/ml. Lopinavir AUC over a 12 hour dosing interval averaged

113.2 ± 60.5 g•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.

Effects of food on oral absorption

Administration of a single 400/100 mg dose of Kaletra tablets under fed conditions (high fat, 872 kcal, 56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf. Therefore, Kaletra tablets may be taken with or without food. Kaletra tablets have also shown less pharmacokinetic variability under all meal conditions compared to Kaletra soft capsules.

Distribution

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients.

Biotransformation

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

Elimination

After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged

5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.

Once-daily dosing: the pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multiple dosing of 800/200 mg Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SD

lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 g/ml, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was

5.5 ± 5.4 g/ml. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 g•h/ml.

As compared to the BID regimen, the once-daily dosing is associated with a reduction in the Cmin/Ctrough values of approximately 50%.

Special Populations

Paediatrics

There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of Kaletra oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-

state AUC, Cmax, and Cmin were 72.6 ± 31.1 g•h/ml, 8.2 ± 2.9 g/ml and 3.4 ± 2.1 g/ml, respectively after Kaletra oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were

85.8 ± 36.9 g•h/ml, 10.0 ± 3.3 g/ml and 3.6 ± 3.5 g/ml, respectively after 300/75 mg/m2 twice daily with nevirapine (n=12). The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the 300/75 mg/m2 twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.

Gender, Race and Age

Kaletra pharmacokinetics have not been studied in older people. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified.

Pregnancy and postpartum

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 weeks of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 mg/100 mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age of gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) twice daily until subjects were 2 weeks postpartum. Plasma concentrations of lopinavir were measured over four 12-hour periods during second trimester (20-24 weeks gestation), third trimester before dose

increase (30 weeks gestation), third trimester after dose increase (32 weeks gestation), and at 8 weeks post-partum. The dose increase did not result in a significant increase in the plasma lopinavir concentration.

In another open-label pharmacokinetic study, 19 HIV-infected pregnant women received lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy during pregnancy from before conception. A series of blood samples were collected pre-dose and at intervals over the course of 12 hours in trimester 2 and trimester 3, at birth, and 4–6 weeks postpartum (in women who continued treatment post-delivery) for pharmacokinetic analysis of total and unbound levels of plasma lopinavir concentrations.

The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets 400/100 mg twice daily are presented in Table 6 (see section 4.2).

Table 6

Mean (%CV) Steady-State Pharmacokinetic Parameters of Lopinavir

in HIV-Infected Pregnant Women

Pharmacokinetic

2nd Trimester

3rd Trimester

Postpartum

Parameter

n = 17*

n = 23

n = 17**

AUC0-12 μghr/mL

68.7 (20.6)

61.3 (22.7)

94.3 (30.3)

Cmax

7.9 (21.1)

7.5 (18.7)

9.8 (24.3)

Cpredose μg /mL

4.7 (25.2)

4.3 (39.0)

6.5 (40.4)

* n = 18 for Cmax

** n = 16 for Cpredose

Renal Insufficiency

Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Insufficiency

The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).

5.3 Preclinical safety data

Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.

During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir

did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.

In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance.

The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8).

In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights, increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.

Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk.

Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet contents:

Copovidone

Sorbitan laurate

Colloidal anhydrous silica

Sodium stearyl fumarate

Film-coating:

Hypromellose

Titanium dioxide

Macrogols type 400 (Polyethylene glycol 400)

Hydroxypropyl cellulose

Talc

Colloidal anhydrous silica

Macrogols type 3350 (Polyethylene glycol 3350)

Yellow ferric oxide E172

Polysorbate 80

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottles closed with propylene caps. Each bottle contains 120 tablets.

Two pack sizes are available:

1 bottle of 120 tablets

Multipack containing 360 (3 bottles of 120) film-coated tablets

Blisters packs - polyvinyl chloride (PVC) blisters with fluoropolymer foil backing Two pack sizes are available:

-carton containing 120 film-coated tablets

-multipack containing 120 (3 cartons of 40) film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

AbbVie Ltd

Maidenhead

SL6 4UB

United Kingdom

8. MARKETING AUTHORISATION NUMBERS

EU/1/01/172/004

EU/1/01/172/005

EU/1/01/172/007

EU/1/01/172/008

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 March 2001

Date of latest renewal: 20 March 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

1. NAME OF THE MEDICINAL PRODUCT

Kaletra 100 mg/25 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as a pharmacokinetic enhancer.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

Pale yellow debossed with [Abbott logo] and “KC”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected children above the age of 2 years, adolescents and adults.

The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.

Kaletra tablets must be swallowed whole and not chewed, broken or crushed.

Posology

Adults and adolescents

The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twice daily taken with or without food. In adult patients, in cases where once-daily dosing is considered necessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four 200/50 mg tablets) once daily with or without food. The use of a once-daily dosing should be limited to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than 3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the population) and should take into account the risk of a lesser sustainability of the virologic suppression (see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standard twice-daily dosing. An oral solution is available to patients who have difficulty swallowing. Refer to the Summary of Product Characteristics for Kaletra oral solution for dosing instructions.

Paediatric population (2 years of age and above)

The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or with a Body Surface Area (BSA)* greater than 1.4 m2. For children weighing less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able to swallow tablets, refer to the dosing guideline tables below. For children unable to swallow tablets, please refer to the Kaletra oral solution Summary of Product Characteristics. Based on the current data available, Kaletra should not be administered once daily in paediatric patients (see section 5.1).

Before prescribing Kaletra 100/25 mg tablets, infants and young children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a Kaletra tablet, Kaletra oral solution formulation should be prescribed.

The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on body weight and BSA.

Paediatric dosing guidelines without concomitant efavirenz or nevirapine*

Weight (kg)

Body Surface Area (m2)

Recommended number of

 

 

100/25 mg tablets twice-daily

 

 

 

15 to 25

≥ 0.5 to < 0.9

2 tablets (200/50 mg)

> 25 to 35

≥ 0.9 to < 1.4

3 tablets (300/75 mg)

> 35

≥ 1.4

4 tablets (400/100 mg)

*weight based dosing recommendations are based on limited data

If more convenient for patients, the Kaletra 200/50 mg tablets may also be considered alone or in combination with the Kaletra 100/25 mg tablet to achieve the recommended dose.

* Body surface area can be calculated with the following equation:

BSA (m2) = √ (Height (cm) X Weight (kg) / 3600)

Children less than 2 years of age

The safety and efficacy of Kaletra in children aged less than 2 years have not been established. Currently available data are described in section 5.2 but no recommendation on the posology can be made.

Concomitant Therapy: Efavirenz or nevirapine

The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on BSA when used in combination with efavirenz or nevirapine in children.

Paediatric dosing guidelines with concomitant efavirenz or nevirapine

Body Surface Area (m2)

Recommended number of

 

100/25 mg tablets twice-daily

 

 

≥ 0.5 to < 0.8

2 tablets (200/50 mg)

≥ 0.8 to < 1.2

3 tablets (300/75 mg)

≥ 1.2 to < 1.4

4 tablets (400/100 mg)

≥ 1.4

5 tablets (500/125 mg)

If more convenient for patients, the Kaletra 200/50 mg tablets may also be considered alone or in combination with the Kaletra 100/25 mg tablet to achieve the recommended dose.

