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Aptivus (tipranavir) – Summary of product characteristics - J05AE09

Updated on site: 05-Oct-2017

Medication nameAptivus
ATC CodeJ05AE09
Substancetipranavir
ManufacturerBoehringer Ingelheim International GmbH

1.NAME OF THE MEDICINAL PRODUCT

Aptivus 250 mg soft capsules

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 250 mg tipranavir.

Excipients with known effect: Each soft capsule contains

100.0 mg ethanol, 455.0 mg macrogolglycerol ricinoleate and 12.6 mg sorbitol

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Soft capsule.

Pink, oblong soft gelatin capsules imprinted with “TPV 250” in black.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Aptivus, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated adults and adolescents 12 years of age or older with virus resistant to multiple protease inhibitors. Aptivus should only be used as part of an active combination antiretroviral regimen in patients with no other therapeutic options.

In deciding to initiate treatment with Aptivus, co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of Aptivus. Initiation of treatment should take into account the combinations of mutations which may negatively impact the virological response to Aptivus, co- administered with low dose ritonavir (see section 5.1).

4.2Posology and method of administration

Aptivus must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with Aptivus (especially as regards the contraindications, warnings and undesirable effects sections).

Aptivus should be prescribed by physicians who are experienced in the treatment of HIV-1 infection.

Posology

Adults and adolescents (from 12 – 18 years of age)

The recommended dose of Aptivus is 500 mg, co-administered with 200 mg ritonavir (low dose ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).

Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy profile of the combination.

Since currently only limited efficacy and safety data are available for adolescents (see section 5.1) close monitoring of virologic response and tolerance is particularly warranted in this patient group.

Missed dose

Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of Aptivus and ritonavir at the regularly scheduled time.

Elderly

Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see section 5.2).

In general, caution should be exercised in the administration and monitoring of Aptivus in older people reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy (see section 4.4).

Liver impairment

Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase of tipranavir exposure and a worsening of its safety profile. Therefore, Aptivus should be used with caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child- Pugh Class A). Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment

No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Aptivus capsules in children aged 2 to 12 years has not been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Also, appropriate dose adjustments for children under 12 years cannot be achieved with Aptivus capsules. Aptivus oral solution is available for children between 2 and 12 years of age (please refer to the respective SmPC for further details).

The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data are available.

Method of administration Oral use.

Aptivus soft capsules co-administered with low dose ritonavir should be taken with food (see section 5.2).

4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with moderate or severe (Child-Pugh B or C) hepatic impairment.

Combination of rifampicin with Aptivus with concomitant low dose ritonavir is contraindicated (see section 4.5).

Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These active substances include antiarrhythmics (such as amiodarone, bepridil, quinidine), antihistamines (such as astemizole, terfenadine), ergot derivatives (such as

dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (such as cisapride), antipsychotics (such as pimozide, sertindole, quetiapine), sedatives/hypnotics (such as orally administered midazolam and triazolam) and HMG-CoA reductase inhibitors (such as simvastatin and lovastatin) (see section 4.5). Also the use of the alpha-1 adrenoceptor antagonist alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. In addition, co-administration of Aptivus with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure (see section 4.5).

Co-administration of colchicine with Aptivus/ritonavir in patients with renal or hepatic impairment (see section 4.5).

4.4Special warnings and precautions for use

Aptivus must be administered with low dose ritonavir to ensure its therapeutic effect (see section 4.2). Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly.

Aptivus is not a cure for HIV-1 infection or AIDS. Patients receiving Aptivus or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

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.

Switching from Aptivus capsules to the oral solution

Aptivus capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution. Also, the composition of the oral solution is different from that of the capsules, with the high vitamin E content being especially noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore patients should not be switched from Aptivus capsules to Aptivus oral solution (see sections 5.1 and 5.2).

Switching from Aptivus oral solution to the capsules

Aptivus oral solution is not interchangeable with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the same dose as capsules. However, children previously treated with Aptivus oral solution and becoming 12 years of age should be switched to capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule formulation of Aptivus could be associated with decreased exposure. Therefore, it is recommended that patients switching from Aptivus oral solution to capsules at the age of 12 years are closely monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).

Liver disease

Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic insufficiency. Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. 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 reaction. Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination therapy and should be monitored according to standard practice. Aptivus with ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease.

Aptivus co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised when administering Aptivus to patients with liver enzyme abnormalities or with a history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.

Aptivus therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN, unless the potential benefit justifies the potential risk.

Aptivus therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then rechallenge with Aptivus may be considered when ASAT/ALAT have returned to the patient’s baseline levels.

Liver monitoring

Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when Aptivus and low dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic impairment, chronic hepatitis B or C, or other underlying liver disease.

Treatment-naïve patients

In a study performed in antiretroviral naïve adult patients, tipranavir 500 mg with ritonavir 200 mg twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend towards a lower efficacy). The study was prematurely stopped after 60 weeks.

Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients (see section 4.2).

Renal impairment

Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected in patients with renal impairment.

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 has been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Bleeding

RESIST participants receiving Aptivus with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving Aptivus, many of whom had other medical conditions or were receiving concomitant medicinal products that

may have caused or contributed to these events. However, in some cases the role of Aptivus cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the Aptivus clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving Aptivus with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3).

Aptivus, co-administered with low dose ritonavir, should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medicinal products known to increase the risk of bleeding such as antiplatelet agents and anticoagulants or who are taking supplemental vitamin E. Based on the limits of exposure available from observation in clinical trials, it is recommended not to co-administer to patients more than 1,200 IU vitamin E per day.

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. A higher increase of blood lipids were seen with tipranavir/ritonavir than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic 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 pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with Aptivus, co-administered with low dose ritonavir.

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

Rash

Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been reported in subjects receiving Aptivus, co-administered with low dose ritonavir. At 48-weeks in Phase III trials, rash of various types was observed in 15.5% males and 20.5% females receiving Aptivus co- administered with low dose ritonavir. Additionally, in one interaction trial, in healthy female volunteers administered a single dose of ethinyl oestradiol followed by Aptivus co-administered with low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving Aptivus co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.

Osteonecrosis

Although the aetiology 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.

Interactions

The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. The mechanisms and potential mechanisms contributing to the interaction profile of tipranavir are described (see section 4.5).

Abacavir and zidovudine

The concomitant use of Aptivus, co-administered with low dose ritonavir, with zidovudine or abacavir, results in a significant decrease in plasma concentration of these nucleoside reverse transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or abacavir with Aptivus, co-administered with low dose ritonavir, is not-recommended unless there are no other available NRTIs suitable for patient management (see section 4.5).

Protease inhibitors

Concomitant use of Aptivus, co-administered with low dose ritonavir, with the protease inhibitors amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir) in a dual-boosted regimen, results in significant decreases in plasma concentrations of these protease inhibitors. A significant decrease in plasma concentrations of atazanavir and a marked increase of tipranavir and ritonavir concentrations was observed when Aptivus, associated with low dose ritonavir, was co- administered with atazanavir (see section 4.5). No data are currently available on interactions of tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than those listed above. Therefore, the co-administration of tipranavir, co-administered with low dose ritonavir, with protease inhibitors is not recommended.

Oral contraceptives and oestrogens

Since levels of ethinyl oestradiol are decreased, the co-administration of Aptivus co-administered with low dose ritonavir is not recommended. Alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-administered with Aptivus co-administered with low dose ritonavir (see section 4.5). Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency. Women using oestrogens may have an increased risk of non serious rash.

Anticonvulsants

Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Aptivus may be less effective due to decreased tipranavir plasma concentrations in patients taking these agents concomitantly.

Halofantrine, lumefantrine

Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of halofantrine and lumefantrine with Aptivus co-administered with low dose ritonavir, is not recommended.

Disulfiram/metronidazole

Aptivus soft capsules contain alcohol (7% ethanol, ie 100 mg per capsule or up to 200 mg per dose) which can produce disulfiram-like reactions when co-administered with disulfiram or other medicinal products which produce this reaction (e.g. metronidazole).

Fluticasone

Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone or other glucocorticoids that are metabolised by CYP3A4 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).

Atorvastatin

Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations of atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5). However, if atorvastatin is specifically required for patient management, it should be started with the lowest dose and careful monitoring is necessary.

Omeprazole and other proton pump inhibitors

The combined use of Aptivus with ritonavir with either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended (see section 4.5).

Colchicine

In patients with normal renal and hepatic function, a reduction in colchicine dosage or an interruption of colchicine treatment is recommended in co-administration (see section 4.5).

Salmeterol

Concomitant use of salmeterol and Aptivus, co-administered with low dose ritonavir, is not recommended (see section 4.5).

Bosentan

Due to the marked hepatotoxicity of bosentan and the potential for increasing the liver toxicity associated with Aptivus, co-administered with low dose ritonavir, this combination is not recommended.

Warnings related to certain excipients

Due to Aptivus containing small amounts of sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.

Aptivus contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.

This medicinal product contains 7 vol % ethanol (alcohol), i.e. up to 400 mg per daily dose, equivalent to 8 ml of beer, or less than 4 ml of wine. Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

4.5Interaction with other medicinal products and other forms of interaction

The interaction profile of Aptivus, co-administered with low dose ritonavir, is complex and requires special attention in particular in combination with other antiretroviral agents.

Interaction studies have only been performed in adults.

Metabolic profile of tipranavir

Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co- administered with ritonavir at the recommended dosage (see section 4.2) there is a net inhibition of P450 CYP3A. Co-administration of Aptivus and low dose ritonavir with agents primarily metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could alter their therapeutic and undesirable effects (see list and details of considered agents, below). Agents that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse reactions are detailed in this section, and listed in section 4.3.

A cocktail study was conducted in 16 healthy volunteers with twice-daily 500 mg tipranavir with 200 mg ritonavir capsule administration for 10 days to assess the net effect on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4 (midazolam) and P-glycoprotein (P-gp) (digoxin). At steady state, there was a significant induction of CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and

intestinal CYP 3A4 activities were observed. P-gp activity is significantly inhibited after the first dose,

but there was a slight induction at steady state. Practical recommendations deriving from this study are displayed below.

Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition, because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of tipranavir with ritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of treatment. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases.

In vitro studies show that tipranavir is a substrate and also an inhibitor of P-gp.

It is difficult to predict the net effect of Aptivus co-administered with low dose ritonavir on oral bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.

Co-administration of Aptivus and agents that induce CYP3A and/or P-gp may decrease tipranavir concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co- administration of Aptivus and medicinal products that inhibit P-gp may increase tipranavir plasma concentrations.

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

Interaction table

Interactions between Aptivus 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”).

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of Aptivus/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with this recommended dosage. Nevertheless, the results of many of these interaction studies can be extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r

750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the recommended dosage of Aptivus/r.

Drugs by therapeutic area

Interaction

Recommendations concerning

 

Geometric mean change (%)

co-administration

 

 

 

Anti-infectives

Antiretrovirals

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no dosage adjustment of Aptivus is required when co-administered with these agents.

Abacavir 300 mg BID

Abacavir Cmax ↓ 46%

The concomitant use of Aptivus, co-

(TPV/r 750/100 mg BID)

Abacavir AUC ↓ 36%

administered with low dose

 

 

ritonavir, with abacavir is not

 

The clinical relevance of this

recommended unless there are no

 

reduction has not been

other available NRTIs suitable for

 

established, but may decrease the

patient management. In such cases

 

efficacy of abacavir.

no dosage adjustment of abacavir

 

 

can be recommended (see section

 

Mechanism unknown.

4.4).

Didanosine 200 mg BID, ≥

Didanosine Cmax ↓ 43%

Dosing of enteric-coated didanosine

60 kg - 125 mg BID, < 60 kg

Didanosine AUC ↓ 33%

and Aptivus soft capsules, co-

(TPV/r 250/200 mg BID)

 

administered with low dose

 

 

 

ritonavir, should be separated by at

(TPV/r 750/100 mg BID)

Didanosine Cmax ↓ 24%

least 2 hours to avoid formulation

 

 

Didanosine AUC ↔

incompatibility.

 

 

The clinical relevance of this

 

 

 

reduction in didanosine

 

 

 

concentrations has not been

 

 

 

established.

 

 

 

Mechanism unknown.

 

Emtricitabine

Potential interactions with renal

No dosage adjustment necessary in

No interaction study

transporters cannot be fully

patients with normal renal function.

performed

excluded.

In case of concomitant

 

 

 

administration of emtricitabine and

 

 

 

Aptivus/ritonavir, renal function

 

 

 

should be evaluated before initiating

 

 

 

the co-administration.

Lamivudine 150 mg BID

No clinically significant

No dosage adjustment necessary.

(TPV/r 750/100 mg BID)

interaction is observed.

 

Stavudine

No clinically significant

No dosage adjustment necessary.

40 mg BID > 60 kg

interaction is observed.

 

30 mg BID < 60 kg

 

 

(TPV/r 750/100 mg BID)

 

 

Zidovudine 300 mg BID

Zidovudine Cmax ↓ 49%

The concomitant use of Aptivus, co-

(TPV/r 750/100 mg BID)

Zidovudine AUC ↓ 36%

administered with low dose

 

 

 

ritonavir with zidovudine is not

 

 

The clinical relevance of this

recommended unless there are no

 

 

reduction has not been

other available NRTIs suitable for

 

 

established, but may decrease the

patient management. In such cases

 

 

efficacy of zidovudine.

no dosage adjustment of zidovudine

 

 

 

can be recommended (see section

 

 

Mechanism unknown.

4.4).

Tenofovir 300 mg QD

No clinically significant

No dosage adjustment necessary.

(TPV/r 750/200 mg BID)

interaction is observed.

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

Efavirenz 600 mg QD

 

No clinically significant interaction

No dosage adjustment necessary.

 

 

is observed.

 

Etravirine

 

Etravirine Cmax ↓ 71%

Co-administration of etravirine and

 

 

Etravirine AUC ↓ 76%

Aptivus/ritonavir is not

 

 

Etravirine Cmin ↓ 82%

recommended.

 

 

Concomitant use of

 

 

 

Aptivus/ritonavir caused a decrease

 

 

 

of etravirine exposure that could

 

 

 

significantly impair the virologic

 

 

 

response to etravirine.

 

Nevirapine

 

The limited data available from a

No dosage adjustment necessary.

No interaction study

 

phase IIa study in HIV-infected

 

performed

 

patients suggest that no significant

 

 

 

interaction is expected between

 

 

 

nevirapine and TPV/r. Moreover a

 

 

 

study with TPV/r and another

 

 

 

NNRTI (efavirenz) did not show

 

 

 

any clinically relevant interaction

 

 

 

(see above).

 

Rilpivirine

Concomitant use of rilpivirine with

Close monitoring for signs of

No interaction study

some ritonavir-boosted protease

rilpivirine toxicity and possibly also

performed

inhibitors has demonstrated an

dose adjustment of rilpivirine is

 

increase in the plasma

recommended when co-

 

concentrations of rilpivirine.

administered with Aptivus/ritonavir.

Protease inhibitors (PIs)

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

Amprenavir/ritonavir

Amprenavir Cmax ↓ 39%

The concomitant use of Aptivus, co-

600/100 mg BID

Amprenavir AUC ↓ 44%

administered with low dose

 

Amprenavir Cmin ↓ 55%

ritonavir, with amprenavir/ritonavir

 

 

is not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in amprenavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of amprenavir

 

established.

is strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Atazanavir/ritonavir

Atazanavir Cmax ↓ 57%

The concomitant use of Aptivus, co-

300/100 mg QD

Atazanavir AUC ↓ 68%

administered with low dose

(TPV/r 500/100 mg BID)

Atazanavir Cmin ↓ 81%

ritonavir, with atazanavir/ritonavir

 

 

is not recommended.

 

Mechanism unknown.

If the co-administration is

 

Tipranavir Cmax 8%

nevertheless considered necessary, a

 

close monitoring of the safety of

 

Tipranavir AUC 20%

tipranavir and a monitoring of

 

Tipranavir Cmin 75%

plasma concentrations of atazanavir

 

 

are strongly encouraged (see section

 

Inhibition of CYP 3A4 by

4.4).

