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Reyataz (atazanavir sulphate) – Summary of product characteristics - J05AE08

Updated on site: 09-Oct-2017

Medication nameReyataz
ATC CodeJ05AE08
Substanceatazanavir sulphate
ManufacturerBristol-Myers Squibb Pharma EEIG

1.NAME OF THE MEDICINAL PRODUCT

REYATAZ 100 mg hard capsules

REYATAZ 150 mg hard capsules

REYATAZ 200 mg hard capsules

REYATAZ 300 mg hard capsules

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

REYATAZ 100 mg hard capsules

Each capsule contains 100 mg of atazanavir (as sulphate).

Excipient with known effect: 54.79 mg of lactose per capsule.

REYATAZ 150 mg hard capsules

Each capsule contains 150 mg of atazanavir (as sulphate).

Excipient with known effect: 82.18 mg of lactose per capsule.

REYATAZ 200 mg hard capsules

Each capsule contains 200 mg of atazanavir (as sulphate).

Excipient with known effect: 109.57 mg of lactose per capsule.

REYATAZ 300 mg hard capsules

Each capsule contains 300 mg of atazanavir (as sulphate).

Excipient with known effect: 164.36 mg of lactose per capsule.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Hard capsule

REYATAZ 100 mg hard capsules

Opaque blue and white capsule printed with white and blue inks, with "BMS 100 mg" on one half and with "3623" on the other half.

REYATAZ 150 mg hard capsules

Opaque blue and powder blue capsule printed with white and blue inks, with "BMS 150 mg" on one half and with "3624" on the other half.

REYATAZ 200 mg hard capsules

Opaque blue capsule printed with white ink, with "BMS 200 mg" on one half and with "3631" on the other half.

REYATAZ 300 mg hard capsules

Opaque red and blue capsule printed with white ink, with "BMS 300 mg" on one half and with "3622" on the other half.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

REYATAZ capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV- 1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products (see section 4.2).

Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations).

The choice of REYATAZ in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).

4.2Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Adults

The recommended dose of REYATAZ capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1). (See also section 4.4 Withdrawal of ritonavir only under restrictive conditions).

Paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg)

The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. REYATAZ capsules must be taken with ritonavir and have to be taken with food.

Table 1: Dose for paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg) for REYATAZ capsules with ritonavir

Body Weight (kg)

REYATAZ once daily dose

ritonavir once daily dosea

15 to less than 35

200 mg

100 mg

at least 35

300 mg

100 mg

a Ritonavir capsules, tablets or oral solution.

Paediatric patients (at least 3 months of age and weighing at least 5 kg): REYATAZ oral powder is available for paediatric patients at least 3 months of age and weighing at least 5 kg (see Summary of Product Characteristics for REYATAZ oral powder). Switching to REYATAZ capsules from REYATAZ oral powder is encouraged as soon as patients are able to consistently swallow capsules.

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation (see Summary of Product Characteristics for REYATAZ oral powder).

Special populations Renal impairment

No dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).

Hepatic impairment

REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ with ritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ with ritonavir must not be used in patients with moderate to severe hepatic impairment

(see sections 4.3, 4.4 and 5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen

(see section 4.4), unboosted REYATAZ could be maintained in patients with mild hepatic impairment

at a dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg once daily with food (see section 5.2). Unboosted REYATAZ must not be used in patients with severe hepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g., tenofovir disoproxil fumarate or H2-receptor antagonists).

If tenofovir disoproxil fumarate or an H2-receptor antagonist is needed, a dose increase to REYATAZ 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receiving both tenofovir disoproxil fumarate and an H2-receptor antagonist.

(See section 4.4 Withdrawal of ritonavir only under restrictive conditions).

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

During this time, postpartum patients should follow the same dose recommendation as for non- pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

REYATAZ should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.

Method of administration:

For oral use. The capsules should be swallowed whole.

4.3Contraindications

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

REYATAZ is contraindicated in patients with severe hepatic insufficiency

(see sections 4.2, 4.4 and 5.2). REYATAZ with ritonavir is contraindicated in patients with moderate hepatic insufficiency (see sections 4.2, 4.4 and 5.2).

Co-administration with simvastatin or lovastatin (see section 4.5).

Combination of rifampicin (see section 4.5).

Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see sections 4.4 and 4.5.

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on

parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

Co-administration with products containing St. John’s wort (Hypericum perforatum) (see section 4.5).

4.4Special warnings and precautions for use

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.

Co-administration of REYATAZ with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).