Hepatic impairment

In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra must not be given to these patients (see section 4.3).

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Pregnancy and postpartum

No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum.

Once-daily administration of lopinavir/ritonavir is not recommended for pregnant women due to the lack of pharmacokinetic and clinical data.

Method of administration

Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or crushed. Kaletra tablets can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Severe hepatic insufficiency.

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include:

Medicinal product class

Medicinal products

Rationale

 

within class

 

 

 

Concomitant medicinal product levels increased

 

 

 

 

Alpha1-adrenoreceptor

Alfuzosin

Increased plasma concentrations of alfuzosin

antagonist

 

which may lead to severe hypotension. The

 

 

concomitant administration with alfuzosin is

 

 

contraindicated (see section 4.5).

Antianginal

Ranolazine

Increased plasma concentrations of ranolazine

 

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section 4.5).

Antiarrhythmics

Amiodarone,

Increased plasma concentrations of amiodarone

 

dronedarone

and dronedarone. Thereby, increasing the risk of

 

 

arrhythmias or other serious adverse reactions.

Antibiotic

Fusidic Acid

Increased plasma concentrations of fusidic acid.

 

 

The concomitant administration with fusidic acid

 

 

is contraindicated in dermatological infections.

 

 

(see section 4.5).

Anti-gout

Colchicine

Increased plasma concentrations of colchicine.

 

 

Potential for serious and/or life-threatening

 

 

reactions in patients with renal and/or hepatic

 

 

impairment (see sections 4.4 and 4.5).

Antihistamines

Astemizole, terfenadine

Increased plasma concentrations of astemizole

 

 

and terfenadine. Thereby, increasing the risk of

 

 

serious arrhythmias from these agents.

Antipsychotics/

Lurasidone

Increased plasma concentrations of lurasidone

Neuroleptics

 

which may increase the potential for serious

 

 

and/or life-threatening reactions (see section 4.5).

 

Pimozide

Increased plasma concentrations of pimozide.

 

 

Thereby, increasing the risk of serious

 

 

haematologic abnormalities, or other serious

 

 

adverse effects from this agent.

 

Quetiapine

Increased plasma concentrations of quetiapine

 

 

which may lead to coma. The concomitant

 

 

administration with quetiapine is contraindicated

 

 

(see section 4.5).

Ergot alkaloids

Dihydroergotamine,

Increased plasma concentrations of ergot

 

ergonovine,

derivatives leading to acute ergot toxicity,

 

ergotamine,

including vasospasm and ischaemia.

 

methylergonovine

 

GI motility agent

Cisapride

Increased plasma concentrations of cisapride.

 

 

Thereby, increasing the risk of serious

 

 

arrhythmias from this agent.

HMG Co-A Reductase

Lovastatin, simvastatin

Increased plasma concentrations of lovastatin and

Inhibitors

 

simvastatin; thereby, increasing the risk of

 

 

myopathy including rhabdomyolysis (see section

 

 

4.5).

Phosphodiesterase

Avanafil

Increased plasma concentrations of avanail (see

(PDE5) inhibitors

 

sections 4.4 and 4.5)

 

Sildenafil

Contraindicated when used for the treatment of

 

 

pulmonary arterial hypertension (PAH) only.

 

 

Increased plasma concentrations of sildenafil.

 

 

Thereby, increasing the potential for sildenafil-

 

 

associated adverse events (which include

 

 

hypotension and syncope). See section 4.4 and

 

 

section 4.5 for co-administration of sildenafil in

 

 

patients with erectile dysfunction.

 

Vardenafil

Increased plasma concentrations of vardenafil

 

 

(see sections 4.4 and 4.5)

Sedatives/hypnotics

Oral midazolam,

Increased plasma concentrations of oral

 

triazolam

midazolam and triazolam. Thereby, increasing

 

 

the risk of extreme sedation and respiratory

 

 

depression from these agents.

 

 

For caution on parenterally administered

 

 

midazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

 

 

 

Herbal products

St. John’s wort

Herbal preparations containing St John’s wort

 

 

(Hypericum perforatum) due to the risk of

decreased plasma concentrations and reduced clinical effects of lopinavir and ritonavir (see section 4.5).

4.4 Special warnings and precautions for use

Patients with coexisting conditions

Hepatic impairment

The safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant

antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction was serious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and close monitoring should be performed during treatment.

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Pancreatitis

Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution InflammatorySyndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and can occur many months after initiation of treatment.

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see section 5.1).

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Interactions with medicinal products

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).

The combination of Kaletra with:

-tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended (see section 4.5);

-riociguat is not recommended (see section 4.5);

-vorapaxar is not recommended (see section 4.5);

-fusidic acid in osteo-articular infections is not recommended (see section 4.5);

-salmeterol is not recommended (see section 4.5);

-rivaroxaban is not recommended (see section 4.5).

The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these medicinal products is expected to substantially increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra is contraindicated (see section 4.3).

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse reactions. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3).

Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).

Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5).

Other

Kaletra is not a cure for HIV infection or AIDS. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS.

4.5 Interaction with other medicinal products and other forms of interaction

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A

in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).

Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products.

Medicinal products that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in section 4.3.

All interaction studies, when otherwise not stated, were performed using Kaletra capsules, which gives an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below.

Interaction table

Interactions between Kaletra and co-administered medicinal products are listed in the table below

(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as

“BID” and three times daily as "TID").

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of lopinavir/ritonavir (i.e. 400/100 mg twice daily).

Co-administered drug

Effects on drug levels

 

Clinical recommendation

by therapeutic area

 

 

concerning co-administration

 

Geometric Mean Change (%) in

 

with Kaletra

 

AUC, Cmax, Cmin

 

 

 

Mechanism of interaction

 

 

Antiretroviral Agents

 

 

 

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

 

Stavudine, Lamivudine

Lopinavir: ↔

 

No dose adjustment necessary.

 

 

 

 

Abacavir, Zidovudine

Abacavir, Zidovudine:

 

The clinical significance of reduced

 

Concentrations may be reduced

 

abacavir and zidovudine

 

due to increased glucuronidation

 

concentrations is unknown.

 

by Kaletra.

 

 

Tenofovir, 300 mg QD

Tenofovir:

 

No dose adjustment necessary.

 

AUC: ↑ 32%

 

Higher tenofovir concentrations

 

Cmax: ↔

 

could potentiate tenofovir

 

Cmin: ↑ 51%

 

associated adverse events, including

 

Lopinavir: ↔

 

renal disorders.

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

Efavirenz, 600 mg QD

Lopinavir:

 

The Kaletra tablets dosage should

 

AUC: ↓ 20%

 

be increased to 500/125 mg twice

 

Cmax: ↓ 13%

 

daily when co-administered with

 

Cmin: ↓ 42%

 

efavirenz.

Efavirenz, 600 mg QD

 

 

Kaletra must not be administered

 

Lopinavir: ↔

 

once daily in combination with

(Lopinavir/ritonavir

(Relative to 400/100 mg BID

 

efavirenz.