 

atazanavir/ritonavir and induction

 

 

by tipranavir/r.

 

Lopinavir/ritonavir

Lopinavir Cmax ↓ 47%

The concomitant use of Aptivus, co-

400/100 mg BID

Lopinavir AUC ↓ 55%

administered with low dose

 

Lopinavir Cmin ↓ 70%

ritonavir, with lopinavir/ritonavir is

 

 

not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in lopinavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of lopinavir is

 

established.

strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Saquinavir/ritonavir

Saquinavir Cmax ↓ 70%

The concomitant use of Aptivus, co-

600/100 mg QD

Saquinavir AUC ↓ 76%

administered with low dose

 

Saquinavir Cmin ↓ 82%

ritonavir, with saquinavir/ritonavir

 

 

is not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in saquinavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of saquinavir is

 

established.

strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Protease inhibitors other

No data are currently available on

Combination with Aptivus, co-

than those listed above

interactions of tipranavir, co-

administered with low dose

 

administered with low dose

ritonavir, is not recommended (see

 

ritonavir, with protease inhibitors

section 4.4)

 

other than those listed above.

 

Fusion inhibitors

Enfuvirtide

In studies where tipranavir co-

The clinical impact of the observed

No interaction study

administered with low-dose

data, especially regarding the

performed

ritonavir was used with or without

tipranavir with ritonavir safety

 

enfuvirtide, it has been observed

profile, remains unknown.

 

that the steady-state plasma

Nevertheless, the clinical data

 

tipranavir trough concentration of

available from the RESIST trials did

 

patients receiving enfuvirtide were

not suggest any significant

 

45% higher as compared to patients

alteration of the tipranavir with

 

not receiving enfuvirtide. No

ritonavir safety profile when

 

information is available for the

combined with enfuvirtide as

 

parameters AUC and Cmax.

compared to patients treated with

 

A pharmacokinetic interaction is

tipranavir with ritonavir without

 

mechanistically unexpected and the

enfuvirtide.

 

interaction has not been confirmed

 

 

in a controlled interaction study.

 

Integrase strand transfer inhibitors

 

Raltegravir 400 mg BID

Raltegravir Cmax

No particular dose adjustment is

 

Raltegravir AUC 0-12↔

recommended.

 

Raltegravir C12: ↓ 45%

 

 

Despite an almost half reduction of

 

 

C12, previous clinical studies with

 

 

this combination did not evidence

 

 

an impaired outcome.

 

 

The mechanism of action is thought

 

 

to be induction of

 

 

glucuronosyltransferase by

 

 

tipranavir/r.

 

Pharmacokinetic enhancer

 

 

Cobicistat and cobicistat-

When co-administered, tipranavir

Aptivus/ritonavir should not be

containing products

and cobicistat exposures are

administered concomitantly with

 

markedly lower compared to that of

cobicistat or cobicistat-containing

 

tipranavir when boosted with low

products.

 

dose ritonavir.

 

Anti-HCV agents

 

 

Boceprevir

In a pharmacokinetic study of

Coadministration of boceprevir

No interaction study

healthy volunteers, boceprevir

with Aptivus/ritonavir is not

performed

decreased the exposure of ritonavir,

recommended.

 

and some ritonavir-boosted protease

 

 

inhibitors. Boceprevir exposure was

 

 

reduced when co-administered with

 

 

ritonavir-boosted lopinavir or

 

 

ritonavir-boosted darunavir. These

 

 

drug-drug interactions may reduce

 

 

the effectiveness of HIV protease

 

 

inhibitors and/or boceprevir when

 

 

co-administered.

 

Telaprevir

Telaprevir is metabolized in the

Coadministration of telaprevir with

No interaction study

liver by CYP3A and is a P-

Aptivus/ritonavir is not

performed

glycoprotein (P-gp) substrate, but

recommended.

 

other enzymes may be involved in

 

 

the metabolism. When

 

 

Aptivus/ritonavir is co-administered

 

 

with telaprevir, a decrease or an

 

 

increase of telaprevir exposure

 

could be expected. There is a heterogeneous effect of telaprevir on ritonavir-boosted protease inhibitor drug plasma levels, depending on the protease inhibitors. Therefore, a modification of Aptivus exposure cannot be ruled out.

Antifungals

Fluconazole 200 mg QD

Fluconazole ↔

No dosage adjustments are

(Day 1) then 100 mg QD

 

recommended. Fluconazole doses

 

Tipranavir Cmax ↑ 32%

200 mg/day are not recommended.

 

Tipranavir AUC ↑ 50%

 

 

Tipranavir Cmin ↑ 69%

 

 

Mechanism unknown

 

Itraconazole

Based on theoretical considerations

Itraconazole or ketoconazole should

Ketoconazole

tipranavir, co-administered with

be used with caution (doses

No interaction study

low dose ritonavir, is expected to

200 mg/day are not

performed

increase itraconazole or

recommended).

 

ketoconazole concentrations.

 

 

Based on theoretical considerations,

 

 

tipranavir or ritonavir

 

 

concentrations might increase upon

 

 

co-administration with itraconazole

 

 

or ketoconazole.

 

Voriconazole

Due to multiple CYP isoenzyme

Based on the known interaction of

No interaction study

systems involved in voriconazole

voriconazole with low dose

performed

metabolism, it is difficult to predict

ritonavir (see voriconazole SmPC)

 

the interaction with tipranavir, co-

the co-administration of tipranavir/r

 

administered with low-dose

and voriconazole should be

 

ritonavir.

avoided, unless an assessment of

 

 

the benefit/risk to the patient

 

 

justifies the use of voriconazole.

Anti-gouts

 

 

Colchicine

Based on theoretical considerations,

A reduction in colchicine dosage or

No interaction study

colchicine concentrations may

an interruption of colchicine

performed

increase upon co-administration

treatment is recommended in

 

with tipranavir and low dose

patients with normal renal or

 

ritonavir, due to tipranavir/ritonavir

hepatic function if treatment with

 

CYP3A and P-gp inhibition.

Aptivus/ritonavir is required (see

 

However a decrease of colchicine

section 4.4).

 

concentrations cannot be excluded

In patients with renal or hepatic

 

since both tipranavir and ritonavir

impairment, co-administration of

 

exhibit inducing potential towards

colchicine in patients on

 

CYP3A and P-gp.

Aptivus/ritonavir is contraindicated

 

Colchicine is a substrate of

(see section 4.3).

 

 

 

CYP3A4 and P-gp (an intestinal

 

 

efflux transporter).

 

Antibiotics

Clarithromycin 500 mg

Clarithromycin Cmax

Whilst the changes in

BID

Clarithromycin AUC ↑ 19%

clarithromycin parameters are not

 

Clarithromycin Cmin ↑ 68%

considered clinically relevant, the

 

 

reduction in the 14-OH metabolite

 

14-OH-clarithromycin Cmax ↓ 97%

AUC should be considered for the

 

14-OH-clarithromycin AUC ↓ 97%

treatment of infections caused by

 

14-OH-clarithromycin Cmin ↓ 95%

Haemophilus influenzae in which

 

 

the 14-OH metabolite is most

 

Tipranavir Cmax ↑ 40%

active. The increase of tipranavir

 

Tipranavir AUC ↑ 66%

Cmin may be clinically relevant.

 

Tipranavir Cmin ↑ 100%

Patients using clarithromycin at

 

 

doses higher than 500 mg twice

 

CYP 3A4 inhibition by tipranavir/r

daily should be carefully monitored

 

and P-gp (an intestinal efflux

for signs of toxicity of

 

transporter) inhibition by

clarithromycin and tipranavir. For

 

clarithromycin.

patients with renal impairment dose

 

 

reduction of clarithromycin should

 

 

be considered (see clarithromycin

 

 

and ritonavir product information).

Rifabutin 150 mg QD

Rifabutin Cmax ↑ 70%

Dosage reductions of rifabutin by at

 

Rifabutin AUC ↑ 190%

least 75% of the usual 300 mg/day

 

Rifabutin Cmin ↑ 114%

are recommended (ie 150 mg on

 

 

alternate days, or three times per

 

25-O-desacetylrifabutin Cmax ↑ 3.2

week). Patients receiving rifabutin

 

fold

with Aptivus, co-administered with

 

25-O-desacetylrifabutin AUC ↑ 21

low dose ritonavir, should be

 

fold

closely monitored for emergence of

 

25-O-desacetylrifabutin Cmin ↑ 7.8

adverse events associated with

 

fold

rifabutin therapy. Further dosage

 

Inhibition of CYP 3A4 by

reduction may be necessary.

 

 

 

tipranavir/r

 

 

No clinically significant change is

 

 

observed in tipranavir PK

 

 

parameters.

 

Rifampicin

Co-administration of protease

Concomitant use of Aptivus, co-

 

inhibitors with rifampicin

administered with low dose

 

substantially decreases protease

ritonavir, and rifampicin is

 

inhibitor concentrations. In the case

contraindicated (see section 4.3).

 

of tipranavir co-administered with

Alternate antimycobacterial agents

 

low dose ritonavir, concomitant use

such as rifabutin should be

 

with rifampicin is expected to result

considered.

 

in sub-optimal levels of tipranavir

 

 

which may lead to loss of virologic

 

 

response and possible resistance to

 

 

tipranavir.

 

Antimalarial

 

 

Halofantrine

Based on theoretical considerations,

Due to their metabolic profile and

Lumefantrine

tipranavir, co-administered with

inherent risk of inducing torsades

No interaction study

low dose ritonavir, is expected to

de pointes, administration of

performed

increase halofantrine and

halofantrine and lumefantrine with

 

lumefantrine concentrations.

Aptivus, co-administered with low

 

 

dose ritonavir, is not recommended

 

Inhibition of CYP 3A4 by

(see section 4.4).

 

tipranavir/r

 

Anticonvulsants

Carbamazepine 200 mg

Carbamazepine total* Cmax ↑ 13%

Carbamazepine should be used with

BID

Carbamazepine total* AUC ↑ 16%

caution in combination with

 

Carbamazepine total* Cmin ↑ 23%

Aptivus, co-administered with low

 

 

dose ritonavir. Higher doses of

 

*Carbamazepine total = total of

carbamazepine (> 200 mg) may

 

carbamazepine and epoxy-

result in even larger decreases in

 

carbamazepine (both are

tipranavir plasma concentrations

 

pharmacologically active moieties).

(see section 4.4).

 

The increase in carbamazepine total

 

 

PK parameters is not expected to

 

 

have clinical consequences.

 

 

Tipranavir Cmin ↓ 61% (compared to

 

 

historical data)

 

 

The decrease in tipranavir

 

 

concentrations may result in

 

 

decreased effectiveness.

 

 

Carbamazepine induces CYP3A4.

 

Phenobarbital

Phenobarbital and phenytoin induce

Phenobarbital and phenytoin should

Phenytoin

CYP3A4.

be used with caution in combination

No interaction study

 

with Aptivus, co-administered with

performed

 

low dose ritonavir (see section 4.4).

Antispasmodic

 

 

Tolterodine

Based on theoretical considerations,

Co-administration is not

No interaction study

tipranavir, co-administered with

recommended.

performed

low dose ritonavir, is expected to

 

 

increase tolterodine concentrations.

 

 

Inhibition of CYP 3A4 and CYP

 

 

2D6 by tipranavir/r

 

Endothelin receptor antagonists

 

Bosentan

Based on theoretical considerations,

Co-administration of bosentan and

 

bosentan concentrations may

Aptivus with low dose ritonavir is

 

increase upon co-administration

not recommended (see section 4.4).

 

with tipranavir and low dose

 

 

ritonavir.

 

 

Inhibition of CYP 3A4 by

 

 

tipranavir/r

 

HMG CoA reductase inhibitors

 

Atorvastatin 10 mg QD

Atorvastatin Cmax ↑ 8.6 fold

Co-administration of atorvastatin

 

Atorvastatin AUC ↑ 9.4 fold

and Aptivus, co-administered with

 

Atorvastatin Cmin ↑ 5.2 fold

low dose ritonavir, is not

 

 

recommended. Other HMG-CoA

 

Tipranavir ↔

reductase inhibitors should be

 

 

considered such as pravastatin,

 

Inhibition of CYP 3A4 by

fluvastatin or rosuvastatin (See also

 

tipranavir/r

section 4.4 and rosuvastatin and

 

 

pravastatin recommendations). In

 

 

cases where co-administration is

 

 

necessary, the dose of 10 mg

 

 

atorvastatin daily should not be

 

 

exceeded. It is recommended to

 

 

start with the lowest dose and

 

 

careful clinical monitoring is

 

 

necessary (see section 4.4).

Rosuvastatin 10 mg QD

Rosuvastatin Cmax ↑ 123%

Co-administration of Aptivus, co-

 

Rosuvastatin AUC ↑ 37%

administered with low dose

 

Rosuvastatin Cmin ↑ 6%

ritonavir, and rosuvastatin should

 

 

be initiated with the lowest dose

 

Tipranavir ↔

(5 mg/day) of rosuvastatin, titrated

 

 

to treatment response, and

 

Mechanism unknown.

accompanied with careful clinical

 

 

monitoring for rosuvastatin

 

 

associated symptoms as described

 

 

in the label of rosuvastatin.

Pravastatin

Based on similarities in the

Co-administration of Aptivus, co-

No interaction study

elimination between pravastatin and

administered with low dose

performed

rosuvastatin, TPV/r could increase

ritonavir, and pravastatin should be

 

the plasma levels of pravastatin.

initiated with the lowest dose

 

 

(10 mg/day) of pravastatin, titrated

 

Mechanism unknown.

to treatment response, and

 

 

accompanied with careful clinical

 

 

monitoring for pravastatin

 

 

associated symptoms as described

 

 

in the label of pravastatin.

 

 

 

Simvastatin

The HMG-CoA reductase inhibitors

The concomitant use of Aptivus,

Lovastatin

simvastatin and lovastatin are

co-administered with low dose

No interaction study

highly dependent on CYP3A for

ritonavir, with simvastatin or

performed

metabolism.

lovastatin are contra-indicated due

 

 

to an increased risk of myopathy,

 

 

including rhabdomyolysis (see

 

 

section 4.3).

HERBAL PRODUCTS

 

 

St. John’s wort (Hypericum

Plasma concentrations of tipranavir

Herbal preparations containing St.

perforatum)

can be reduced by concomitant use

John’s wort must not be combined

No interaction study

of the herbal preparation St John’s

with Aptivus, co-administered with

performed

wort (Hypericum perforatum). This

low dose ritonavir. Co-

 

is due to induction of drug

administration of Aptivus with

 

metabolising enzymes by St John’s

ritonavir, with St. John’s wort is

 

wort.

expected to substantially decrease

 

 

tipranavir and ritonavir

 

 

concentrations and may result in

 

 

sub-optimal levels of tipranavir and

 

 

lead to loss of virologic response

 

 

and possible resistance to

 

 

tipranavir.

Inhaled beta agonists

 

 

Salmeterol

The concurrent administration of

Concurrent administration of

 

tipranavir and low dose ritonavir

Aptivus, co-administered with low

 

may result in increased risk of

dose ritonavir, is not recommended.

 

cardiovascular adverse events

 

 

associated with salmeterol,

 

 

including QT prolongation,

 

 

palpitations and sinus tachycardia.

 

 

Inhibition of CYP 3A4 by

 

 

tipranavir/r.

 

Oral contraceptives / Oestrogens

Ethinyl oestradiol 0.035 mg

Ethinyl oestradiol Cmax ↓ 52%

The concomitant administration

/ Norethindrone 1.0 mg QD

Ethinyl oestradiol AUC ↓ 43%

with Aptivus, co-administered with

(TPV/r 750/200 mg BID)

 

low dose ritonavir, is not

 

Mechanism unknown

recommended. Alternative or

 

 

additional contraceptive measures

 

Norethindrone Cmax

are to be used when oestrogen

 

Norethindrone AUC ↑ 27%

based oral contraceptives are co-

 

 

administered with Aptivus and low

 

Tipranavir ↔

dose ritonavir. Patients using

 

 

oestrogens as hormone replacement

 

 

therapy should be clinically

 

 

monitored for signs of oestrogen

 

 

deficiency (see sections 4.4 and

 

 

4.6).