500/125 mg BID)

administered alone)

 

 

 

 

 

 

Nevirapine, 200 mg

Lopinavir:

 

The Kaletra tablets dosage should

BID

AUC: ↓ 27%

 

be increased to 500/125 mg twice

 

Cmax: ↓ 19%

 

daily when co-administered with

 

Cmin: ↓ 51%

 

nevirapine.

 

 

 

Kaletra must not be administered

 

 

 

once daily in combination with

 

 

 

nevirapine.

Etravirine

Etravirine :

No dose adjustment necessary

 

AUC: ↓ 35%

 

(Lopinavir/ritonavir

Cmin: ↓ 45%

 

tablet 400/100 mg BID)

Cmax: ↓ 30%

 

 

Lopinavir :

 

 

AUC: ↔

 

 

Cmin: ↓ 20%

 

 

Cmax: ↔

 

Rilpivirine

Rilpivirine:

Concomitant use of Kaletra with

 

AUC: ↑ 52%

rilpivirine causes an increase in the

(Lopinavir/ritonavir

Cmin: ↑ 74%

plasma concentrations of rilpivirine,

capsule 400/100 mg

Cmax: ↑ 29%

but no dose adjustment is required.

BID)

Lopinavir:

 

 

 

 

AUC: ↔

 

 

Cmin: ↓ 11%

 

 

Cmax: ↔

 

 

(inhibition of CYP3A enzymes)

 

HIV CCR5 – antagonist

 

 

Maraviroc

Maraviroc:

The dose of maraviroc should be

 

AUC: ↑ 295%

decreased to 150 mg twice daily

 

Cmax: ↑ 97%

during co-administration with

 

Due to CYP3A inhibition by

Kaletra 400/100 mg twice daily.

 

lopinavir/ritonavir.

 

Integrase inhibitor

 

 

Raltegravir

Raltegravir:

No dose adjustment necessary

 

AUC: ↔

 

 

Cmax: ↔

 

 

C12: ↓ 30%

 

 

Lopinavir: ↔

 

Co-administration with other HIV protease inhibitors (PIs)

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Fosamprenavir/

Fosamprenavir:

Co-administration of increased

ritonavir (700/100 mg

Amprenavir concentrations are

doses of fosamprenavir (1400 mg

BID)

significantly reduced.

BID) with lopinavir/ritonavir

 

 

(533/133 mg BID) to protease

(Lopinavir/ritonavir

 

inhibitor-experienced patients

400/100 mg BID)

 

resulted in a higher incidence of

 

 

gastrointestinal adverse events and

or

 

elevations in triglycerides with the

 

 

combination regimen without

Fosamprenavir

 

increases in virological efficacy,

(1400 mg BID)

 

when compared with standard doses

 

 

of fosamprenavir/ritonavir.

(Lopinavir/ritonavir

 

Concomitant administration of these

533/133 mg BID)

 

medicinal products is not

 

 

recommended.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

amprenavir.

Indinavir, 600 mg BID

Indinavir:

The appropriate doses for this

 

AUC: ↔

combination, with respect to

 

Cmin: ↑ 3.5-fold

efficacy and safety, have not been

 

Cmax: ↓

established.

 

(relative to indinavir 800 mg TID

 

 

alone)

 

 

Lopinavir: ↔

 

 

(relative to historical comparison)

 

Saquinavir

Saquinavir: ↔

No dose adjustment necessary.

1000 mg BID

 

 

Tipranavir/ritonavir

Lopinavir:

Concomitant administration of these

(500/100 mg BID)

AUC: ↓ 55%

medicinal products is not

 

Cmin: ↓ 70%

recommended.

 

Cmax: ↓ 47%

 

Acid reducing agents

 

 

Omeprazole (40 mg

Omeprazole: ↔

No dose adjustment necessary

QD)

Lopinavir: ↔

 

 

 

Ranitidine (150 mg

Ranitidine: ↔

No dose adjustment necessary

single dose)

 

 

Alpha1 adrenoreceptor antagonist

 

Alfuzosin

Alfuzosin:

Concomitant administration of

 

Due to CYP3A inhibition by

Kaletra and alfuzosin is contra-

 

lopinavir/ritonavir, concentrations

indicated (see section 4.3) as

 

of alfuzosin are expected to

alfuzosin-related toxicity, including

 

increase.

hypotension, may be increased.

Analgesics

 

 

Fentanyl

Fentanyl:

Careful monitoring of adverse

 

Increased risk of side-effects

effects (notably respiratory

 

(respiratory depression, sedation)

depression but also sedation) is

 

due to higher plasma

recommended when fentanyl is

 

concentrations because of

concomitantly administered with

 

CYP3A4 inhibition by Kaletra

Kaletra.

Antianginal

 

 

Ranolazine

Due to CYP3A inhibition by

The concomitant administration of

 

lopinavir/ritonavir, concentrations

Kaletra and ranolazine is

 

of ranolazine are expected to

contraindicated (see section 4.3).

 

increase.

 

Antiarrhythmics

 

 

Amiodarone,

Amiodarone, Dronedarone:

Concomitant administration of

Dronedarone

Concentrations may be increased

Kaletra and amiodarone or

 

due to CYP3A4 inhibition by

dronedarone is contraindicated (see

 

Kaletra.

section 4.3) as the risk of

 

 

arrhythmias or other serious adverse

 

 

reactions may be increased.

Digoxin

Digoxin:

Caution is warranted and

 

Plasma concentrations may be

therapeutic drug monitoring of

 

increased due to P-glycoprotein

digoxin concentrations, if available,

 

inhibition by Kaletra. The

is recommended in case of

 

increased digoxin level may

co-administration of Kaletra and

 

lessen over time as Pgp induction

digoxin. Particular caution should

 

develops.

be used when prescribing Kaletra in

 

 

patients taking digoxin as the acute

 

 

inhibitory effect of ritonavir on Pgp

 

 

is expected to significantly increase

 

 

digoxin levels. Initiation of digoxin

 

 

in patients already taking Kaletra is

 

 

likely to result in lower than

 

 

expected increases of digoxin

 

 

concentrations.

Bepridil, Systemic

Bepridil, Systemic Lidocaine,

Caution is warranted and

Lidocaine, and

Quinidine:

therapeutic drug concentration

Quinidine

Concentrations may be increased

monitoring is recommended when

 

when co-administered with

available.

 

Kaletra.

 

Antibiotics

 

 

Clarithromycin

Clarithromycin:

For patients with renal impairment

 

Moderate increases in

(CrCL < 30 ml/min) dose reduction

 

clarithromycin AUC are expected

of clarithromycin should be

 

due to CYP3A inhibition by

considered (see section 4.4).

 

Kaletra.

Caution should be exercised in

 

 

administering clarithromycin with

 

 

Kaletra to patients with impaired

 

 

hepatic or renal function.

Anticancer agents

 

 

Afatinib

Afatinib:

Caution should be exercised in

 

AUC: ↑

administering afatinib with Kaletra.

(Ritonavir 200 mg twice

Cmax: ↑

Refer to the afatinib SmPC for

daily)

 

dosage adjustment

 

The extent of increase depends on

recommendations. Monitor for

 

the timing of ritonavir

ADRs related to afatinib.

 

administration.

 

 

Due to BCRP (breast cancer

 

 

resistance protein/ABCG2) and

 

 

acute P-gp inhibition by Kaletra

 

Ceritinib

Serum concentrations may be

Caution should be exercised in

 

increased due to CYP3A and

administering ceritinib with Kaletra.

 

P-gp inhibition by Kaletra.

Refer to the ceritinib SmPC for

 

 

dosage adjustment

 

 

recommendations. Monitor for

 

 

ADRs related to ceritinib.

Most tyrosine kinase

Most tyrosine kinase inhibitors

Careful monitoring of the tolerance

inhibitors such as

such as dasatinib and nilotinib,

of these anticancer agents.

dasatinib and nilotinib,

also vincristine and vinblastine:

 

vincristine, vinblastine

Risk of increased adverse events

 

 

due to higher serum

 

 

concentrations because of

 

 

CYP3A4 inhibition by Kaletra.

 

Anticoagulants

Warfarin

Warfarin:

It is recommended that INR

 

Concentrations may be affected

(international normalised ratio) be

 

when co-administered with

monitored.

 

Kaletra due to CYP2C9

 

 

induction.

 

Rivaroxaban

Rivaroxaban:

Co-administration of rivaroxaban

 

AUC: ↑ 153%

and Kaletra may increase

(Ritonavir 600 mg twice

Cmax: ↑ 55%

rivaroxaban exposure which may

daily)

Due to CYP3A and P-gp

increase the risk of bleeding.

 

inhibition by lopinavir/ritonavir.

The use of rivaroxaban is not

 

 

recommended in patients receiving

 

 

concomitant treatment with Kaletra

 

 

(see section 4.4).

Vorapaxar

Serum concentrations may be

The coadministration of vorapaxar

 

increased due to CYP3A

with Kaletra is not recommended

 

inhibition by Kaletra.

(see section 4.4 and refer to the

 

 

vorapaxar SmPC).

Anticonvulsants

 

 

Phenytoin

Phenytoin:

Caution should be exercised in

 

Steady-state concentrations was

administering phenytoin with

 

moderately decreased due to

Kaletra.

 

CYP2C9 and CYP2C19 induction

Phenytoin levels should be

 

by Kaletra.

monitored when co-administering

 

 

with lopinavir/ritonavir.

 

Lopinavir:

When co-administered with

 

Concentrations are decreased due

phenytoin, an increase of Kaletra

 

to CYP3A induction by

dosage may be envisaged. Dose

 

phenytoin.

adjustment has not been evaluated

 

 

in clinical practice.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

phenytoin.

Carbamazepine and

Carbamazepine:

Caution should be exercised in

Phenobarbital

Serum concentrations may be

administering carbamazepine or

 

increased due to CYP3A

phenobarbital with Kaletra.

 

inhibition by Kaletra.

Carbamazepine and phenobarbital

 

 

levels should be monitored when

 

Lopinavir:

co-administering with

 

Concentrations may be decreased

lopinavir/ritonavir.

 

due to CYP3A induction by

When co-administered with

 

carbamazepine and phenobarbital.

carbamazepine or phenobarbital, an

 

 

increase of Kaletra dosage may be

 

 

envisaged. Dose adjustment has not

 

 

been evaluated in clinical practice.

 

 

Kaletra must not be administered

 

 

once daily in combination with

 

 

cabamazepine and phenobarbital.

Lamotrigine and

Lamotrigine:

Patients should be monitored

Valproate

AUC: ↓ 50%

closely for a decreased VPA effect

 

Cmax: ↓ 46%

when Kaletra and valproic acid or

 

Cmin: ↓ 56%

valproate are given concomitantly.

 

Due to induction of lamotrigine

In patients starting or stopping

 

glucuronidation

Kaletra while currently taking

 

Valproate: ↓

maintenance dose of lamotrigine:

 

lamotrigine dose may need to be

 

 

increased if Kaletra is added, or

 

 

decreased if Kaletra is discontinued;

 

 

therefore plasma lamotrigine

 

 

monitoring should be conducted,

 

 

particularly before and during 2

 

 

weeks after starting or stopping

 

 

Kaletra, in order to see if

 

 

lamotrigine dose adjustment is

 

 

needed.

 

 

In patients currently taking Kaletra

 

 

and starting lamotrigine: no dose

 

 

adjustments to the recommended

 

 

dose escalation of lamotrigine

 

 

should be necessary.

 

 

 

Antidepressants and Anxiolytics

 

Trazodone single dose

Trazodone:

It is unknown whether the

 

AUC: ↑ 2.4-fold

combination of lopinavir/ritonavir

(Ritonavir, 200 mg

 

causes a similar increase in

BID)

Adverse events of nausea,

trazodone exposure. The

 

dizziness, hypotension and

combination should be used with

 

syncope were observed following

caution and a lower dose of

 

co-administration of trazodone

trazodone should be considered.

 

and ritonavir.

 

Antifungals

 

 

Ketoconazole and

Ketoconazole, Itraconazole:

High doses of ketoconazole and

Itraconazole

Serum concentrations may be

itraconazole (> 200 mg/day) are not

 

increased due to CYP3A

recommended.

 

inhibition by Kaletra.

 

Voriconazole

Voriconazole:

Co-administration of voriconazole

 

Concentrations may be decreased.

and low dose ritonavir (100 mg

 

 

BID) as contained in Kaletra should

 

 

be avoided unless an assessment of

 

 

the benefit/risk to patient justifies

 

 

the use of voriconazole.

Anti-gout agents:

Colchicine single dose

Colchicine:

Concomitant administration of

 

AUC: ↑ 3-fold

Kaletra with colchicine in patients

(Ritonavir 200 mg twice

Cmax: ↑ 1.8-fold

with renal and/or hepatic

daily)

Due to P-gp and/or CYP3A4

impairment is contraindicated due

 

inhibition by ritonavir.

to a potential increase of colchicine-

 

 

related serious and/or

 

 

life-threatening reactions such as

 

 

neuromuscular toxicity (including

 

 

rhabdomyolysis) (see sections 4.3

 

 

and 4.4). A reduction in colchicine

 

 

dosage or an interruption of

 

 

colchicine treatment is

 

 

recommended in patients with

 

 

normal renal or hepatic function if

 

 

treatment with Kaletra is required.

 

 

Refer to colchicine prescribing

 

 

information.

Anti-infectives

 

 

Fusidic acid

Fusidic acid:

Concomitant administration of

 

Concentrations may be increased

Kaletra with fusidic acid is contra-

 

due to CYP3A inhibition by

indicated in dermatological

 

lopinavir/ritonavir.

indications due to the increased risk

 

 

of adverse events related to fusidic

 

 

acid, notably rhabdomyolysis (see

 

 

section 4.3). When used for osteo-

 

 

articular infections, where the co-

 

 

administration is unavoidable, close

 

 

clinical monitoring for muscular

 

 

adverse events is strongly

 

 

recommended (see section 4.4).