Phosphodiesterase 5 (PDE5) inhibitors

 

Sildenafil

Co-administration of tipranavir and

Particular caution should be used

Vardenafil

low dose ritonavir with PDE5

when prescribing the

No interaction study

inhibitors is expected to

phosphodiesterase (PDE5)

performed

substantially increase PDE5

inhibitors sildenafil or vardenafil in

 

concentrations and may result in an

patients receiving Aptivus, co-

 

increase in PDE5 inhibitor-

administered with low dose

 

associated adverse events including

ritonavir.

 

hypotension, visual changes and

A safe and effective dose has not

 

priapism.

been established when used with

 

 

Aptivus, co-administered with low

 

CYP 3A4 inhibition by tipranavir/ r

dose ritonavir. There is increased

 

 

potential for PDE5 inhibitor-

 

 

associated adverse events (which

 

 

include visual disturbances,

 

 

hypotension, prolonged erection,

 

 

and syncope).

 

 

Co-administrationof

 

 

Aptivus/ritonavir with sildenafil,

 

 

when used to treat pulmonary

 

 

arterial hypertension, is

 

 

contraindicated.

Tadalafil 10 mg QD

Tadalafil first-dose Cmax ↓ 22%

It is recommended to prescribe

 

Tadalafil first-dose AUC ↑ 133%

tadalafil after at least 7 days of

 

 

Aptivus with ritonavir dosing.

 

CYP 3A4 inhibition and induction

A safe and effective dose has not

 

by tipranavir/r

been established when used with

 

 

Aptivus, co-administered with low

 

Tadalafil steady-state Cmax ↓ 30%

dose ritonavir. There is increased

 

Tadalafil steady-state AUC ↔

potential for PDE5 inhibitor-

 

 

associated adverse events (which

 

No clinically significant change is

include visual disturbances,

 

observed in tipranavir PK

hypotension, prolonged erection,

 

parameters.

and syncope).

Narcotic analgesics

 

 

Methadone 5 mg QD

Methadone Cmax ↓ 55%

Patients should be monitored for

 

Methadone AUC ↓ 53%

opiate withdrawal syndrome.

 

Methadone Cmin ↓ 50%

Dosage of methadone may need to

 

R-methadone Cmax ↓ 46%

be increased.

 

 

 

R-methadone AUC ↓ 48%

 

 

 

 

 

S-methadone Cmax ↓ 62%

 

 

S-methadone AUC ↓ 63%

 

 

Mechanism unknown

 

Meperidine

Tipranavir, co-administered with

Dosage increase and long-term use

No interaction study

low dose ritonavir, is expected to

of meperidine with Aptivus, co-

performed

decrease meperidine concentrations

administered with low dose

 

and increase normeperidine

ritonavir, are not recommended due

 

metabolite concentrations.

to the increased concentrations of

 

 

the metabolite normeperidine which

 

 

has both analgesic activity and CNS

 

 

stimulant activity (e.g. seizures).

Buprenorphine/Naloxone

Buprenorphine ↔

Due to reduction in the levels of the

 

Norbuprenorphine AUC 79%

active metabolite norbuprenorphine,

 

co-administration of Aptivus, co-

 

Norbuprenorphine Cmax 80%

administered with low dose

 

Norbuprenorphine Cmin 80%

ritonavir, and

 

 

buprenorphine/naloxone may result

 

 

in decreased clinical efficacy of

 

 

buprenorphine. Therefore, patients

 

 

should be monitored for opiate

 

 

withdrawal syndrome.

Immunosupressants

 

 

Cyclosporin

Concentrations of cyclosporin,

More frequent concentration

Tacrolimus

tacrolimus, or sirolimus cannot be

monitoring of these medicinal

Sirolimus

predicted when co-administered

products is recommended until

No interaction study

with tipranavir co-administered

blood levels have been stabilised.

performed

with low dose ritonavir, due to

 

 

conflicting effect of tipranavir, co-

 

 

administered with low dose

 

 

ritonavir, on CYP 3A and P-gp.

 

Antithrombotics

 

 

Warfarin 10 mg QD

First-dose tipranavir/r:

Aptivus, co-administered with low

 

S-warfarin Cmax

dose ritonavir, when combined with

 

S-warfarin AUC ↑ 18%

warfarin may be associated with

 

 

changes in INR (International

 

Steady-state tipranavir/r:

Normalised Ratio) values, and may

 

S-warfarin Cmax ↓ 17%

affect anticoagulation

 

S-warfarin AUC ↓ 12%

(thrombogenic effect) or increase

 

 

the risk of bleeding. Close clinical

 

Inhibition of CYP 2C9 with first-

and biological (INR measurement)

 

dose tipranavir/r, then induction of

monitoring is recommended when

 

CYP 2C9 with steady-state

warfarin and tipranavir are

 

tipranavir/r

combined.

 

 

 

Antacids

 

 

aluminium- and magnesium-

Tipranavir Cmax ↓ 25%

Dosing of Aptivus, co-administered

based antacid QD

Tipranavir AUC ↓ 27%

with low dose ritonavir, with

 

 

antacids should be separated by at

 

Mechanism unknown

least a two hours time interval.

Proton pump inhibitors (PPIs)

 

Omeprazole 40 mg QD

Omeprazole Cmax ↓ 73%

The combined use of Aptivus, co-

 

Omeprazole AUC ↓ 70%

administered with low dose

 

 

ritonavir, with either omeprazole or

 

Similar effects were observed for

esomeprazole is not recommended

 

the S-enantiomer, esomeprazole.

(see section 4.4). If unavoidable,

 

 

upward dose adjustments for either

 

Induction of CYP 2C19 by

omeprazole or esomeprazole may

 

tipranavir/r

be considered based on clinical

 

 

response to therapy. There are no

 

Tipranavir ↔

data available indicating that

 

 

omeprazole or esomeprazole dose

 

 

adjustments will overcome the

 

 

observed pharmacokinetic

 

 

interaction. Recommendations for

 

 

maximal doses of omeprazole or

 

 

esomeprazole are found in the

 

 

corresponding product information.

 

 

No tipranavir with ritonavir dose

 

 

adjustment is required.

Lansoprazole

Based on the metabolic profiles of

The combined use of Aptivus, co-

Pantoprazole

tipranavir/r and the proton pump

administered with low dose

Rabeprazole

inhibitors, an interaction can be

ritonavir, with proton pump

No interaction study

expected. As a result of CYP3A4

inhibitors is not recommended (see

performed

inhibition and CYP2C19 induction

section 4.4). If the co-

 

by tipranavir/r, lansoprazole and

administration is judged

 

pantoprazole plasma concentrations

unavoidable, this should be done

 

are difficult to predict. Rabeprazole

under close clinical monitoring.

 

plasma concentrations might

 

 

decrease as a result of induction of

 

 

CYP2C19 by tipranavir/r.

 

H2-receptor antagonists

 

 

No interaction study

No data are available for H2-

An increase in gastric pH that may

performed

receptor antagonists in combination

result from H2-receptor antagonist

 

with tipranavir and low dose

therapy is not expected to have an

 

ritonavir.

impact on tipranavir plasma

 

 

concentrations.

 

 

 

Antiarrhythmics

 

 

Amiodarone

Based on theoretical considerations,

The concomitant use of Aptivus,

Bepridil

tipranavir, co-administered with

co-administered with low dose

Quinidine

low dose ritonavir, is expected to

ritonavir, with amiodarone, bepridil

No interaction study

increase amiodarone, bepridil and

or quinidine is contraindicated due

performed

quinidine concentrations.

to potential serious and/or life

 

Inhibition of CYP 3A4 by

threatening events (see section 4.3)

 

 

 

tipranavir/r

 

Flecainide

Based on theoretical considerations,

The concomitant use of Aptivus,

Propafenone

tipranavir, co-administered with

co-administered with low dose

Metoprolol (given in heart

low dose ritonavir, is expected to

ritonavir, with flecainide,

failure)

increase flecainide, propafenone

propafenone or metoprolol is

No interaction study

and metoprolol concentrations.

contraindicated (see section 4.3)

performed

Inhibition of CYP 2D6

 

 

 

 

by tipranavir/r

 

Antihistamines

 

 

Astemizole

Based on theoretical considerations,

The concomitant use of Aptivus,

Terfenadine

tipranavir, co-administered with

co-administered with low dose

No interaction study

low dose ritonavir, is expected to

ritonavir, with astemizole or

performed

increase astemizole and terfenadine

terfenadine is contraindicated due to

 

concentrations.

potential serious and/or life

 

Inhibition of CYP 3A4 by

threatening events (see section 4.3)

 

 

 

tipranavir/r

 

Ergot derivatives

Dihydroergotamine

Based on theoretical considerations,

The concomitant use of Aptivus,

Ergonovine

tipranavir, co-administered with

co-administered with low dose

Ergotamine

low dose ritonavir, is expected to

ritonavir, with dihydroergotamine,

Methylergonovine

increase dihydroergotamine,

ergonovine, ergotamine or

No interaction study

ergonovine, ergotamine and

methylergonovine is

performed

methylergonovine concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

 

tipranavir/r

 

Gastrointestinal motility agents

 

Cisapride

Based on theoretical considerations,

The concomitant use of Aptivus,

No interaction study

tipranavir, co-administered with

co-administered with low dose

performed

low dose ritonavir, is expected to

ritonavir, with cisapride is

 

increase cisapride concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

 

tipranavir/r

 

Antipsychotics

 

 

Pimozide

Based on theoretical considerations,

The concomitant use of Aptivus,

Sertindole

tipranavir, co-administered with

co-administered with low dose

Quetiapine

low dose ritonavir, is expected to

ritonavir, with pimozide, sertindole,

No interaction study

increase pimozide, sertindole and

or quetiapine is contraindicated due

performed

quetiapine concentrations.

to potential serious and/or life

 

 

threatening events, including coma

 

Inhibition of CYP 3A4 by

(see section 4.3)

 

tipranavir/r

 

Sedatives/hypnotics

 

 

Midazolam 2 mg QD (iv)

First-dose tipranavir/r:

Concomitant use of Aptivus, co-

 

Midazolam Cmax

administered with low dose

 

Midazolam AUC ↑ 5.1 fold

ritonavir, and oral midazolam is

 

 

contra-indicated (see section 4.3). If

 

Steady-state tipranavir/r:

Aptivus with ritonavir is

 

Midazolam Cmax ↓ 13%

administered with parenteral

 

Midazolam AUC ↑ 181%

midazolam, close clinical

Midazolam 5 mg QD (po)

 

monitoring for respiratory

First-dose tipranavir/r

depression and/or prolonged

 

Midazolam Cmax ↑ 5.0 fold

sedation should be instituted and

 

Midazolam AUC ↑ 27 fold

dosage adjustment should be

 

Steady-state tipranavir/r

considered.

 

 

 

Midazolam Cmax ↑ 3.7 fold

 

 

Midazolam AUC ↑ 9.8 fold

 

 

Ritonavir is a potent inhibitor of

 

 

CYP3A4 and therefore affect drugs

 

 

metabolised by this enzyme.

 

Triazolam

Based on theoretical considerations,

The concomitant use of Aptivus,

No interaction study

tipranavir, co-administered with

co-administered with low dose

performed

low dose ritonavir, is expected to

ritonavir, with triazolam is

 

increase triazolam concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

 

tipranavir/r

 

Nucleoside analogue DNA polymerase inhibitors

Valaciclovir 500 mg single

Co-administration of valaciclovir,

Valaciclovir and Aptivus with low

dose

tipranavir and low dose ritonavir

dose ritonavir, may be co-

 

was not associated with clinically

administered without dose

 

relevant pharmacokinetic effects.

adjustment.

 

Tipranavir: ↔

 

 

Valaciclovir: ↔

 

Alpha 1-adrenoreceptor antagonists

 

Alfuzosin

Based on theoretical considerations,

The concomitant use of Aptivus,

 

co-administration of tipranavir with

co-administered with low dose

 

low dose ritonavir and alfuzosin

ritonavir, with alfuzosin is

 

results in increased alfuzosin

contraindicated.

 

concentrations and may result in

 

 

hypotension.

 

 

CYP 3A4 inhibition by tipranavir/r

 

Others

 

 

Theophylline

Based on data from the cocktail

Theophylline plasma concentrations

No interaction study

study where caffeine (CYP1A2

should be monitored during the first

performed

substrate) AUC was reduced by

two weeks of co-administration

 

43%, tipranavir with ritonavir is

with Aptivus, co-administered with

 

expected to decrease theophylline

low dose ritonavir, and the

 

concentrations.

theophylline dose should be

 

Induction of CYP 1A2 by

increased as needed.

 

 

 

tipranavir/r

 

Desipramine

tipranavir, co-administered with

Dosage reduction and concentration

No interaction study

low dose ritonavir, is expected to

monitoring of desipramine is

performed

increase desipramine concentrations

recommended.

 

Inhibition of CYP 2D6 by

 

 

tipranavir/r

 

Digoxin 0.25 mg QD iv

First-dose tipranavir/r

Monitoring of digoxin serum

 

Digoxin Cmax

concentrations is recommended

 

Digoxin AUC ↔

until steady state has been obtained.

 

Steady-state tipranavir/r

 

 

Digoxin Cmax ↓ 20%

 

 

Digoxin AUC ↔

 

Digoxin 0.25 mg QD po

First-dose tipranavir/r

 

 

Digoxin Cmax ↑ 93%

 

 

Digoxin AUC ↑ 91%

 

 

Transient inhibition of P-gp by

 

 

tipranavir/r, followed by induction

 

 

of P-gp by tipranavir/r at steady-

 

 

state

 

 

Steady-state tipranavir/r

 

 

Digoxin Cmax ↓ 38%

 

 

Digoxin AUC ↔

 

Trazodone

In a pharmacokinetic study

The combination should be used

Interaction study performed

performed in healthy volunteers,

with caution and a lower dose of

only with ritonavir

concomitant use of low dose

trazodone should be considered.

 

ritonavir (200 mg twice daily) with

 

 

a single dose of trazodone led to an

 

 

increased plasma concentration of

 

 

trazodone (AUC increased by

 

 

2.4 fold). Adverse events of nausea,

 

 

dizziness, hypotension and syncope

 

 

have been observed following co-

 

 

administration of trazodone and

 

 

ritonavir in this study. However, it

 

 

is unknown whether the

 

 

combination of tipranavir with

 

 

ritonavir might cause a larger

 

 

increase in trazodone exposure.

 

Bupropion 150 mg BID

Bupropion Cmax ↓ 51%

If the co-administration with

 

Bupropion AUC ↓ 56%

bupropion is judged unavoidable,

 

 

this should be done under close

 

Tipranavir ↔

clinical monitoring for bupropion

 

 

efficacy, without exceeding the

 

The reduction of bupropion plasma

recommended dosage, despite the

 

levels is likely due to induction of

observed induction.

 

CYP2B6 and UGT activity by RTV

 

Loperamide 16 mg QD

Loperamide Cmax ↓ 61%

A pharmacodynamic interaction

 

Loperamide AUC ↓ 51%

study in healthy volunteers

 

 

demonstrated that administration of

 

Mechanism unknown

loperamide and Aptivus, co-

 

 

administered with low dose

 

Tipranavir Cmax

ritonavir, does not cause any

 

Tipranavir AUC ↔

clinically relevant change in the

 

Tipranavir Cmin ↓ 26%

respiratory response to carbon

 

 

dioxide. The clinical relevance of

 

 

the reduced loperamide plasma

 

 

concentration is unknown.