Antimycobacterials

 

 

Bedaquiline

Bedaquiline:

Due to the risk of bedaquiline

(single dose)

AUC: ↑ 22%

related adverse events, the

(Lopinavir/ritonavir

Cmax: ↔

combination of bedaquiline and

 

lopinavir/ritonavir should be

400/100 mg BID,

A more pronounced effect on

avoided. If the benefit outweighs

multiple dose)

bedaquiline plasma exposures

the risk, co-administration of

 

may be observed during

bedaquiline with lopinavir/ritonavir

 

prolonged co-administration with

must be done with caution. More

 

lopinavir/ritonavir.

frequent electrocardiogram

 

 

monitoring and monitoring of

 

CYP3A4 inhibition likely due to

transaminases is recommended (see

 

lopinavir/ritonavir.

section 4.4 and refer to the

 

 

bedaquiline SmPC).

Delamanid (100 mg

Delamanid:

Due to the risk of QTc prolongation

BID)

AUC: ↑ 22%

associated with DM-6705, if

 

 

co-administration of delamanid with

(Lopinavir/ritonavir

DM-6705 (delamanid active

lopinavir/ritonavir is considered

400/100 mg BID)

metabolite):

necessary, very frequent ECG

 

AUC: ↑ 30%

monitoring throughout the full

 

 

delamanid treatment period is

 

A more pronounced effect on

recommended (see section 4.4 and

 

DM-6705 exposure may be

refer to the delamanid SmPC).

 

observed during prolonged co-

 

 

administration with

 

 

lopinavir/ritonavir.

 

Rifabutin, 150 mg QD

Rifabutin (parent drug and active

When given with Kaletra the

 

25-O-desacetyl metabolite):

recommended dose of rifabutin is

 

AUC: ↑ 5.7-fold

150 mg 3 times per week on set

 

Cmax: ↑ 3.5-fold

days (for example Monday-

 

 

Wednesday-Friday). Increased

 

 

monitoring for rifabutin-associated

 

 

adverse reactions including

 

 

neutropenia and uveitis is warranted

 

 

due to an expected increase in

 

 

exposure to rifabutin. Further

 

 

dosage reduction of rifabutin to

 

 

150 mg twice weekly on set days is

 

 

recommended for patients in whom

 

 

the 150 mg dose 3 times per week is

 

 

not tolerated. It should be kept in

 

 

mind that the twice weekly dosage

 

 

of 150 mg may not provide an

 

 

optimal exposure to rifabutin thus

 

 

leading to a risk of rifamycin

 

 

resistance and a treatment failure.

 

 

No dose adjustment is needed for

 

 

Kaletra.

Rifampicin

Lopinavir:

Co-administration of Kaletra with

 

Large decreases in lopinavir

rifampicin is not recommended as

 

concentrations may be observed

the decrease in lopinavir

 

due to CYP3A induction by

concentrations may in turn

 

rifampicin.

significantly decrease the lopinavir

 

 

therapeutic effect. A dose

 

 

adjustment of Kaletra

 

 

400 mg/400 mg (i.e. Kaletra

 

 

400/100 mg + ritonavir 300 mg)

 

 

twice daily has allowed

 

 

compensating for the CYP 3A4

 

 

inducer effect of rifampicin.

 

 

However, such a dose adjustment

 

 

might be associated with ALT/AST

 

 

elevations and with increase in

 

 

gastrointestinal disorders.

 

 

Therefore, this co-administration

 

 

should be avoided unless judged

 

 

strictly necessary. If this

 

 

co-administration is judged

 

 

unavoidable, increased dose of

 

 

Kaletra at 400 mg/400 mg twice

 

 

daily may be administered with

 

 

rifampicin under close safety and

 

 

therapeutic drug monitoring. The

 

 

Kaletra dose should be titrated

 

 

upward only after rifampicin has

 

 

been initiated (see section 4.4).

Antipsychotics

 

 

Lurasidone

Due to CYP3A inhibition by

The concomitant administration

 

lopinavir/ritonavir, concentrations

with lurasidone is contraindicated

 

of lurasidone are expected to

(see section 4.3).

 

increase.

 

Quetiapine

Due to CYP3A inhibition by

Concomitant administration of

 

lopinavir/ritonavir, concentrations

Kaletra and quetiapine is

 

of quetiapine are expected to

contraindicated as it may increase

 

increase.

quetiapine-related toxicity.

Benzodiazepines

 

 

Midazolam

Oral Midazolam:

Kaletra must not be co-administered

 

AUC: ↑ 13-fold

with oral midazolam (see section

 

Parenteral Midazolam:

4.3), whereas caution should be

 

AUC: ↑ 4-fold

used with co-administration of

 

Due to CYP3A inhibition by

Kaletra and parenteral midazolam.

 

Kaletra

If Kaletra is co-administered with

 

 

parenteral midazolam, it should be

 

 

done in an intensive care unit (ICU)

 

 

or similar setting which ensures

 

 

close clinical monitoring and

 

 

appropriate medical management in

 

 

case of respiratory depression

 

 

and/or prolonged sedation. Dosage

 

 

adjustment for midazolam should be

 

 

considered especially if more than a

 

 

single dose of midazolam is

 

 

administered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol

 

Salmeterol:

The combination may result in

 

 

Concentrations are expected to

increased risk of cardiovascular

 

 

increase due to CYP3A inhibition

adverse events associated with

 

 

by lopinavir/ritonavir.

salmeterol, including QT

 

 

 

prolongation, palpitations and sinus

 

 

 

tachycardia.

 

 

 

Therefore, concomitant

 

 

 

administration of Kaletra with

 

 

 

salmeterol is not recommended (see

 

 

 

section 4.4).

Calcium channel blockers

 

 

Felodipine, Nifedipine,

 

Felodipine, Nifedipine,

Clinical monitoring of therapeutic

and Nicardipine

 

Nicardipine:

and adverse effects is recommended

 

 

Concentrations may be increased

when these medicines are

 

 

due to CYP3A inhibition by

concomitantly administered with

 

 

Kaletra.

Kaletra.

Corticosteroids

 

 

Dexamethasone

 

Lopinavir:

Clinical monitoring of antiviral

 

 

Concentrations may be decreased

efficacy is recommended when

 

 

due to CYP3A induction by

these medicines are concomitantly

 

 

dexamethasone.

administered with Kaletra.

 

 

 

 

Inhaled, injectable or

 

Fluticasone propionate, 50 g

Greater effects may be expected

intranasal fluticasone

 

intranasal 4 times daily:

when fluticasone propionate is

propionate, budesonide,

 

Plasma concentrations ↑

inhaled. Systemic corticosteroid

triamcinolone

 

Cortisol levels ↓ 86%

effects including Cushing's

 

 

 

syndrome and adrenal suppression

 

 

 

have been reported in patients

 

 

 

receiving ritonavir and inhaled or

 

 

 

intranasally administered

 

 

 

fluticasone propionate; this could

 

 

 

also occur with other corticosteroids

 

 

 

metabolised via the P450 3A

 

 

 

pathway e.g. budesonide and

 

 

 

triamcinolone. Consequently,

 

 

 

concomitant administration of

 

 

 

Kaletra and these glucocorticoids is

 

 

 

not recommended unless the

 

 

 

potential benefit of treatment

 

 

 

outweighs the risk of systemic

 

 

 

corticosteroid effects (see section

 

 

 

4.4). A dose reduction of the

 

 

 

glucocorticoid should be considered

 

 

 

with close monitoring of local and

 

 

 

systemic effects or a switch to a

 

 

 

glucocorticoid, which is not a

 

 

 

substrate for CYP3A4 (e.g.

 

 

 

beclomethasone). Moreover, in

 

 

 

case of withdrawal of

 

 

 

glucocorticoids progressive dose

 

 

 

reduction may have to be performed

 

 

 

over a longer period.

Phosphodiesterase(PDE5) inhibitors

Avanafil

Avanafil:

The use of avanafil with Kaletra is

(ritonavir 600 mg BID)

AUC: ↑ 13-fold

contraindicated (see section 4.3).

 

Due to CYP3A inhibition by

 

 

lopinavir/ritonavir.

 

 

 

 

Tadalafil

Tadalafil:

For the treatment of pulmonary

 

AUC: ↑ 2-fold

arterial hypertension:

 

Due to CYP3A4 inhibition by

Co-administration of Kaletra with

 

lopinavir/ritonavir.

sildenafil is contraindicated (see

 

 

section 4.3). Co-administration of

 

 

Kaletra with tadalafil is not

 

 

recommended.

Sildenafil

Sildenafil:

 

AUC: ↑ 11-fold

For erectile dysfunction:

 

Due to CYP3A inhibition by

 

lopinavir/ritonavir.

Particular caution must be used

 

 

when prescribing sildenafil or

 

 

tadalafil in patients receiving

 

 

Kaletra with increased monitoring

 

 

for adverse events including

 

 

hypotension, syncope, visual

 

 

changes and prolonged erection (see

 

 

section 4.4).

 

 

When co-administered with Kaletra,

 

 

sildenafil doses must not exceed

 

 

25 mg in 48 hours and tadalafil

 

 

doses must not exceed 10 mg every

 

 

72 hours.

 

 

 

Vardenafil

Vardenafil:

The use of vardenafil with Kaletra

 

AUC: ↑ 49-fold

is contraindicated (see section 4.3).

 

Due to CYP3A inhibition by

 

 

Kaletra.

 

HCV Protease Inhibitors

 

 

Boceprevir 800 mg

Boceprevir:

It is not recommended to

three times daily

AUC: ↓ 45%

co-administer Kaletra and

 

Cmax: ↓ 50%

boceprevir.

 

Cmin: ↓ 57%

 

 

Lopinavir:

 

 

AUC: ↓ 34%

 

 

Cmax: ↓ 30%

 

 

Cmin: ↓ 43%

 

Simeprevir 200 mg

Simeprevir:

It is not recommended to

daily (ritonavir 100 mg

AUC: ↑ 7.2-fold

co-administer Kaletra and

BID)

Cmax: ↑ 4.7-fold

simeprevir.

 

Cmin: ↑ 14.4-fold

 

Telaprevir 750 mg

Telaprevir:

It is not recommended to

three times daily

AUC: ↓ 54%

co-administer Kaletra and

 

Cmax: ↓ 53%

telaprevir.

 

Cmin: ↓ 52%

 

 

Lopinavir: ↔

 

Herbal products

St John’s wort

Lopinavir:

Herbal preparations containing St

(Hypericum perforatum)

Concentrations may be reduced

John’s wort must not be combined

 

due to induction of CYP3A by the

with lopinavir and ritonavir. If a

 

herbal preparation St John’s wort.

patient is already taking St John’s

 

 

wort, stop St John’s wort and if

 

 

possible check viral levels.

 

 

Lopinavir and ritonavir levels may

 

 

increase on stopping St John’s wort.

 

 

The dose of Kaletra may need

 

 

adjusting. The inducing effect may

 

 

persist for at least 2 weeks after

 

 

cessation of treatment with St

 

 

John’s wort (see section 4.3).

 

 

Therefore, Kaletra can be started

 

 

safely 2 weeks after cessation of St

 

 

John's wort.

Immunosuppressants

 

 

Cyclosporin, Sirolimus

Cyclosporin, Sirolimus

More frequent therapeutic

(rapamycin), and

(rapamycin), Tacrolimus:

concentration monitoring is

Tacrolimus

Concentrations may be increased

recommended until plasma levels of

 

due to CYP3A inhibition by

these products have been stabilised.

 

Kaletra.

 

Lipid lowering agents

 

 

Lovastatin and

Lovastatin, Simvastatin:

Since increased concentrations of

Simvastatin

Markedly increased plasma

HMG-CoA reductase inhibitors

 

concentrations due to CYP3A

may cause myopathy, including

 

inhibition by Kaletra.

rhabdomyolysis, the combination of

 

 

these agents with Kaletra is

 

 

contraindicated (see section 4.3).

Atorvastatin

Atorvastatin:

The combination of Kaletra with

 

AUC: ↑ 5.9-fold

atorvastatin is not recommended. If

 

Cmax: ↑ 4.7-fold

the use of atorvastatin is considered

 

Due to CYP3A inhibition by

strictly necessary, the lowest

 

Kaletra.

possible dose of atorvastatin should

 

 

be administered with careful safety

 

 

monitoring (see section 4.4).

Rosuvastatin, 20 mg QD

Rosuvastatin:

Caution should be exercised and

 

AUC: ↑ 2-fold

reduced doses should be considered

 

Cmax: ↑ 5-fold

when Kaletra is co-administered

 

While rosuvastatin is poorly

with rosuvastatin (see section 4.4).

 

metabolised by CYP3A4, an

 

 

increase of its plasma

 

 

concentrations was observed.

 

 

The mechanism of this interaction

 

 

may result from inhibition of

 

 

transport proteins.

 

Fluvastatin or

Fluvastatin, Pravastatin:

If treatment with an HMG-CoA

Pravastatin

No clinical relevant interaction

reductase inhibitor is indicated,

 

expected.

fluvastatin or pravastatin is

 

Pravastatin is not metabolised by

recommended.

 

CYP450.

 

 

Fluvastatin is partially

 

 

metabolised by CYP2C9.

 

Opioids

Buprenorphine, 16 mg

Buprenorphine: ↔

No dose adjustment necessary.

QD

 

 

Methadone

Methadone: ↓

Monitoring plasma concentrations

 

 

of methadone is recommended.

Oral Contraceptives

 

 

Ethinyl Oestradiol

Ethinyl Oestradiol: ↓

In case of co-administration of

 

 

Kaletra with contraceptives

 

 

containing ethinyl oestradiol

 

 

(whatever the contraceptive

 

 

formulation e.g. oral or patch),

 

 

additional methods of contraception

 

 

must be used.

Smoking cessation aids

 

 

Bupropion

Buproprion and its active

If the co-administration of

 

metabolite, hydroxybupropion:

lopinavir/ritonavir with bupropion

 

AUC and Cmax ↓ ~50%

is judged unavoidable, this should

 

 

be done under close clinical

 

This effect may be due to

monitoring for bupropion efficacy,

 

induction of bupropion

without exceeding the

 

metabolism.

recommended dosage, despite the

 

 

observed induction.

Vasodilating agents

 

 

Bosentan

Lopinavir - ritonavir:

Caution should be exercised in

 

Lopinavir/ritonavir plasma

administering Kaletra with

 

concentrations may decrease due

bosentan.