Fluticasone propionate

In a clinical study where ritonavir

Concomitant administration of

Interaction study performed

100 mg capsules bid were co-

Aptivus, co-administered with low

only with ritonavir

administered with 50 µg intranasal

dose ritonavir, and these

 

fluticasone propionate (4 times

glucocorticoids is not recommended

 

daily) for 7 days in healthy subjects,

unless the potential benefit of

 

the fluticasone propionate plasma

treatment outweighs the risk of

 

levels increased significantly,

systemic corticosteroid effects (see

 

whereas the intrinsic cortisol levels

section 4.4). A dose reduction of the

 

decreased by approximately 86%

glucocorticoid should be considered

 

(90% confidence interval 82-89%).

with close monitoring of local and

 

Greater effects may be expected

systemic effects or a switch to a

 

when fluticasone propionate is

glucocorticoid, which is not a

 

inhaled. Systemic corticosteroid

substrate for CYP3A4 (e.g.

 

effects including Cushing's

beclomethasone). Moreover, in case

 

syndrome and adrenal suppression

of withdrawal of glucocorticoids

 

have been reported in patients

progressive dose reduction may

 

receiving ritonavir and inhaled or

have to be performed over a longer

 

intranasally administered

period. The effects of high

 

fluticasone propionate; this could

fluticasone systemic exposure on

 

also occur with other corticosteroids

ritonavir plasma levels are as yet

 

metabolised via the P450 3A

unknown.

 

pathway e.g. budesonide.

 

 

It is unknown whether the

 

 

combination of tipranavir with

 

 

ritonavir might cause a larger

 

 

increase in fluticasone exposure.

 

4.6Fertility, pregnancy and lactation

Contraception in males and females

Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment (see section 4.5).

Pregnancy

There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding

Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving Aptivus.

Fertility

Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir showed no adverse effect on fertility (see section 5.3).

4.7Effects on ability to drive and use machines

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8Undesirable effects

Summary of the safety profile

Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post marketing experience (see section 4.4).

Aptivus co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is therefore needed in patients treated with Aptivus, co-administered with low dose ritonavir (see section 4.4).

Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Aptivus should therefore be used with caution in patients co-infected with hepatitis B or C. Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Tabulated summary of adverse reactions

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n=1397) and are listed below by system organ class and frequency according to the following categories:

Very common (≥ 1/10), common (≥ 1/100 to 1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to 1/1,000)

Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post- marketing experience:

Blood and lymphatic system disorders

uncommon

neutropenia, anaemia, thrombocytopenia

Immune system disorders

 

 

 

uncommon

hypersensitivity

Metabolism and nutrition disorders

 

 

 

common

hypertriglyceridaemia, hyperlipidaemia

uncommon

anorexia, decreased appetite, weight decreased,

 

hyperamylasaemia, hypercholesterolaemia,

 

diabetes mellitus, hyperglycaemia

rare

dehydration

 

 

Psychiatric disorders

 

 

 

uncommon

insomnia, sleep disorder

 

 

Nervous system disorders

 

 

 

common

headache

 

 

uncommon

dizziness, neuropathy peripheral, somnolence

 

 

rare

intracranial haemorrhage*

 

 

Respiratory, thoracic and

 

mediastinal disorders

 

uncommon

dyspnoea

 

 

Gastrointestinal disorders

 

 

 

very common

diarrhoea, nausea

 

 

common

vomiting, flatulence, abdominal pain, abdominal

 

distension, dyspepsia

uncommon

gastrooesophageal reflux disease, pancreatitis

 

 

rare

lipase increased

 

 

Hepatobiliary disorders

 

 

 

uncommon

hepatic enzyme increased (ALAT, ASAT),

 

cytolytic hepatitis, liver function test abnormal

 

(ALAT, ASAT), hepatitis toxic

 

 

rare

hepatic failure (including fatal outcome),

 

hepatitis, hepatic steatosis, hyperbilirubinaemia

 

 

Skin and subcutaneous tissue disorders

 

 

 

common

rash

 

 

uncommon

pruritus, exanthem

 

 

Musculoskeletal and connective

 

tissue disorders

 

uncommon

myalgia, muscle spasms

 

 

Renal and urinary disorders

 

 

 

uncommon

renal failure

 

 

General disorders and administration site conditions

common

fatigue

 

 

uncommon

pyrexia, influenza like illness, malaise

 

 

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with ritonavir administration. The clinical significance of these observations has not been fully explored.

Hepatotoxicity

After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with tipranavir with ritonavir.

Metabolic parameters

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

Hyperlipidaemia

Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir with ritonavir arm and 15.6% in the comparator arm.

Bleeding

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials (n=6300).

RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of tipranavir cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the Aptivus clinical trials.

Rash

An interaction study in women between tipranavir, co-administered with low dose ritonavir, and ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs. 12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST- 2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%),

increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count (5.7%).

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

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 these events can occur many months after initiation of treatment (see section 4.4). Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.

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).

Paediatric population

In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 28 children who were 12 years of age or above received Aptivus capsules. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients aged 12 to 18 years who took Aptivus capsules (reported in 2 or more children, Trial 1182.14, week 48 analyses, Full Analysis Set).

Total patients treated (N)

Events [N(%)]

 

Vomiting/ retching

3 (10.7)

Nausea

2 (7.1)

Abdominal pain1

2 (7.1)

Rash2

3 (10.7)

Insomnia

2 (7.1)

ALAT increased

4 (14.3)

1Includes abdominal pain (N=1) and dyspepsia (N=1).

2Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruritic, and urticaria

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

Human experience with tipranavir overdose is very limited. No specific signs and symptoms of overdose are known. Generally, an increased frequency and higher severity of adverse reactions may result from overdose.

There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed

substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09

Mechanism of action

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Antiviral activity in vitro

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% and 90% effective concentrations (EC50 and EC90) ranging from 0.03 to 0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in vitro to tipranavir with EC50 values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively. Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75- fold in conditions where human serum is present.

Resistance

The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3- fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same conditions. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.

Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a 10-fold decrease in tipranavir susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials, 276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre- existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross-resistance

Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 clinical isolates showing post-treatment decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from highly treatment experienced patients who have received multiple peptidic protease inhibitors.

ECG evaluation

The effect of tipranavir with low dose of ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: tipranavir/ritonavir (500/200 mg), tipranavir/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.8 ms) for the supra-therapeutic 750/200 mg dose. Hence tipranavir at therapeutic dose with low dose of ritonavir did not prolong the QTc interval but may do so at supratherapeutic dose.

Clinical pharmacodynamic data

This indication is based on the results of two phase III studies, performed in highly pre-treated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus in mostly treatment-experienced adolescent patients aged 12 to 18 years.

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with 500 mg tipranavir co-administered with low dose ritonavir (200 mg; twice daily) plus an optimised background regimen (OBR) individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.

All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations on codons 33, 82, 84 or 90.

After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to tipranavir with ritonavir in a separate roll-over study.

The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median baseline CD4 cell counts were 158 and 166 cells/mm3, respectively, (ranges 1-1893 and 1-

1184 cells/mm3); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log10 copies/ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log10 copies/ml).

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four mutations. In addition the majority of participants had mutations associated with both NRTI and NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples. There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41- fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented

for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of patients with genotypically resistant strains in the Table below.

Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment- experienced patients)

RESIST study

Tipranavir/RTV

 

CPI/RTV**

p-value

 

n (%)

N

n (%)

N

 

Overall population

 

 

 

 

 

0.0001

FAS

255 (34.2)

114 (15.5)

PP

171 (37.7)

(17.1)

0.0001

- with ENF (FAS)

85 (50.0)

(20.7)

0.0001

- without ENF (FAS)

170 (29.5)

(14.3)

0.0001

Genotypically Resistant

 

 

 

 

 

 

LPV/rtv

 

 

 

 

 

0.0001

FAS

66 (28.9)

23 (9.5)

PP

47 (32.2)

13 (9.1)

0.0001

APV/rtv

 

 

 

 

 

0.0001

FAS

50 (33.3)

(14.9)

PP

38 (39.2)

(18.3)

0.0010

SQV/rtv

 

 

 

 

 

0.0001

FAS

22 (30.6)

(7.0)

PP

11 (28.2)

(5.7)

0.0650

IDV/rtv

 

 

 

 

 

 

FAS

6 (46.2)

(5.3)

0.0026

PP

3 (50.0)

(7.1)

0.0650

*Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure

**Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 600 mg/100 mg twice daily (n=194)

ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all randomised and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/ml in patients receiving tipranavir with ritonavir versus -0.22 log10 copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving tipranavir with ritonavir (N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm.

The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (e.g. enfuvirtide).

At present there are no results from controlled trials evaluating the effect of tipranavir on clinical progression of HIV.

Paediatric population

HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose, compared to the 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non- protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance testing. All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500 mg/200 mg twice daily could change to Aptivus capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic and immunologic responses through 48 weeks.

No data are available on the efficacy and safety of Aptivus capsules in children less than 12 years of age. Since Aptivus capsules and oral solution are not bioequivalent, results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2). In patients with a body surface area of less than 1.33 m2 appropriate dose adjustments cannot be achieved with the capsule formulation.

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients receiving Aptivus capsules are displayed in the tables below. Data on the 29 patients who switched to capsules during the first 48 weeks are presented. Due to limitations in the study design (e.g. non- randomized switch allowed according to patient/clinician decision), any comparisons between patients taking capsules and oral solution are not meaningful.

Baseline characteristics for patients 12 – 18 years of age who took capsule

Variable

 

Value

Number of Patients

 

Age-Median (years)

 

15.1

Gender

% Male

48.3%

Race

% White

69.0%

 

% Black

31.0%

 

% Asian

0.0%

Baseline HIV-1 RNA

Median

4.6 (3.0 – 6.8)

(log10 copies/ml)

(Min – Max)

 

 

% with VL >

27.6%

 

100,000 copies/ml

 

Baseline CD4+

Median

330 (12 – 593)

(cells/mm3)

(Min – Max)

 

 

% ≤ 200

27.6%

 

 

 

Baseline % CD4+ cells

Median

18.5% (3.1% –

 

(Min – Max)

37.4%)

 

 

 

Previous ADI*

% with Category C

29.2%

Treatment history

% with any ARV

96.6%

 

Median # previous

 

NRTIs

 

 

Median # previous

 

NNRTIs

 

 

Median # previous

 

PIs

 

* AIDS defining illness

 

 

Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule

Endpoint

Result

Number of patients

Primary efficacy endpoint:

31.0%

% with VL < 400

 

Median change from baseline

-0.79

in log10 HIV-1 RNA (copies/ml)

 

Median change from baseline

in CD4+ cell count (cells/mm3)

 

Median change from baseline

3%

in % CD4+ cells

 

Analyses of tipranavir resistance in treatment experienced patients

Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to tipranavir with ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

Primary PI mutations

Analyses were conducted to assess virological outcome by the number of primary PI mutations (any change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

Mutations at protease codons 33, 82, 84 and 90

A reduced virological response was observed in patients with viral strains harbouring two or more mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

Tipranavir resistance-associated mutations

Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir- associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has been established.

This score has been determined from the selected RESIST patient population having specific mutation inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see table below).

Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log10 copies/ml decrease in viral load compared to baseline), according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

 

New ENF

No New

 

 

ENF*

Number of

TPV/r

TPV/r

TPV Score

 

 

Mutations**

 

 

0,1

73%

53%

61%

33%

75%

27%

59%

23%

≥ 5

47%

13%

All patients

61%

29%

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

 

New ENF

No New

 

 

ENF*

Number of

TPV/r

TPV/r

TPV Score

 

 

Mutations**

 

 

0, 1

-2.3

-1.6

-2.1

-1.1

-2.4

-0.9

-1.7

-0.8

≥ 5

-1.9

-0.6

All patients

-2.0

-1.0

*Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Tipranavir phenotypic resistance

Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

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.

5.2Pharmacokinetic properties

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2). Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose- ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0- 12h, Cmax and Cmin and decreases the clearance of tipranavir. 500 mg Tipranavir co-administered with low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without ritonavir.

Absorption

Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor and appears to be a potent P-gp inducer as well. Data suggest that, although ritonavir is a P-gp inhibitor, the net effect of Aptivus, co- administered with low dose ritonavir, at the proposed dose regimen at steady-state, is P-gp induction. Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear pharmacokinetics at steady state.

Dosing with Aptivus capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), occurring approximately 3 hours after administration. The mean steady-state trough concentration prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for female patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was 5.5 (females) or 6.0 hours (males).

Effects of food on oral absorption

Food improves the tolerability of tipranavir with ritonavir. Therefore Aptivus, co-administered with low dose ritonavir, should be given with food.

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of antacids (see section 4.5).

Distribution

Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% 0.006%; HIV-positive subjects 0.019% 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 M. The unbound fraction of tipranavir appeared to be independent of total concentration over this concentration range.

No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Biotransformation

In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.

The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver.

The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a 14C-tipranavir human study (500 mg 14C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination

Administration of 14C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg ritonavir; twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500 mg/200 mg twice daily with a light meal.

Special populations

Although data available at this stage are currently limited to allow a definitive analysis, they suggest that the pharmacokinetic profile is unchanged in older people and comparable between races. By contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir concentrations than males. After four weeks of Aptivus 500 mg with 200 mg ritonavir (twice daily) the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. This difference in concentrations does not warrant a dose adjustment.

Renal impairment

Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic impairment

In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment is required in patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 4.4).

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).

Paediatric population

The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

5.3Preclinical safety data

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co- administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those seen in the tipranavir single agent toxicological studies.

The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The effects were reversible with termination of treatment. Additional changes included bleeding in rats at

high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or even below the human exposure levels at the recommended clinical dose.

In in vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving Aptivus with ritonavir. The clinical implications of these findings are not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At maternal doses producing systemic exposure levels similar to or below those at the recommended clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of genetic toxicity in a battery of in vitro and in vivo tests.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Capsule contents

Macrogolglycerol ricinoleate

Ethanol

Mono/diglycerides of caprylic/capric acid

Propylene glycol

Purified water

Trometamol

Propyl gallate

Capsule shell Gelatin

Red iron oxide (E172) Propylene glycol Purified water

‘Sorbitol special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin) Titanium dioxide (E171)

Black printing ink

Propylene glycol

Black iron oxide (E172)

Polyvinyl acetate phthalate

Macrogol

Ammonium hydroxide

6.2Incompatibilities

Not applicable.

6.3Shelf life

3 years.

In use storage: 60 days (below 25°C), after first opening of the bottle. It is advisable that the patient writes the date of opening the bottle on the label and/or carton.

6.4Special precautions for storage

Store in a refrigerator (2°C - 8°C).

6.5Nature and contents of container

High density polyethylene (HDPE) bottle with two-piece child-resistant closure (outer and inner shell polypropylene, with a pulpboard/aluminium liner). Each bottle contains 120 soft capsules.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005

Date of latest renewal: 19 June 2015

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

Aptivus 100 mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 100 mg tipranavir.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution.

Clear yellow viscous liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Aptivus, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pre-treated children from 2 to 12 years of age with virus resistant to multiple protease inhibitors. Aptivus should only be used as part of an active combination antiretroviral regimen in patients with no other therapeutic options (see sections 4.4 and 5.1).

In deciding to initiate treatment with Aptivus, co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of Aptivus. Initiation of treatment should take into account the combinations of mutations which may negatively impact the virological response to Aptivus, co- administered with low dose ritonavir (see section 5.1).

4.2 Posology and method of administration

Aptivus must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir must therefore be consulted prior to initiation of therapy with Aptivus (especially as regards the contraindications, warnings and undesirable effects sections).

Aptivus should be prescribed by physicians who are experienced in the treatment of HIV-1 infection.

Aptivus with ritonavir should not be used in treatment-naïve patients.

Posology

The recommended dose for children (age 2 to 12 years) is 375 mg/m2 Aptivus co-administered with 150 mg/m2 ritonavir, twice daily. The paediatric dose should not exceed the 500 mg/200 mg dose.