 

to CYP3A4 induction by

When Kaletra is administered

 

bosentan.

concomitantly with bosentan, the

 

 

efficacy of the HIV therapy should

 

Bosentan:

be monitored and patients should be

 

AUC: ↑ 5-fold

closely observed for bosentan

 

Cmax: ↑ 6-fold

toxicity, especially during the first

 

Initially, bosentan Cmin: ↑ by

week of co-administration.

 

approximately 48-fold.

 

 

Due to CYP3A4 inhibition by

 

 

lopinavir/ritonavir.

 

Riociguat

Serum concentrations may be

The coadministration of riociguat

 

increased due to CYP3A and

with Kaletra is not recommended

 

P-gp inhibition by Kaletra.

(see section 4.4 and refer to

 

 

riociguat SmPC).

Other medicinal products

Based on known metabolic profiles, clinically significant interactions are not expected between

Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

4.6 Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed.

Breastfeeding

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that mothers infected by HIV do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.

Fertility

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).

4.8 Undesirable effects

a. Summary of the safety profile

The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, of which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may be greater with once-daily dosing of Kaletra. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.

It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4).

b. Tabulated list of adverse reactions

Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:

The following events have been identified as adverse reactions. The frequency category includes all reported events of moderate to severe intensity, regardless of the individual causality assessment. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥ 1/10), common (≥ 1/100

to < 1/10), uncommon (≥ 1/1000 to < 1/100) and not known (cannot be estimated from the available data).

Events noted as having frequency “Not known” were identified via post-marketing surveillance.

Undesirable effects in clinical studies and post-marketing in adult patients

System organ class

Frequency

Adverse reaction

 

 

 

Infections and infestations

Very common

Upper respiratory tract infection

 

Common

Lower respiratory tract infection, skin infections

 

 

including cellulitis, folliculitis and furuncle

Blood and lymphatic system

Common

Anaemia, leucopenia, neutropenia,

disorders

 

lymphadenopathy

Immune system disorders

Common

Hypersensitivity including urticaria and

 

 

angioedema

 

Uncommon

Immune reconstitution inflammatory syndrome

Endocrine disorders

Uncommon

Hypogonadism

Metabolism and nutrition

Common

Blood glucose disorders including diabetes

disorders

 

mellitus, hypertriglyceridaemia,

 

 

hypercholesterolemia, weight decreased,

 

 

decreased appetite

 

Uncommon

Weight increased, increased appetite

Psychiatric disorders

Common

Anxiety

 

Uncommon

Abnormal dreams, libido decreased

Nervous system disorders

Common

Headache (including migraine), neuropathy

 

 

(including peripheral neuropathy), dizziness,

 

 

insomnia

 

Uncommon

Cerebrovascular accident, convulsion,

 

 

dysgeusia, ageusia, tremor

Eye disorders

Uncommon

Visual impairment

Ear and labyrinth disorders

Uncommon

Tinnitus, vertigo

Cardiac disorders

Uncommon

Atherosclerosis such as myocardial infarction,

 

 

atrioventricular block, tricuspid valve

 

 

incompetence

Vascular disorders

Common

Hypertension

 

Uncommon

Deep vein thrombosis

Gastrointestinal disorders

Very common

Diarrhoea, nausea

 

Common

Pancreatitis1, vomiting, gastrooesophageal

 

 

reflux disease, gastroenteritis and colitis,

 

 

abdominal pain (upper and lower), abdominal

 

 

distension, dyspepsia, haemorrhoids, flatulence

 

Uncommon

Gastrointestinal haemorrhage including

 

 

gastrointestinal ulcer, duodenitis, gastritis and

 

 

rectal haemorrhage, stomatitis and oral ulcers,

 

 

faecal incontinence, constipation, dry mouth

Hepatobiliary disorders

Common

Hepatitis including AST, ALT and GGT

 

 

increases

 

Uncommon

Hepatic steatosis, hepatomegaly, cholangitis,

 

 

hyperbilirubinemia

 

Not known

Jaundice

Skin and subcutaneous tissue

Common

Rash including maculopapular rash,

disorders

 

dermatitis/rash including eczema and seborrheic

 

 

dermatitis, night sweats, pruritus

 

Uncommon

Alopecia, capillaritis, vasculitis

 

Not known

Stevens-Johnson syndrome, erythema

 

 

multiforme

Musculoskeletal and connective

Common

Myalgia, musculoskeletal pain including

tissue disorders

 

arthralgia and back pain, muscle disorders such

 

 

as weakness and spasms

 

Uncommon

Rhabdomyolysis, osteonecrosis

Renal and urinary disorders

Uncommon

Creatinine clearance decreased, nephritis,

 

 

haematuria

Reproductive system and breast

Common

Erectile dysfunction, menstrual disorders -

disorders

 

amenorrhoea, menorrhagia

General disorders and

Common

Fatigue including asthenia

administration site conditions

 

 

1 See section 4.4: pancreatitis and lipids

c. Description of selected adverse reactions

Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

d. Paediatric populations

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see Table in section b).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

To date, there is limited human experience of acute overdose with Kaletra.

The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.

There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, combinations, ATC code: J05AR10

Mechanism of action

Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Effects on the electrocardiogram

QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once-daily or twice-daily LPV/r doses at steady state. No subject experienced an

increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose. Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4).

Antiviral activity in vitro

The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir against

HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.

Resistance

In vitro selection of resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Analysis of resistance in ARV-naïve patientsIn clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has not been observed in naïve patients without significant protease inhibitor resistance at baseline. See further the detailed description of the clinical studies.

Analysis of resistance in PI-experienced patients

The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from patients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Antiviral activity of Kaletra in patients failing protease inhibitor therapy

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma

HIV RNA ≤ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold, 10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively. In

addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz,

particularly in patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of patients not receiving Kaletra.

Cross-resistance

Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor- experienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.

Clinical results

The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of 48 to 360 weeks duration.

Adult Use

Patients without prior antiretroviral therapy

Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm3 (range: 2 to

949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml).

Table 1

Outcomes at Week 48: Study M98-863

 

Kaletra (N=326)

Nelfinavir (N=327)

HIV RNA < 400 copies/ml*

75%

63%

HIV RNA < 50 copies/ml*†

67%

52%

Mean increase from baseline in

CD4+ T-cell count (cells/mm3)

 

 

* intent to treat analysis where patients with missing values are considered virologic failures

† p < 0.001

One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack of resistance to lopinavir was confirmed by phenotypic analysis.

Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Given the pharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this study might not be strictly extrapolable when other backbone regimens are used with Kaletra. Patients were randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 400/100 mg twice daily (n = 331). Further stratification within each group was 1:1 (tablet versus soft capsule). Patients were administered either the tablet or the soft capsule formulation for 8 weeks, after which all patients were administered the tablet formulation once daily or twice daily for the remainder of the study. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Protocol defined non-inferiority of once-daily dosing compared with twice-daily dosing was demonstrated if the lower bound of the 95% confidence interval for the difference in proportion of subjects responding (once daily minus twice daily) excluded -12% at Week 48. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to 7.0 log10 copies/ml).