Aptivus/ritonavir dose (375 mg/m2 Aptivus + 150 mg/m2 ritonavir)

 

Dose

 

Dose

Volume

BSA Range

Aptivus

Volume

ritonavir

ritonavir

(m2)

(mg)

Aptivus (ml)

(mg)

(ml)

0.37 – 0.42

1.4

0.7

0.43 – 0.47

1.6

0.8

0.48 – 0.52

1.8

0.9

0.53 – 0.58

0.59 – 0.63

2.2

1.1

0.64 – 0.68

2.4

1.2

0.69 - 0.74

2.6

1.3

0.75 – 0.79

2.8

1.4

0.80 – 0.84

1.5

0.85 – 0.90

3.2

1.6

0.91 – 0.95

3.4

1.7

0.96 – 1.00

3.6

1.8

1.01 - 1.06

3.8

1.9

1.07 – 1.11

1.12 – 1.16

4.2

2.1

1.17 – 1.22

4.4

2.2

1.23 – 1.27

4.6

2.3

1.28 – 1.32

4.8

2.4

> 1.33

2.5

Doses of ritonavir lower than 150 mg/m2 twice daily, should not be used as they might alter the efficacy profile of the combination.

Aptivus is available as soft capsules for adults and adolescents from 12 years of age (please refer to the respective SmPC for further details). Patients treated with Aptivus and reaching the age of 12 years should be switched to the capsule formulation (see sections 4.4 and 5.1).

Missed dose

Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose of tipranavir and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next dose of tipranavir and ritonavir at the regularly scheduled time.

Liver impairment

Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase of tipranavir exposure and a worsening of its safety profile. Therefore, Aptivus should be used with caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child- Pugh Class A). Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment

No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data are available.

Method of administration Oral use.

Aptivus oral solution co-administered with low dose oral solution ritonavir should be taken with food (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with moderate or severe (Child-Pugh B or C) hepatic impairment.

Combination of rifampicin with Aptivus with concomitant low dose ritonavir is contraindicated (see section 4.5).

Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These active substances include antiarrhythmics (such as amiodarone, bepridil, quinidine), antihistamines (such as astemizole, terfenadine), ergot derivatives (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (such as cisapride), antipsychotics (such as pimozide, sertindole, quetiapine), sedatives/hypnotics (such as orally administered midazolam and triazolam) and HMG-CoA reductase inhibitors (such as simvastatin and lovastatin) (see section 4.5). Also the use of the alpha-1 adrenoceptor antagonist alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. In addition, co-administration of Aptivus with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure (see section 4.5).

Co-administration of colchicine with Aptivus/ritonavir in patients with renal or hepatic impairment (see section 4.5).

4.4 Special warnings and precautions for use

Aptivus must be administered with low dose ritonavir to ensure its therapeutic effect (see section 4.2). Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly.

Aptivus is not a cure for HIV-1 infection or AIDS. Patients receiving Aptivus or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.

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.

Switching from Aptivus capsules to the oral solution

Aptivus capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution. Also, the composition of the oral solution is different from that of the capsules, with the high vitamin E content being especially noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore patients should not be switched from Aptivus capsules to Aptivus oral solution (see sections 5.1 and 5.2).

Switching from Aptivus oral solution to the capsules

Aptivus oral solution is not interchangeable with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the same dose as capsules. However, children previously treated with Aptivus oral solution and becoming 12 years of age should be switched to capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule formulation of Aptivus could be associated with decreased exposure. Therefore, it is recommended that patients switching from Aptivus oral solution to capsules at the age of 12 years are closely monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).

Liver disease

Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic insufficiency. Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. 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 reaction. Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination therapy and should be monitored according to standard practice. Aptivus with ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease.

Aptivus co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised when administering Aptivus to patients with liver enzyme abnormalities or with a history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.

Aptivus therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN, unless the potential benefit justifies the potential risk.

Aptivus therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause is identified (e.g. acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then rechallenge with Aptivus may be considered when ASAT/ALAT have returned to the patient’s baseline levels.

Liver monitoring

Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when Aptivus and low dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic impairment, chronic hepatitis B or C, or other underlying liver disease.

Treatment-naïve patients

In a study performed in antiretroviral naïve adult patients, tipranavir 500 mg with twice daily, as compared to lopinavir/ritonavir, was associated with an excess in significant (grade 3 and 4) transaminase elevations without any advantage in terms towards a lower efficacy). The study was prematurely stopped after 60 weeks.

Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients.

ritonavir 200 mg the occurrence of of efficacy (trend

Renal impairment

Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected in patients with renal impairment.

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 has been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Bleeding

RESIST participants receiving Aptivus with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving Aptivus, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of Aptivus cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the Aptivus clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving Aptivus with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3).

Aptivus, co-administered with low dose ritonavir, should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medicinal products known to increase the risk of bleeding such as antiplatelet agents and anticoagulants or who are taking supplemental vitamin E. Patients taking Aptivus oral solution should be advised not to take any supplemental vitamin E.

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. A higher increase of blood lipids were seen with tipranavir/ritonavir than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic 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 pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with Aptivus, co-administered with low dose ritonavir.

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

Rash

Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been reported in subjects receiving Aptivus, co-administered with low dose ritonavir. At 48-weeks in Phase

III trials, rash of various types was observed in 15.5% males and 20.5% females receiving Aptivus co- administered with low dose ritonavir. Additionally, in one interaction trial, in healthy female volunteers administered a single dose of ethinyl oestradiol followed by Aptivus co-administered with low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving Aptivus co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.

Osteonecrosis

Although the aetiology 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.

Interactions

The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. The mechanisms and potential mechanisms contributing to the interaction profile of tipranavir are described (see section 4.5).

Abacavir and zidovudine

The concomitant use of Aptivus, co-administered with low dose ritonavir, with zidovudine or abacavir, results in a significant decrease in plasma concentration of these nucleoside reverse transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or abacavir with Aptivus, co-administered with low dose ritonavir, is not-recommended unless there are no other available NRTIs suitable for patient management (see section 4.5).

Protease inhibitors

Concomitant use of Aptivus, co-administered with low dose ritonavir, with the protease inhibitors amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir) in a dual-boosted regimen, results in significant decreases in plasma concentrations of these protease inhibitors. A significant decrease in plasma concentrations of atazanavir and a marked increase of tipranavir and ritonavir concentrations was observed when Aptivus, associated with low dose ritonavir, was co- administered with atazanavir (see section 4.5). No data are currently available on interactions of tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than those listed above. Therefore, the co-administration of tipranavir, co-administered with low dose ritonavir, with protease inhibitors is not recommended.

Oral contraceptives and oestrogens

Since levels of ethinyl oestradiol are decreased, the co-administration of Aptivus co-administered with low dose ritonavir is not recommended. Alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-administered with Aptivus co-administered with low dose ritonavir (see section 4.5). Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency. Women using oestrogens may have an increased risk of non serious rash.

Anticonvulsants

Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Aptivus may be less effective due to decreased tipranavir plasma concentrations in patients taking these agents concomitantly.

Halofantrine, lumefantrine

Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of halofantrine and lumefantrine with Aptivus co-administered with low dose ritonavir, is not recommended.

Fluticasone

Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone or other glucocorticoids that are metabolised by CYP3A4 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).

Atorvastatin

Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations of atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5). However, if atorvastatin is specifically required for patient management, it should be started with the lowest dose and careful monitoring is necessary.

Omeprazole and other proton pump inhibitors

The combined use of Aptivus with ritonavir with either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended (see section 4.5).

Colchicine

In patients with normal renal and hepatic function, a reduction in colchicine dosage or an interruption of colchicine treatment is recommended in co-administration (see section 4.5).

Salmeterol

Concomitant use of salmeterol and Aptivus, co-administered with low dose ritonavir, is not recommended (see section 4.5).

Bosentan

Due to the marked hepatotoxicity of bosentan and the potential for increasing the liver toxicity associated with Aptivus,co-administered with low dose ritonavir, this combination is not recommended.

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of Aptivus, co-administered with low dose ritonavir, is complex and requires special attention in particular in combination with other antiretroviral agents.

Interaction studies have only been performed in adults.

Metabolic profile of tipranavir

Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co- administered with ritonavir at the recommended dosage (see section 4.2) there is a net inhibition of P450 CYP3A. Co-administration of Aptivus and low dose ritonavir with agents primarily metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could alter their therapeutic and undesirable effects (see list and details of considered agents, below). Agents that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse reactions are detailed in this section, and listed in section 4.3.

A cocktail study was conducted in 16 healthy volunteers with twice-daily tipranavir 500 mg with ritonavir 200 mg capsule administration for 10 days to assess the net effect on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4 (midazolam) and P-glycoprotein (P-gp) (digoxin). At steady state, there was a significant induction of CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4 activities were observed. P-gp activity is significantly inhibited after the first dose, but there was a slight induction at steady state. Practical recommendations deriving from this study are displayed below. This study was also conducted with Aptivus oral solution 500 mg with ritonavir

200 mg and showed the same CYP P450 and P-gp interactions as the Aptivus capsule 500 mg with ritonavir 200 mg. Based on the results from this study, Aptivus oral solution might be expected to have a similar interaction profile as the capsules.

Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition, because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of tipranavir with ritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of treatment. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases.

In vitro studies show that tipranavir is a substrate and also an inhibitor of P-gp.

It is difficult to predict the net effect of Aptivus co-administered with low dose ritonavir on oral bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.

Co-administration of Aptivus and agents that induce CYP3A and/or P-gp may decrease tipranavir concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co- administration of Aptivus and medicinal products that inhibit P-gp may increase tipranavir plasma concentrations.

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

Interaction table

Interactions between Aptivus 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”).

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of Aptivus/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with this recommended dosage. Nevertheless, the results of many of these interaction studies can be extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r

750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the recommended dosage of Aptivus/r.

Drugs by Therapeutic Area

Interaction

Recommendations concerning

 

Geometric mean change (%)

co-administration

 

 

 

Anti-infectives

Antiretrovirals

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no dosage adjustment of Aptivus is required when co-administered with these agents.

Abacavir 300 mg BID

Abacavir Cmax ↓ 46%

The concomitant use of Aptivus, co-

(TPV/r 750/100 mg BID)

Abacavir AUC ↓ 36%

administered with low dose

 

 

ritonavir, with abacavir is not

 

The clinical relevance of this

recommended unless there are no

 

reduction has not been

other available NRTIs suitable for

 

established, but may decrease the

patient management. In such cases

 

efficacy of abacavir.

no dosage adjustment of abacavir

 

 

can be recommended (see section

 

Mechanism unknown.

4.4).

Didanosine 200 mg BID, ≥

Didanosine Cmax ↓ 43%

Dosing of enteric-coated didanosine

60 kg - 125 mg BID, < 60 kg

Didanosine AUC ↓ 33%

and Aptivus soft capsules, co-

(TPV/r 250/200 mg BID)

 

administered with low dose

 

 

ritonavir, should be separated by at

(TPV/r 750/100 mg BID)

Didanosine Cmax ↓ 24%

least 2 hours to avoid formulation

 

 

Didanosine AUC ↔

incompatibility.

 

 

The clinical relevance of this

 

 

 

reduction in didanosine

 

 

 

concentrations has not been

 

 

 

established.

 

 

 

Mechanism unknown.

 

Emtricitabine

Potential interactions with renal

No dosage adjustment necessary in

No interaction study

transporters cannot be fully

patients with normal renal function.

performed

excluded.

In case of concomitant

 

 

 

administration of emtricitabine and

 

 

 

Aptivus/ritonavir, renal function

 

 

 

should be evaluated before initiating

 

 

 

the co-administration.

Lamivudine 150 mg BID

No clinically significant

No dosage adjustment necessary.

(TPV/r 750/100 mg BID)

interaction is observed.

 

Stavudine

No clinically significant

No dosage adjustment necessary.

40 mg BID > 60 kg

interaction is observed.

 

30 mg BID < 60 kg

 

 

(TPV/r 750/100 mg BID)

 

 

Zidovudine 300 mg BID

Zidovudine Cmax ↓ 49%

The concomitant use of Aptivus, co-

(TPV/r 750/100 mg BID)

Zidovudine AUC ↓ 36%

administered with low dose

 

 

 

ritonavir with zidovudine is not

 

 

The clinical relevance of this

recommended unless there are no

 

 

reduction has not been

other available NRTIs suitable for

 

 

established, but may decrease the

patient management. In such cases

 

 

efficacy of zidovudine.

no dosage adjustment of zidovudine

 

 

 

can be recommended (see section

 

 

Mechanism unknown.

4.4).

Tenofovir 300 mg QD

No clinically significant

No dosage adjustment necessary.

(TPV/r 750/200 mg BID)

interaction is observed.

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

Efavirenz 600 mg QD

 

No clinically significant interaction

No dosage adjustment necessary.

 

 

is observed.

 

Etravirine

 

Etravirine Cmax ↓ 71%

Co-administration of etravirine and

 

 

Etravirine AUC ↓ 76%

Aptivus/ritonavir is not

 

 

Etravirine Cmin ↓ 82%

recommended.

 

 

Concomitant use of

 

 

 

Aptivus/ritonavir caused a decrease

 

 

 

of etravirine exposure that could

 

 

 

significantly impair the virologic

 

 

 

response to etravirine.

 

Nevirapine

 

The limited data available from a

No dosage adjustment necessary.

No interaction study

 

phase IIa study in HIV-infected

 

performed

 

patients suggest that no significant

 

 

 

interaction is expected between

 

 

 

nevirapine and TPV/r. Moreover a

 

 

 

study with TPV/r and another

 

 

 

NNRTI (efavirenz) did not show

 

 

 

any clinically relevant interaction

 

 

 

(see above).

 

Rilpivirine

 

Concomitant use of rilpivirine with

Close monitoring for signs of

No interaction study

 

some ritonavir-boosted protease

rilpivirine toxicity and possibly also

performed

 

inhibitors has demonstrated an

dose adjustment of rilpivirine is

 

increase in the plasma

recommended when co-

 

concentrations of rilpivirine.

administered with Aptivus/ritonavir.

Protease inhibitors (PIs)

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

Amprenavir/ritonavir

Amprenavir Cmax ↓ 39%

The concomitant use of Aptivus, co-

600/100 mg BID

Amprenavir AUC ↓ 44%

administered with low dose

 

Amprenavir Cmin ↓ 55%

ritonavir, with amprenavir/ritonavir

 

 

is not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in amprenavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of amprenavir

 

established.

is strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Atazanavir/ritonavir

Atazanavir Cmax ↓ 57%

The concomitant use of Aptivus, co-

300/100 mg QD

Atazanavir AUC ↓ 68%

administered with low dose

(TPV/r 500/100 mg BID)

Atazanavir Cmin ↓ 81%

ritonavir, with atazanavir/ritonavir

 

 

is not recommended.

 

Mechanism unknown.

If the co-administration is

 

Tipranavir Cmax 8%

nevertheless considered necessary, a

 

close monitoring of the safety of

 

Tipranavir AUC 20%

tipranavir and a monitoring of

 

Tipranavir Cmin 75%

plasma concentrations of atazanavir

 

 

are strongly encouraged (see section

 

Inhibition of CYP 3A4 by

4.4).

 

atazanavir/ritonavir and induction

 

 

by tipranavir/r.

 

Lopinavir/ritonavir

Lopinavir Cmax ↓ 47%

The concomitant use of Aptivus, co-

400/100 mg BID

Lopinavir AUC ↓ 55%

administered with low dose

 

Lopinavir Cmin ↓ 70%

ritonavir, with lopinavir/ritonavir is

 

 

not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in lopinavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of lopinavir is

 

established.

strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Saquinavir/ritonavir

Saquinavir Cmax ↓ 70%

The concomitant use of Aptivus, co-

600/100 mg QD

Saquinavir AUC ↓ 76%

administered with low dose

 

Saquinavir Cmin ↓ 82%

ritonavir, with saquinavir/ritonavir

 

 

is not recommended.

 

The clinical relevance of this

If the combination is nevertheless

 

reduction in saquinavir

considered necessary, a monitoring

 

concentrations has not been

of the plasma levels of saquinavir is

 

established.

strongly encouraged (see section

 

Mechanism unknown.

4.4).

 

 

Protease inhibitors other

No data are currently available on

Combination with Aptivus, co-

than those listed above

interactions of tipranavir, co-

administered with low dose

 

administered with low dose

ritonavir, is not recommended (see

 

ritonavir, with protease inhibitors

section 4.4)

 

other than those listed above.

 

Fusion inhibitors

 

 

Enfuvirtide

In studies where tipranavir co-

The clinical impact of the observed

No interaction study

administered with low-dose

data, especially regarding the

performed

ritonavir was used with or without

tipranavir with ritonavir safety

 

enfuvirtide, it has been observed

profile, remains unknown.

 

that the steady-state plasma

Nevertheless, the clinical data

 

tipranavir trough concentration of

available from the RESIST trials did

 

patients receiving enfuvirtide were

not suggest any significant

 

45% higher as compared to patients

alteration of the tipranavir with

 

not receiving enfuvirtide. No

ritonavir safety profile when

 

information is available for the

combined with enfuvirtide as

 

parameters AUC and Cmax.

compared to patients treated with

 

A pharmacokinetic interaction is

tipranavir with ritonavir without

 

mechanistically unexpected and the

enfuvirtide.

 

interaction has not been confirmed

 

 

in a controlled interaction study.

 

Integrase strand transfer inhibitors

 

Raltegravir 400 mg BID

Raltegravir Cmax

No particular dose adjustment is

 

Raltegravir AUC 0-12↔

recommended.

 

Raltegravir C12: ↓ 45%

 

 

Despite an almost half reduction of

 

 

C12, previous clinical studies with

 

 

this combination did not evidence

 

 

an impaired outcome.

 

 

The mechanism of action is thought

 

 

to be induction of

 

 

glucuronosyltransferase by

 

 

tipranavir/r.

 

Pharmacokinetic enhancer

 

 

Cobicistat and cobicistat-

When co-administered, tipranavir

Aptivus/ritonavir should not be

containing products

and cobicistat exposures are

administered concomitantly with

 

markedly lower compared to that of

cobicistat or cobicistat-containing

 

tipranavir when boosted with low

products.

 

dose ritonavir.

 

Anti-HCV agents

 

 

Boceprevir

In a pharmacokinetic study of

Co-administration of boceprevir

No interaction study

healthy volunteers, boceprevir

with Aptivus/ritonavir is not

performed

decreased the exposure of ritonavir,

recommended.

 

and some ritonavir-boosted protease

 

 

inhibitors. Boceprevir exposure was

 

 

reduced when co-administered with

 

 

ritonavir-boosted lopinavir or

 

 

ritonavir-boosted darunavir. These

 

 

drug-drug interactions may reduce

 

 

the effectiveness of HIV protease

 

 

inhibitors and/or boceprevir when

 

 

co-administered.

 

Telaprevir

Telaprevir is metabolized in the

Co-administration of telaprevir with

No interaction study

liver by CYP3A and is a P-

Aptivus/ritonavir is not

performed

glycoprotein (P-gp) substrate, but

recommended.

 

other enzymes may be involved in

 

 

the metabolism. When

 

 

Aptivus/ritonavir is co-administered

 

 

with telaprevir, a decrease or an

 

 

increase of telaprevir exposure

 

 

could be expected. There is a

 

 

heterogeneous effect of telaprevir

 

 

on ritonavir-boosted protease

 

inhibitor drug plasma levels, depending on the protease inhibitors. Therefore, a modification of Aptivus exposure cannot be ruled out.

Antifungals

Fluconazole 200 mg QD

Fluconazole ↔

No dosage adjustments are

(Day 1) then 100 mg QD

 

recommended. Fluconazole doses

 

Tipranavir Cmax ↑ 32%

200 mg/day are not recommended.

 

Tipranavir AUC ↑ 50%

 

 

Tipranavir Cmin ↑ 69%

 

 

Mechanism unknown

 

Itraconazole

Based on theoretical considerations

Itraconazole or ketoconazole should

Ketoconazole

tipranavir, co-administered with

be used with caution (doses

No interaction study

low dose ritonavir, is expected to

200 mg/day are not

performed

increase itraconazole or

recommended).

 

ketoconazole concentrations.

 

 

Based on theoretical considerations,

 

 

tipranavir or ritonavir

 

 

concentrations might increase upon

 

 

co-administration with itraconazole

 

 

or ketoconazole.

 

Voriconazole

Due to multiple CYP isoenzyme

Based on the known interaction of

No interaction study

systems involved in voriconazole

voriconazole with low dose

performed

metabolism, it is difficult to predict

ritonavir (see voriconazole SmPC)

 

the interaction with tipranavir, co-

the co-administration of tipranavir/r

 

administered with low-dose

and voriconazole should be

 

ritonavir.

avoided, unless an assessment of

 

 

the benefit/risk to the patient

 

 

justifies the use of voriconazole.

Anti-gouts

 

 

Colchicine

Based on theoretical considerations,

A reduction in colchicine dosage or

No interaction study

colchicine concentrations may

an interruption of colchicine

performed

increase upon co-administration

treatment is recommended in

 

with tipranavir and low dose

patients with normal renal or

 

ritonavir, due to tipranavir/ritonavir

hepatic function if treatment with

 

CYP3A and P-gp inhibition.

Aptivus/ritonavir is required (see

 

However a decrease of colchicine

section 4.4). In patients with renal

 

concentrations cannot be excluded

or hepatic impairment, co-

 

since both tipranavir and ritonavir

administration of colchicine in

 

exhibit inducing potential towards

patients on Aptivus/ritonavir is

 

CYP3A and P-gp.

contraindicated (see section 4.3).

 

Colchicine is a substrate of

 

 

CYP3A4 and P-gp (an intestinal

 

 

efflux transporter).

 

Antibiotics

 

 

Clarithromycin 500 mg

Clarithromycin Cmax

Whilst the changes in

BID

Clarithromycin AUC ↑ 19%

clarithromycin parameters are not

 

Clarithromycin Cmin ↑ 68%

considered clinically relevant, the

 

 

reduction in the 14-OH metabolite

 

14-OH-clarithromycin Cmax ↓ 97%

AUC should be considered for the

 

14-OH-clarithromycin AUC ↓ 97%

treatment of infections caused by

 

14-OH-clarithromycin Cmin ↓ 95%

Haemophilus influenzae in which

 

 

the 14-OH metabolite is most

 

Tipranavir Cmax ↑ 40%

active. The increase of tipranavir

 

Tipranavir AUC ↑ 66%

Cmin may be clinically relevant.

 

Tipranavir Cmin ↑ 100%

Patients using clarithromycin at

 

 

doses higher than 500 mg twice

 

CYP 3A4 inhibition by tipranavir/r

daily should be carefully monitored

 

and P-gp (an intestinal efflux

for signs of toxicity of

 

transporter) inhibition by

clarithromycin and tipranavir. For

 

clarithromycin.

patients with renal impairment dose

 

 

reduction of clarithromycin should

 

 

be considered (see clarithromycin

 

 

and ritonavir product information).

Rifabutin 150 mg QD

Rifabutin Cmax ↑ 70%

Dosage reductions of rifabutin by at

 

Rifabutin AUC ↑ 190%

least 75% of the usual 300 mg/day

 

Rifabutin Cmin ↑ 114%

are recommended (ie 150 mg on

 

 

alternate days, or three times per

 

25-O-desacetylrifabutin Cmax ↑ 3.2

week). Patients receiving rifabutin

 

fold

with Aptivus, co-administered with

 

25-O-desacetylrifabutin AUC ↑ 21

low dose ritonavir, should be

 

fold

closely monitored for emergence of

 

25-O-desacetylrifabutin Cmin ↑ 7.8

adverse events associated with

 

fold

rifabutin therapy. Further dosage

 

Inhibition of CYP 3A4 by

reduction may be necessary.

 

 

 

tipranavir/r

 

 

No clinically significant change is

 

 

observed in tipranavir PK

 

 

parameters.

 

Rifampicin

Co-administration of protease

Concomitant use of Aptivus, co-

 

inhibitors with rifampicin

administered with low dose

 

substantially decreases protease

ritonavir, and rifampicin is

 

inhibitor concentrations. In the case

contraindicated (see section 4.3).

 

of tipranavir co-administered with

Alternate antimycobacterial agents

 

low dose ritonavir, concomitant use

such as rifabutin should be

 

with rifampicin is expected to result

considered.

 

in sub-optimal levels of tipranavir

 

 

which may lead to loss of virologic

 

 

response and possible resistance to

 

 

tipranavir.

 

Antimalarial

 

 

Halofantrine

Based on theoretical considerations,

Due to their metabolic profile and

Lumefantrine

tipranavir, co-administered with

inherent risk of inducing torsades

No interaction study

low dose ritonavir, is expected to

de pointes, administration of

performed

increase halofantrine and

halofantrine and lumefantrine with

 

lumefantrine concentrations.

Aptivus, co-administered with low

 

 

dose ritonavir, is not recommended

 

Inhibition of CYP 3A4 by

(see section 4.4).

 

tipranavir/r

 

Anticonvulsants

 

 

Carbamazepine 200 mg

Carbamazepine total* Cmax ↑ 13%

Carbamazepine should be used with

BID

Carbamazepine total* AUC ↑ 16%

caution in combination with

 

Carbamazepine total* Cmin ↑ 23%

Aptivus, co-administered with low

 

 

dose ritonavir. Higher doses of

 

*Carbamazepine total = total of

carbamazepine (> 200 mg) may

 

carbamazepine and epoxy-

result in even larger decreases in

 

carbamazepine (both are

tipranavir plasma concentrations

 

pharmacologically active moieties).

(see section 4.4).

 

The increase in carbamazepine total

 

 

PK parameters is not expected to

 

 

have clinical consequences.

 

 

Tipranavir Cmin ↓ 61% (compared to

 

 

historical data)

 

 

The decrease in tipranavir

 

 

concentrations may result in

 

 

decreased effectiveness.

 

 

Carbamazepine induces CYP3A4.

 

Phenobarbital

Phenobarbital and phenytoin induce

Phenobarbital and phenytoin should

Phenytoin

CYP3A4.

be used with caution in combination

No interaction study

 

with Aptivus, co-administered with

performed

 

low dose ritonavir (see section 4.4).

Antispasmodic

 

 

Tolterodine

Based on theoretical considerations,

Co-administration is not

No interaction study

tipranavir, co-administered with

recommended.

performed

low dose ritonavir, is expected to

 

 

increase tolterodine concentrations.

 

 

Inhibition of CYP 3A4 and CYP

 

 

2D6 by tipranavir/r

 

Endothelin receptor antagonists

 

Bosentan

Based on theoretical considerations,

Co-administration of bosentan and

 

bosentan concentrations may

Aptivus with low dose ritonavir is

 

increase upon co-administration

not recommended

 

with tipranavir and low dose

(see section 4.4).

 

ritonavir.

 

 

Inhibition of CYP 3A4 by

 

 

tipranavir/r

 

HMG CoA reductase inhibitors

 

Atorvastatin 10 mg QD

Atorvastatin Cmax ↑ 8.6 fold

Co-administration of atorvastatin

 

Atorvastatin AUC ↑ 9.4 fold

and Aptivus, co-administered with

 

Atorvastatin Cmin ↑ 5.2 fold

low dose ritonavir, is not

 

 

recommended. Other HMG-CoA

 

Tipranavir ↔

reductase inhibitors should be

 

 

considered such as pravastatin,

 

Inhibition of CYP 3A4 by

fluvastatin or rosuvastatin (See also

 

tipranavir/r

section 4.4 and rosuvastatin and

 

 

pravastatin recommendations). In

 

 

cases where co-administration is

 

 

necessary, the dose of 10 mg

 

 

atorvastatin daily should not be

 

 

exceeded. It is recommended to

 

 

start with the lowest dose and

 

 

careful clinical monitoring is

 

 

necessary (see section 4.4).

Rosuvastatin 10 mg QD

Rosuvastatin Cmax ↑ 123%

Co-administration of Aptivus, co-

 

Rosuvastatin AUC ↑ 37%

administered with low dose

 

Rosuvastatin Cmin ↑ 6%

ritonavir, and rosuvastatin should

 

 

be initiated with the lowest dose

 

Tipranavir ↔

(5 mg/day) of rosuvastatin, titrated

 

 

to treatment response, and

 

Mechanism unknown.

accompanied with careful clinical

 

 

monitoring for rosuvastatin

 

 

associated symptoms as described

 

 

in the label of rosuvastatin.

Pravastatin

Based on similarities in the

Co-administration of Aptivus, co-

No interaction study

elimination between pravastatin and

administered with low dose

performed

rosuvastatin, TPV/r could increase

ritonavir, and pravastatin should be

 

the plasma levels of pravastatin.

initiated with the lowest dose

 

 

(10 mg/day) of pravastatin, titrated

 

Mechanism unknown.

to treatment response, and

 

 

accompanied with careful clinical

 

 

monitoring for pravastatin

 

 

associated symptoms as described

 

 

in the label of pravastatin.

 

 

 

Simvastatin

The HMG-CoA reductase inhibitors

The concomitant use of Aptivus,

Lovastatin

simvastatin and lovastatin are

co-administered with low dose

No interaction study

highly dependent on CYP3A for

ritonavir, with simvastatin or

performed

metabolism.

lovastatin are contra-indicated due

 

 

to an increased risk of myopathy,

 

 

including rhabdomyolysis (see

 

 

section 4.3).

HERBAL PRODUCTS

 

 

St. John’s wort (Hypericum

Plasma concentrations of tipranavir

Herbal preparations containing St.

perforatum)

can be reduced by concomitant use

John’s wort must not be combined

No interaction study

of the herbal preparation St John’s

with Aptivus, co-administered with

performed

wort (Hypericum perforatum). This

low dose ritonavir. Co-

 

is due to induction of drug

administration of Aptivus with

 

metabolising enzymes by St John’s

ritonavir, with St. John’s wort is

 

wort.

expected to substantially decrease

 

 

tipranavir and ritonavir

 

 

concentrations and may result in

 

 

sub-optimal levels of tipranavir and

 

 

lead to loss of virologic response

 

 

and possible resistance to

 

 

tipranavir.

Inhaled beta agonists

 

 

Salmeterol

The concurrent administration of

Concurrent administration of

 

tipranavir and low dose ritonavir

Aptivus, co-administered with low

 

may result in increased risk of

dose ritonavir, is not recommended.

 

cardiovascular adverse events

 

 

associated with salmeterol,

 

 

including QT prolongation,

 

 

palpitations and sinus tachycardia.

 

 

Inhibition of CYP 3A4 by

 

 

tipranavir/r.

 

Oral contraceptives / Oestrogens

 

Ethinyl oestradiol 0.035 mg

Ethinyl oestradiol Cmax ↓ 52%

The concomitant administration

/ Norethindrone 1.0 mg QD

Ethinyl oestradiol AUC ↓ 43%

with Aptivus, co-administered with

(TPV/r 750/200 mg BID)

 

low dose ritonavir, is not

 

Mechanism unknown

recommended. Alternative or

 

 

additional contraceptive measures

 

Norethindrone Cmax

are to be used when oestrogen

 

Norethindrone AUC ↑ 27%

based oral contraceptives are co-

 

 

administered with Aptivus and low

 

Tipranavir ↔

dose ritonavir. Patients using

 

 

oestrogens as hormone replacement

 

 

therapy should be clinically

 

 

monitored for signs of oestrogen

 

 

deficiency (see sections 4.4 and

 

 

4.6).