Table 2

Virologic Response of Study Subjects at Week 48 and Week 96

 

 

Week 48

 

 

Week 96

 

 

QD

BID

 

Difference

QD

BID

 

Difference

 

 

 

 

[95% CI]

 

 

 

[95% CI]

NC= Failure

257/333

251/331

 

1.3 %

216/333

229/331

 

-4.3%

 

(77.2%)

(75.8%)

 

[-5.1, 7.8]

(64.9%)

(69.2%)

 

[-11.5, 2.8]

Observed data

257/295

250/280

 

-2.2%

216/247

229/248

 

-4.9%

 

(87.1%)

(89.3%)

 

[-7.4, 3.1]

(87.4%)

(92.3%)

 

[-10.2, 0.4]

Mean increase from

 

 

 

 

baseline in CD4+ T-cell

 

 

 

 

 

 

 

 

count (cells/mm3)

 

 

 

 

 

 

 

 

Through Week 96, genotypic resistance testing results were available from 25 patients in the QD group and 26 patients in the BID group who had incomplete virologic response. In the QD group, no patient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease inhibitor resistance at baseline demonstrated additional lopinavir resistance on study.

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one patients completed the study (35 patients received the recommended 400/100 mg twice-daily dose throughout the study).

Table 3

Outcomes at Week 360: Study M97-720

 

Kaletra (N=100)

HIV RNA < 400 copies/ml

61%

HIV RNA < 50 copies/ml

59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3)

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance

Patients with prior antiretroviral therapy

M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of once-daily and twice-daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Patients had not been on prior lopinavir/ritonavir therapy. They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. The enrolled population was moderately PI-experienced with more than half of patients having never received prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% were male. Mean baseline CD4+ T-cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/ml (range: 1.7 to 6.6 log10 copies/ml). Around 85% of patients had a viral load of < 100,000 copies/ml.

Table 4

Virologic Response of Study Subjects at Week 48 Study 802

 

QD

BID

Difference

 

 

 

[95% CI]

NC= Failure

171/300

161/299

3.2%

 

(57%)

(53.8%)

[-4.8%, 11.1%]

 

 

 

 

Observed data

171/225

161/223

3.8%

 

(76.0%)

(72.2%)

[-4.3%, 11.9%]

Mean increase from baseline in

 

CD4+ T-cell count (cells/mm3)

 

 

 

Through Week 48, genotypic resistance testing results were available from 75 patients in the QD group and 75 patients in the BID group who had incomplete virologic response. In the QD group, 6/75 (8%) patients demonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 84, 90), as did 12/77 (16%) patients in the BID group.

Paediatric Use

M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or

300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptase inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m2

dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml.

Table 5

Outcomes at Week 48: Study M98-940

 

Antiretroviral Naïve

Antiretroviral

 

(N=44)

Experienced (N=56)

HIV RNA < 400 copies/ml

84%

75%

Mean increase from baseline in

CD4+ T-cell count (cells/mm3)

 

 

KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated the pharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing of lopinavir/ritonavir 100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged <18 years, ≥15 kg in weight, receiving cART that included lopinavir/ritonavir, HIV-1 ribonucleic acid (RNA) <50 copies/ml for at least 24 weeks and able to swallow tablets. At week 48, the efficacy and safety with twice-daily dosing (n=87) in the paediatric population given lopinavir/ritonavir 100 mg/25 mg tablets was consistent with the efficacy and safety findings in previous adult and paediatric studies using lopinavir/ritonavir twice daily. The percentage of patients with confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatric patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-daily dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group. The efficacy data favouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameters significantly favouring the twice-daily regimen (see section 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The

in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.

Absorption

Multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 ± 5.4 g/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7 g/ml. Lopinavir AUC over a 12 hour dosing interval averaged

113.2 ± 60.5 g•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.

Effects of food on oral absorption

Administration of a single 400/100 mg dose of Kaletra tablets under fed conditions (high fat, 872 kcal, 56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf. Therefore, Kaletra tablets may be taken with or without food. Kaletra tablets have also shown less pharmacokinetic variability under all meal conditions compared to Kaletra soft capsules.

Distribution

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients.

Biotransformation

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

Elimination

After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged

5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.

Once-daily dosing: the pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multiple dosing of 800/200 mg Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SD

lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 g/ml, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was

5.5 ± 5.4 g/ml. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 g•h/ml.

As compared to the BID regimen, the once-daily dosing is associated with a reduction in the Cmin/Ctrough values of approximately 50%.

Special Populations

Paediatrics

There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of Kaletra 100/25 mg tablet twice-daily weight-band dosing without nevirapine have been studied in a total of 53 paediatric patients. The lopinavir mean ± standard deviation steady-state AUC, Cmax and

C12 were 112.5 ± 37.1 μg•h/ml, 12.4 ± 3.5 μg/ml and 5.71 ± 2.99 μg/ml, respectively. The twice-daily weight-band dosing without nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.

Gender, Race and Age

Kaletra pharmacokinetics have not been studied in older people. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified.

Pregnancy and postpartum

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 weeks of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 mg/100 mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age of gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) twice daily until subjects were 2 weeks postpartum. Plasma concentrations of lopinavir were measured over four 12-hour periods during second trimester (20-24 weeks gestation), third trimester before dose increase (30 weeks gestation), third trimester after dose increase (32 weeks gestation), and at 8 weeks post-partum. The dose increase did not result in a significant increase in the plasma lopinavir concentration.

In another open-label pharmacokinetic study, 19 HIV-infected pregnant women received lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy during pregnancy from before conception. A series of blood samples were collected pre-dose and at intervals over the course of 12 hours in trimester 2 and trimester 3, at birth, and 4–6 weeks postpartum (in women who continued treatment post-delivery) for pharmacokinetic analysis of total and unbound levels of plasma lopinavir concentrations.

The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets 400/100 mg twice daily are presented in Table 6 (see section 4.2).

Table 6

Mean (%CV) Steady-State Pharmacokinetic Parameters of Lopinavir

in HIV-Infected Pregnant Women

Pharmacokinetic

 

2nd Trimester

3rd Trimester

Postpartum

Parameter

 

n = 17*

n = 23

n = 17**

AUC0-12 μghr/mL

 

68.7 (20.6)

61.3 (22.7)

94.3 (30.3)

Cmax

 

7.9 (21.1)

7.5 (18.7)

9.8 (24.3)

Cpredose μg /mL

 

4.7 (25.2)

4.3 (39.0)

6.5 (40.4)

* n = 18 for Cmax

** n

= 16 for Cpredose

 

 

Renal Insufficiency

Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Insufficiency

The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).

5.3 Preclinical safety data

Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice.

During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.

In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance.

The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8).

In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights, increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans.

Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk.

Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet contents:

Copovidone

Sorbitan laurate

Colloidal anhydrous silica

Sodium stearyl fumarate

Film-coating:

Polyvinyl alcohol

Titanium dioxide

Talc

Macrogols type 3350 (Polyethylene glycol 3350)

Yellow ferric oxide E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottles closed with propylene caps.

Bottle containing 60 film-coated tablets.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

AbbVie Ltd

Maidenhead

SL6 4UB

United Kingdom

8. MARKETING AUTHORISATION NUMBERS

EU/1/01/172/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 March 2001

Date of latest renewal: 20 March 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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