Phosphodiesterase 5 (PDE5) inhibitors

 

Sildenafil

Co-administration of tipranavir and

Particular caution should be used

Vardenafil

low dose ritonavir with PDE5

when prescribing the

No interaction study

inhibitors is expected to

phosphodiesterase (PDE5)

performed

substantially increase PDE5

inhibitors sildenafil or vardenafil in

 

concentrations and may result in an

patients receiving Aptivus, co-

 

increase in PDE5 inhibitor-

administered with low dose

 

associated adverse events including

ritonavir.

 

hypotension, visual changes and

A safe and effective dose has not

 

priapism.

been established when used with

 

 

Aptivus, co-administered with low

 

CYP 3A4 inhibition by tipranavir/ r

dose ritonavir. There is increased

 

 

potential for PDE5 inhibitor-

 

 

associated adverse events (which

 

 

include visual disturbances,

 

 

hypotension, prolonged erection,

 

 

and syncope).

 

 

Co-administration of

 

 

Aptivus/ritonavir with sildenafil,

 

 

when used to treat pulmonary

 

 

arterial hypertension, is

 

 

contraindicated.

Tadalafil 10 mg QD

Tadalafil first-dose Cmax ↓ 22%

It is recommended to prescribe

 

Tadalafil first-dose AUC ↑ 133%

tadalafil after at least 7 days of

 

 

Aptivus with ritonavir dosing.

 

CYP 3A4 inhibition and induction

A safe and effective dose has not

 

by tipranavir/r

been established when used with

 

 

Aptivus, co-administered with low

 

Tadalafil steady-state Cmax ↓ 30%

dose ritonavir. There is increased

 

Tadalafil steady-state AUC ↔

potential for PDE5 inhibitor-

 

 

associated adverse events (which

 

No clinically significant change is

include visual disturbances,

 

observed in tipranavir PK

hypotension, prolonged erection,

 

parameters.

and syncope).

Narcotic analgesics

 

 

Methadone 5 mg QD

Methadone Cmax ↓ 55%

Patients should be monitored for

 

Methadone AUC ↓ 53%

opiate withdrawal syndrome.

 

Methadone Cmin ↓ 50%

Dosage of methadone may need to

 

R-methadone Cmax ↓ 46%

be increased.

 

 

 

R-methadone AUC ↓ 48%

 

 

S-methadone Cmax ↓ 62%

 

 

S-methadone AUC ↓ 63%

 

 

Mechanism unknown

 

Meperidine

Tipranavir, co-administered with

Dosage increase and long-term use

No interaction study

low dose ritonavir, is expected to

of meperidine with Aptivus, co-

performed

decrease meperidine concentrations

administered with low dose

 

and increase normeperidine

ritonavir, are not recommended due

 

metabolite concentrations.

to the increased concentrations of

 

 

the metabolite normeperidine which

 

 

has both analgesic activity and CNS

 

 

stimulant activity (e.g. seizures).

Buprenorphine/Naloxone

Buprenorphine ↔

Due to reduction in the levels of the

 

Norbuprenorphine AUC 79%

active metabolite norbuprenorphine,

 

co-administration of Aptivus, co-

 

Norbuprenorphine Cmax 80%

administered with low dose

 

Norbuprenorphine Cmin 80%

ritonavir, and

 

 

buprenorphine/naloxone may result

 

 

in decreased clinical efficacy of

 

 

buprenorphine. Therefore, patients

 

 

should be monitored for opiate

 

 

withdrawal syndrome.

Immunosupressants

 

 

Cyclosporin

Concentrations of cyclosporin,

More frequent concentration

Tacrolimus

tacrolimus, or sirolimus cannot be

monitoring of these medicinal

Sirolimus

predicted when co-administered

products is recommended until

No interaction study

with tipranavir co-administered

blood levels have been stabilised.

performed

with low dose ritonavir, due to

 

 

conflicting effect of tipranavir, co-

 

 

administered with low dose

 

 

ritonavir, on CYP 3A and P-gp.

 

Antithrombotics

 

 

Warfarin 10 mg QD

First-dose tipranavir /r:

Aptivus, co-administered with low

 

S-warfarin Cmax

dose ritonavir, when combined with

 

S-warfarin AUC ↑ 18%

warfarin may be associated with

 

 

changes in INR (International

 

Steady-state tipranavir/r:

Normalised Ratio) values, and may

 

S-warfarin Cmax ↓ 17%

affect anticoagulation

 

S-warfarin AUC ↓ 12%

(thrombogenic effect) or increase

 

 

the risk of bleeding. Close clinical

 

Inhibition of CYP 2C9 with first-

and biological (INR measurement)

 

dose tipranavir /r, then induction of

monitoring is recommended when

 

CYP 2C9 with steady-state

warfarin and tipranavir are

 

tipranavir/r

combined.

 

 

 

Antacids

 

 

aluminium- and magnesium-

Tipranavir Cmax ↓ 25%

Dosing of Aptivus, co-administered

based antacid QD

Tipranavir AUC ↓ 27%

with low dose ritonavir, with

 

 

antacids should be separated by at

 

Mechanism unknown

least a two hours time interval.

Proton pump inhibitors (PPIs)

 

Omeprazole 40 mg QD

Omeprazole Cmax ↓ 73%

The combined use of Aptivus, co-

 

Omeprazole AUC ↓ 70%

administered with low dose

 

 

ritonavir, with either omeprazole or

 

Similar effects were observed for

esomeprazole is not recommended

 

the S-enantiomer, esomeprazole.

(see section 4.4). If unavoidable,

 

 

upward dose adjustments for either

 

Induction of CYP 2C19 by

omeprazole or esomeprazole may

 

tipranavir/r

be considered based on clinical

 

 

response to therapy. There are no

 

Tipranavir ↔

data available indicating that

 

 

omeprazole or esomeprazole dose

 

 

adjustments will overcome the

 

 

observed pharmacokinetic

 

 

interaction. Recommendations for

 

 

maximal doses of omeprazole or

 

 

esomeprazole are found in the

 

 

corresponding product information.

 

 

No tipranavir with ritonavir dose

 

 

adjustment is required.

Lansoprazole

Based on the metabolic profiles of

The combined use of Aptivus, co-

Pantoprazole

tipranavir/r and the proton pump

administered with low dose

Rabeprazole

inhibitors, an interaction can be

ritonavir, with proton pump

No interaction study

expected. As a result of CYP3A4

inhibitors is not recommended (see

performed

inhibition and CYP2C19 induction

section 4.4). If the co-

 

by tipranavir/r, lansoprazole and

administration is judged

 

pantoprazole plasma concentrations

unavoidable, this should be done

 

are difficult to predict. Rabeprazole

under close clinical monitoring.

 

plasma concentrations might

 

 

decrease as a result of induction of

 

 

CYP2C19 by tipranavir/r.

 

 

 

 

H2-receptor antagonists

 

 

No interaction study

No data are available for H2-

An increase in gastric pH that may

performed

receptor antagonists in combination

result from H2-receptor antagonist

 

with tipranavir and low dose

therapy is not expected to have an

 

ritonavir.

impact on tipranavir plasma

 

 

concentrations.

 

 

 

Antiarrhythmics

 

 

Amiodarone

Based on theoretical considerations,

The concomitant use of Aptivus,

Bepridil

tipranavir, co-administered with

co-administered with low dose

Quinidine

low dose ritonavir, is expected to

ritonavir, with amiodarone, bepridil

No interaction study

increase amiodarone, bepridil and

or quinidine is contraindicated due

performed

quinidine concentrations.

to potential serious and/or life

 

Inhibition of CYP 3A4 by

threatening events (see section 4.3)

 

 

 

tipranavir/r

 

Flecainide

Based on theoretical considerations,

The concomitant use of Aptivus,

Propafenone

tipranavir, co-administered with

co-administered with low dose

Metoprolol (given in heart

low dose ritonavir, is expected to

ritonavir, with flecainide,

failure)

increase flecainide, propafenone

propafenone or metoprolol is

No interaction study

and metoprolol concentrations.

contraindicated (see section 4.3)

performed

Inhibition of CYP 2D6

 

 

 

 

by tipranavir/r

 

Antihistamines

 

 

Astemizole

Based on theoretical considerations,

The concomitant use of Aptivus,

Terfenadine

tipranavir, co-administered with

co-administered with low dose

No interaction study

low dose ritonavir, is expected to

ritonavir, with astemizole or

performed

increase astemizole and terfenadine

terfenadine is contraindicated due to

 

concentrations.

potential serious and/or life

 

Inhibition of CYP 3A4 by

threatening events (see section 4.3)

 

 

 

tipranavir/r

 

Ergot derivatives

 

 

Dihydroergotamine

Based on theoretical considerations,

The concomitant use of Aptivus,

Ergonovine

tipranavir, co-administered with

co-administered with low dose

Ergotamine

low dose ritonavir, is expected to

ritonavir, with dihydroergotamine,

Methylergonovine

increase dihydroergotamine,

ergonovine, ergotamine or

No interaction study

ergonovine, ergotamine and

methylergonovine is

performed

methylergonovine concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

tipranavir/r

Gastrointestinal motility agents

Cisapride

Based on theoretical considerations,

The concomitant use of Aptivus,

No interaction study

tipranavir, co-administered with

co-administered with low dose

performed

low dose ritonavir, is expected to

ritonavir, with cisapride is

 

increase cisapride concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

 

tipranavir/r

 

Antipsychotics

 

 

Pimozide

Based on theoretical considerations,

The concomitant use of Aptivus,

Sertindole

tipranavir, co-administered with

co-administered with low dose

Quetiapine

low dose ritonavir, is expected to

ritonavir, with pimozide, sertindole,

No interaction study

increase pimozide, sertindole and

or quetiapine is contraindicated due

performed

quetiapine concentrations.

to potential serious and/or life

 

 

threatening events, including coma

 

Inhibition of CYP 3A4 by

(see section 4.3)

 

tipranavir/r

 

Sedatives/hypnotics

 

 

Midazolam 2 mg QD (iv)

First-dose tipranavir/r:

Concomitant use of Aptivus, co-

 

Midazolam Cmax

administered with low dose

 

Midazolam AUC ↑ 5.1 fold

ritonavir, and oral midazolam is

 

 

contra-indicated (see section 4.3). If

 

Steady-state tipranavir/r:

Aptivus with ritonavir is

 

Midazolam Cmax ↓ 13%

administered with parenteral

 

Midazolam AUC ↑ 181%

midazolam, close clinical

Midazolam 5 mg QD (po)

 

monitoring for respiratory

First-dose tipranavir/r

depression and/or prolonged

 

Midazolam Cmax ↑ 5.0 fold

sedation should be instituted and

 

Midazolam AUC ↑ 27 fold

dosage adjustment should be

 

Steady-state tipranavir/r

considered.

 

 

 

Midazolam Cmax ↑ 3.7 fold

 

 

Midazolam AUC ↑ 9.8 fold

 

 

Ritonavir is a potent inhibitor of

 

 

CYP3A4 and therefore affect drugs

 

 

metabolised by this enzyme.

 

Triazolam

Based on theoretical considerations,

The concomitant use of Aptivus,

No interaction study

tipranavir, co-administered with

co-administered with low dose

performed

low dose ritonavir, is expected to

ritonavir, with triazolam is

 

increase triazolam concentrations.

contraindicated due to potential

 

 

serious and/or life threatening

 

Inhibition of CYP 3A4 by

events (see section 4.3)

 

tipranavir/r

 

Nucleoside analogue DNA polymerase inhibitors

 

Valaciclovir 500 mg single

Co-administration of valaciclovir,

Valaciclovir and Aptivus with low

dose

tipranavir and low dose ritonavir

dose of ritonavir may be co-

 

was not associated with clinically

administered without dose

 

relevant pharmacokinetic effects.

adjustment.

 

Tipranavir: ↔

 

 

Valaciclovir: ↔

 

Alpha 1-adrenoreceptor antagonists

 

Alfuzosin

Based on theoretical considerations,

The concomitant use of Aptivus,

 

co-administration of tipranavir with

co-administered with low dose

 

low dose ritonavir and alfuzosin

ritonavir, with alfuzosin is

 

results in increased alfuzosin

contraindicated.

 

concentrations and may result in

 

 

hypotension.

 

 

CYP 3A4 inhibition by tipranavir/r

 

Others

 

 

Theophylline

Based on data from the cocktail

Theophylline plasma concentrations

No interaction study

study where caffeine (CYP1A2

should be monitored during the first

performed

substrate) AUC was reduced by

two weeks of co-administration

 

43%, tipranavir with ritonavir is

with Aptivus, co-administered with

 

expected to decrease theophylline

low dose ritonavir, and the

 

concentrations.

theophylline dose should be

 

Induction of CYP 1A2 by

increased as needed.

 

 

 

tipranavir/r

 

Desipramine

Tipranavir, co-administered with

Dosage reduction and concentration

No interaction study

low dose ritonavir, is expected to

monitoring of desipramine is

performed

increase desipramine concentrations

recommended.

 

Inhibition of CYP 2D6 by

 

 

tipranavir/r

 

Digoxin 0.25 mg QD iv

First-dose tipranavir/r

Monitoring of digoxin serum

 

Digoxin Cmax

concentrations is recommended

 

Digoxin AUC ↔

until steady state has been obtained.

 

Steady-state tipranavir/r

 

 

Digoxin Cmax ↓ 20%

 

 

Digoxin AUC ↔

 

Digoxin 0.25 mg QD po

First-dose tipranavir/r

 

 

Digoxin Cmax ↑ 93%

 

 

Digoxin AUC ↑ 91%

 

 

Transient inhibition of P-gp by

 

 

tipranavir/r, followed by induction

 

 

of P-gp by tipranavir/r at steady-

 

 

state

 

 

Steady-state tipranavir/r

 

 

Digoxin Cmax ↓ 38%

 

 

Digoxin AUC ↔

 

Trazodone

In a pharmacokinetic study

The combination should be used

Interaction study performed

performed in healthy volunteers,

with caution and a lower dose of

only with ritonavir

concomitant use of low dose

trazodone should be considered.

 

ritonavir (200 mg twice daily) with

 

 

a single dose of trazodone led to an

 

 

increased plasma concentration of

 

 

trazodone (AUC increased by

 

 

2.4 fold). Adverse events of nausea,

 

 

dizziness, hypotension and syncope

 

 

have been observed following co-

 

 

administration of trazodone and

 

 

ritonavir in this study. However, it

 

 

is unknown whether the

 

 

combination of tipranavir with

 

 

ritonavir might cause a larger

 

 

increase in trazodone exposure.

 

Bupropion 150 mg BID

Bupropion Cmax ↓ 51%

If the co-administration with

 

Bupropion AUC ↓ 56%

bupropion is judged unavoidable,

 

 

this should be done under close

 

Tipranavir ↔

clinical monitoring for bupropion

 

 

efficacy, without exceeding the

 

The reduction of bupropion plasma

recommended dosage, despite the

 

levels is likely due to induction of

observed induction.

 

CYP2B6 and UGT activity by RTV

 

Loperamide 16 mg QD

Loperamide Cmax ↓ 61%

A pharmacodynamic interaction

 

Loperamide AUC ↓ 51%

study in healthy volunteers

 

 

demonstrated that administration of

 

Mechanism unknown

loperamide and Aptivus, co-

 

 

administered with low dose

 

Tipranavir Cmax

ritonavir, does not cause any

 

Tipranavir AUC ↔

clinically relevant change in the

 

Tipranavir Cmin ↓ 26%

respiratory response to carbon

 

 

dioxide. The clinical relevance of

 

 

the reduced loperamide plasma

 

 

concentration is unknown.

Fluticasone propionate

In a clinical study where ritonavir

Concomitant administration of

Interaction study performed

100 mg capsules bid were co-

Aptivus, co-administered with low

only with ritonavir

administered with 50 µg intranasal

dose ritonavir, and these

 

fluticasone propionate (4 times

glucocorticoids is not recommended

 

daily) for 7 days in healthy subjects,

unless the potential benefit of

 

the fluticasone propionate plasma

treatment outweighs the risk of

 

levels increased significantly,

systemic corticosteroid effects (see

 

whereas the intrinsic cortisol levels

section 4.4). A dose reduction of the

 

decreased by approximately 86%

glucocorticoid should be considered

 

(90% confidence interval 82-89%).

with close monitoring of local and

 

Greater effects may be expected

systemic effects or a switch to a

 

when fluticasone propionate is

glucocorticoid, which is not a

 

inhaled. Systemic corticosteroid

substrate for CYP3A4 (e.g.

 

effects including Cushing's

beclomethasone). Moreover, in case

 

syndrome and adrenal suppression

of withdrawal of glucocorticoids

 

have been reported in patients

progressive dose reduction may

 

receiving ritonavir and inhaled or

have to be performed over a longer

 

intranasally administered

period. The effects of high

 

fluticasone propionate; this could

fluticasone systemic exposure on

 

also occur with other corticosteroids

ritonavir plasma levels are as yet

 

metabolised via the P450 3A

unknown.

 

pathway e.g. budesonide.

 

 

It is unknown whether the

 

 

combination of tipranavir with

 

 

ritonavir might cause a larger

 

 

increase in fluticasone exposure.

 

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment (see section 4.5).

Pregnancy

There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding

Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving Aptivus.

Fertility

Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir showed no adverse effect on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile

Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post marketing experience (see section 4.4).

Aptivus co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is therefore needed in patients treated with Aptivus, co-administered with low dose ritonavir (see section 4.4).

Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Aptivus should therefore be used with caution in patients co-infected with hepatitis B or C. Aptivus should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Tabulated summary of adverse reactions

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n=1397) and are listed below by system organ class and frequency according to the following categories:

Very common (≥ 1/10), common (≥ 1/100 to 1/10), uncommon (≥1/1,000 to 1/100), rare (≥1/10,000 to 1/1,000)

Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post- marketing experience:

Blood and lymphatic system disorders

uncommon

neutropenia, anaemia, thrombocytopenia

Immune system disorders

 

 

 

uncommon

hypersensitivity

Metabolism and nutrition disorders

 

 

 

common

hypertriglyceridaemia, hyperlipidaemia

uncommon

anorexia, decreased appetite, weight decreased,

 

hyperamylasaemia, hypercholesterolaemia,

 

diabetes mellitus, hyperglycaemia

rare

dehydration

 

 

Psychiatric disorders

 

 

 

uncommon

insomnia, sleep disorder

 

 

Nervous system disorders

 

 

 

common

headache

 

 

uncommon

dizziness, neuropathy peripheral, somnolence

 

 

rare

intracranial haemorrhage*

 

 

Respiratory, thoracic and

 

mediastinal disorders

 

uncommon

dyspnoea

 

 

Gastrointestinal disorders

 

 

 

very common

diarrhoea, nausea

 

 

common

vomiting, flatulence, abdominal pain, abdominal

 

distension, dyspepsia

uncommon

gastrooesophageal reflux disease, pancreatitis

 

 

rare

lipase increased

 

 

Hepatobiliary disorders

 

 

 

uncommon

hepatic enzyme increased (ALAT, ASAT),

 

cytolytic hepatitis, liver function test abnormal

 

(ALAT, ASAT), hepatitis toxic

 

 

rare

hepatic failure (including fatal outcome),

 

hepatitis, hepatic steatosis, hyperbilirubinaemia

 

 

Skin and subcutaneous tissue disorders

 

 

 

common

rash

 

 

uncommon

pruritus, exanthem

 

 

Musculoskeletal and connective

 

tissue disorders

 

uncommon

myalgia, muscle spasms

 

 

Renal and urinary disorders

 

 

 

uncommon

renal failure

 

 

General disorders and

 

administration site conditions

 

common

fatigue

 

 

uncommon

pyrexia, influenza like illness, malaise

 

 

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the

comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with ritonavir administration. The clinical significance of these observations has not been fully explored.

Hepatotoxicity

After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with tipranavir with ritonavir.

Metabolic parameters

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

Hyperlipidaemia

Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir with ritonavir arm and 15.6% in the comparator arm.

Bleeding

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials (n=6300).

RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of tipranavir cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the Aptivus clinical trials.

Rash

An interaction study in women between tipranavir, co-administered with low dose ritonavir, and ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs. 12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST- 2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count (5.7%).

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

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 these events can occur many months after

initiation of treatment (see section 4.4). Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.

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).

Paediatric population

In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 62 children aged 2 to 12 years received Aptivus oral solution. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the

48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients age 2 to < 12 years (reported in 2 or more children, Trial 1182.14, 48 weeks analyses, Full Analysis Set).

Total patients treated (N)

Events [N(%)]

 

Diarrhoea

4 (6.5)

Vomiting

3 (4.8)

Nausea

3 (4.8)

Abdominal pain1

3 (4.8)

Pyrexia

4 (6.5)

Rash2

4 (6.5)

gamma GT increased

4 (6.5)

ALAT increased

2 (3.2)

Anaemia

2 (3.2)

1 Includes abdominal pain (N=1), dysphagia (N=1) and epigastric discomfort (N=1).

2 Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruritic, and urticaria.

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

Human experience with tipranavir overdose is very limited. No specific signs and symptoms of overdose are known. Generally, an increased frequency and higher severity of adverse reactions may result from overdose.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09

Mechanism of action

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Antiviral activity in vitro

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% and 90% effective concentrations (EC50 and EC90) ranging from 0.03 to 0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in vitro to tipranavir with EC50 values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively. Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75- fold in conditions where human serum is present.

Resistance

The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3- fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same conditions. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.

Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a 10-fold decrease in tipranavir susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials, 276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre- existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross-resistance

Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 clinical isolates showing post-treatment decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from highly treatment experienced patients who have received multiple peptidic protease inhibitors.

ECG evaluation

The effect of tipranavir with low dose of ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: tipranavir/ritonavir (500/200 mg), tipranavir/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.8 ms) for the supra-therapeutic 750/200 mg dose. Hence tipranavir at therapeutic dose with low dose of ritonavir did not prolong the QTc interval but may do so at supratherapeutic dose.

Clinical pharmacodynamic data

This indication is based on the results of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus oral solution in mostly treatment-experienced children aged 2 to 12 years.

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with tipranavir 500 mg co-administered with low dose ritonavir 200 mg (twice daily) plus an optimised background regimen (OBR) individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.

All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations on codons 33, 82, 84 or 90.

After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to tipranavir with ritonavir in a separate roll-over study.

The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median baseline CD4 cell counts were 158 and 166 cells/mm3, respectively, (ranges 1-1893 and 1-

1184 cells/mm3); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log10 copies/ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log10 copies/ml).

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four mutations. In addition the majority of participants had mutations associated with both NRTI and NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples. There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41- fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented

for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of patients with genotypically resistant strains in the Table below.

Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment- experienced patients)

RESIST study

Tipranavir /RTV

CPI/RTV**

p-value

 

n (%)

N

n (%)

N

 

Overall population

 

 

 

 

0.0001

FAS

255 (34.2)

114 (15.5)

PP

171 (37.7)

74 (17.1)

0.0001

- with ENF (FAS)

85 (50.0)

28 (20.7)

0.0001

- without ENF (FAS)

170 (29.5)

(14.3)

0.0001

Genotypically Resistant

 

 

 

 

 

 

LPV/rtv

 

 

 

 

 

0.0001

FAS

66 (28.9)

23 (9.5)

PP

47 (32.2)

13 (9.1)

0.0001

APV/rtv

 

 

 

 

 

0.0001

FAS

50 (33.3)

(14.9)

PP

38 (39.2)

(18.3)

0.0010

SQV/rtv

 

 

 

 

 

0.0001

FAS

22 (30.6)

(7.0)

PP

11 (28.2)

(5.7)

0.0650

IDV/rtv

 

 

 

 

 

 

FAS

6 (46.2)

(5.3)

0.0026

PP

3 (50.0)

(7.1)

0.0650

*Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure

**Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 600 mg/100 mg twice daily (n=194)

ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all randomised and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/ml in patients receiving tipranavir with ritonavir versus -0.22 log10 copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm3 in patients receiving tipranavir with ritonavir (N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm.

The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (e.g. enfuvirtide).

At present there are no results from controlled trials evaluating the effect of tipranavir on clinical progression of HIV.

Paediatric population

HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m2/150 mg/m2 dose, compared to the 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non- protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance testing. All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500 mg/200 mg twice daily could change to Aptivus capsules

from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic and immunologic responses through 48 weeks.

The available clinical data do not support the use of Aptivus oral solution in adolescents or adults. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution (see section 5.2). Due to this and to the high vitamin E content of the oral solution, the risk of adverse reactions (type, frequency and/or severity) may be higher than with the capsule formulation. In patients less than 12 years of age, however, the oral solution is the only available option for treatment with tipranavir, as no data are available on the efficacy and safety of Aptivus capsules in children less than 12 years of age. Since Aptivus capsules and oral solution are not bioequivalent, results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2). Moreover, in patients with a body surface area of less than 1.33 m² appropriate dose adjustments cannot be achieved with the capsule formulation. These factors lead to the conclusion that the benefits outweigh the risks of Aptivus oral solution only in children between 2 and 12 years of age without any other therapeutic option (see section 4.1).

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients receiving Aptivus oral solution are displayed in the tables below.

Baseline characteristics for patients 2 - <12 years treated with Aptivus oral solution

Variable

 

Value

Number of Patients

 

Age-Median (years)

 

8.1

Gender

% Male

59.7%

Race

% White

71.0%

 

% Black

25.8%

 

% Asian

3.2%

Baseline HIV-1 RNA

Median

4.8 (3.3 – 6.0)

(log10 copies/ml)

(Min – Max)

 

 

% with VL >

37.1%

 

100,000 copies/ml

 

Baseline CD4+

Median

600 (24 – 2578)

(cells/mm3)

(Min – Max)

 

 

% ≤ 200

15.5%

 

 

 

Baseline % CD4+ cells

Median

21.9% (1.5% –

 

(Min – Max)

44.0%)

 

 

 

Previous ADI*

% with Category C

48.4%

Treatment history

% with any ARV

96.8%

 

Median # previous

 

NRTIs

 

 

Median # previous

 

NNRTIs

 

 

Median # previous

 

PIs

 

* AIDS defining illness

 

 

Key efficacy results at 48 weeks for patients 2 - <12 years treated with Aptivus oral solution

Endpoint

Result

Number of patients

Primary efficacy endpoint:

50.0%

% with VL < 400

 

Median change from baseline

-2.06

in log10 HIV-1 RNA (copies/ml)

 

Median change from baseline

in CD4+ cell count (cells/mm3)

 

Median change from baseline

5%

in % CD4+ cells

 

Analyses of tipranavir resistance in treatment experienced patients

Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to tipranavir with ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

Primary PI mutations

Analyses were conducted to assess virological outcome by the number of primary PI mutations (any change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

Mutations at protease codons 33, 82, 84 and 90

A reduced virological response was observed in patients with viral strains harbouring two or more mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

Tipranavir resistance-associated mutations

Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir- associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has been established.

This score has been determined from the selected RESIST patient population having specific mutation inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see table below).

Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log10 copies/ml decrease in viral load compared to baseline), according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

 

New ENF

No New

 

 

ENF*

Number of

TPV/r

TPV/r

TPV Score

 

 

Mutations**

 

 

0,1

73%

53%

61%

33%

75%

27%

59%

23%

≥ 5

47%

13%

All patients

61%

29%

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

 

New ENF

No New

 

 

ENF*

Number of

TPV/r

TPV/r

TPV Score

 

 

Mutations**

 

 

0, 1

-2.3

-1.6

-2.1

-1.1

-2.4

-0.9

-1.7

-0.8

≥ 5

-1.9

-0.6

All patients

-2.0

-1.0

*Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Tipranavir phenotypic resistance

Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

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.

5.2 Pharmacokinetic properties

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2). Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose- ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0- 12h, Cmax and Cmin and decreases the clearance of tipranavir. 500 mg tipranavir co-administered with low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without ritonavir.

Absorption

Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor and appears to be a potent P-gp inducer

as well. Data suggest that, although ritonavir is a P-gp inhibitor, the net effect of Aptivus, co- administered with low dose ritonavir, at the proposed dose regimen at steady-state, is P-gp induction. Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear pharmacokinetics at steady state.

Dosing with Aptivus capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), occurring approximately 3 hours after administration. The mean steady-state trough concentration prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for female patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was

5.5 (females) or 6.0 hours (males).

Effects of food on oral absorption

Food improves the tolerability of tipranavir with ritonavir. Therefore Aptivus, co-administered with low dose ritonavir, should be given with food.

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of antacids (see section 4.5).

Distribution

Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% 0.006%; HIV-positive subjects 0.019% 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 M. The unbound fraction of tipranavir appeared to be independent of total concentration over this concentration range.

No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Biotransformation

In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.

The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver.

The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a 14C-tipranavir human study (500 mg 14C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination

Administration of 14C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg ritonavir twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The

effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500 mg/200 mg twice daily with a light meal.

Special populations

Although data available at this stage are currently limited to allow a definitive analysis, they suggest that the pharmacokinetic profile is unchanged in older people and comparable between races. By contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir concentrations than males. After four weeks of Aptivus 500 mg with 200 mg ritonavir (twice daily) the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. This difference in concentrations does not warrant a dose adjustment.

Renal impairment

Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic impairment

In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment is required in patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 4.4).

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. Tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).

Paediatric population

The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

5.3 Preclinical safety data

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co- administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those seen in the tipranavir single agent toxicological studies.

The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The effects were reversible with termination of treatment. Additional changes included bleeding in rats at high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or even below the human exposure levels at the recommended clinical dose.

In in vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving Aptivus with ritonavir. The clinical implications of these findings are not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At maternal doses producing systemic exposure levels similar to or below those at the recommended clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of genetic toxicity in a battery of in vitro and in vivo tests.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol

Vitamin E polyethylene glycol succinate

Purified water

Propylene glycol

Mono/diglycerides of caprylic/capric acid

Sucralose

Butter mint (flavouring)

Butter toffee (flavouring)

Ascorbic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

In use storage: 60 days, after first opening of the bottle. It is advisable that the patient writes the date of opening the bottle on the label and/or carton.

6.4 Special precautions for storage

Do not store below 15°C. Do not refrigerate or freeze.

6.5 Nature and contents of container

Amber glass bottle, with two-piece plastic child-resistant closure (outer shell high density polyethylene (HDPE), inner shell polypropylene resin with a foamed laminated polyethylene liner.. Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml oral syringe, HDPE syringe tip cap and clear LDPE bottle-syringe adapter.

6.6 Special precautions for disposal and other handling

Before taking Aptivus it should be checked that the oral solution is clear and whether there are crystals or other particles at the bottom of the bottle. A small amount of crystals may be observed in the bottle, which does not affect the potency or safety of the product. If observed, crystals are typically seen as a paper-thin layer on the bottom when the bottle is stored upright. Dosing by means of the measuring device remains accurate even when crystals are observed. If there is more than a thin layer of crystals

at the bottom of the bottle or uncertainty about the amount of crystals observed, the bottle should be returned for a replacement as soon as possible. Until the bottle is exchanged the patient should continue to take the usual doses of the oral solution. Patients should be instructed to observe closely for crystals.

The exact dose should be measured using the supplied measuring syringe and adapter, as follows:

1.Open the bottle by pressing down on the cap and turning in an anti-clockwise direction.

2.Remove the syringe cap covering the tip of the oral syringe (the cap will not be attached if this is the first time the oral syringe has been used) and insert the oral syringe into the adapter located in the neck of the bottle. Make sure the oral syringe is tightly inserted.

3.Turn the bottle upside down and gently withdraw the required amount of Aptivus oral solution.

4.Administer Aptivus oral solution immediately. The maximum volume which can be withdrawn

at one time is 5 ml (equivalent to 500 mg tipranavir), which is the maximum single dose for a child with BSA > 1.33 m2.

5.After use of the oral syringe, reapply the syringe cap.

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005

Date of latest renewal: 19 June 2015

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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