Patients with coexisting conditions

Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of REYATAZ has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

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

Renal impairment: No dosage adjustment is needed in patients with renal impairment. However, REYATAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

QT prolongation: Dose related asymptomatic prolongations in PR interval with REYATAZ have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients 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 suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral theraphy. Such changes may in part be linked to the disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating

this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinicallly appropriate.

In clinical studies, REYATAZ (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators.

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of REYATAZ and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Withdrawal of ritonavir only under restrictive conditions

The recommended standard treatment is REYATAZ boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.

The withdrawal of ritonavir from the boosted regimen of REYATAZ is not recommended, but may be considered in adults patients at the dose of 400 mg once daily with food only under the following combined restrictive conditions:

absence of prior virologic failure

undetectable viral load during the last 6 months under current regimen

viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.

REYATAZ given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil fumarate and with other concomitant medications that reduce atazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen) or in case of perceived challenging compliance.

REYATAZ given without ritonavir should not be used in pregnant patients given that it could result of suboptimal exposure of particular concern for the mother infection and vertical transmission.

Cholelithiasis

Cholelithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. In some cases, nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

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 carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occurs many months after initiation of treatment.

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.

Rash and associated syndromes

Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. REYATAZ should be discontinued if severe rash develops.

The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of REYATAZ, REYATAZ may not be restarted.

Interactions with other medicinal products

The combination of REYATAZ with atorvastatin is not recommended (see section 4.5).

Co-administration of REYATAZ with nevirapine or efavirenz is not recommended (see section 4.5). If the co-administration of REYATAZ with an NNRTI is required, an increase in the dose of both REYATAZ and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ and medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile dysfunction in patients receiving REYATAZ. Co-administration of REYATAZ with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and REYATAZ with ritonavir is not recommended, unless an assessment of the benefit/risk justifies the use of voriconazole.

In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected (see section 4.5).

Concomitant use of REYATAZ/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).

Concomitant use of salmeterol and REYATAZ may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and REYATAZ is not recommended (see section 4.5).

The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.

Co-administration of REYATAZ with proton pump inhibitors is not recommended (see section 4.5). If the combination of REYATAZ with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.

Co-administration of REYATAZ with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided (see section 4.5).

Paediatric population

Safety

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Efficacy

Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance.

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicinal product.

4.5Interaction with other medicinal products and other forms of interaction

When REYATAZ and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with REYATAZ and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, REYATAZ is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Other interactions

Interactions between atazanavir and other medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the recommended regimen of atazanavir (see section 4.4).

If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), special attention should be given to atazanavir interactions that may differ in the absence of ritonavir

(see information below Table 2).

Table 2: Interactions between REYATAZ and other medicinal products

Medicinal products by

Interaction

Recommendations concerning

therapeutic area

 

co-administration

 

 

 

ANTI-RETROVIRALS

 

 

 

 

 

Protease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co- administration is not recommended.

Ritonavir 100 mg once daily

Atazanavir AUC: ↑250% (↑144%

Ritonavir 100 mg once daily is

(atazanavir 300 mg once daily)

↑403%)*

used as a booster of atazanavir

Studies conducted in HIV-

Atazanavir Cmax: ↑120% (↑56%

pharmacokinetics.

↑211%)*

 

infected patients.

Atazanavir Cmin: ↑713% (↑359%

 

 

↑1339%)*

 

 

* In a combined analysis, atazanavir

 

 

300 mg and ritonavir 100 mg (n=33)

 

 

was compared to atazanavir 400 mg

 

 

without ritonavir (n=28).

 

 

The mechanism of interaction between

 

 

atazanavir and ritonavir is CYP3A4

 

 

inhibition.

 

Indinavir

Indinavir is associated with indirect

Co-administration of

 

unconjugated hyperbilirubinaemia due

REYATAZ and indinavir is not

 

to inhibition of UGT.

recommended (see section 4.4).

Nucleoside/nucleotide reverse

transcriptase inhibitors (NRTIs)

 

 

 

 

Lamivudine 150 mg twice

No significant effect on lamivudine

Based on these data and because

daily + zidovudine 300 mg

and zidovudine concentrations was

ritonavir is not expected to have

twice daily

observed.

a significant impact on the

(atazanavir 400 mg once daily)

 

pharmacokinetics of NRTIs, the

 

 

co-administration of these

 

 

medicinal products and

 

 

REYATAZ is not expected to

 

 

significantly alter the exposure

 

 

of the co-administered medicinal

 

 

products.

Abacavir

The co-administration of abacavir and

 

 

REYATAZ is not expected to

 

 

significantly alter the exposure of

 

 

abacavir.

 

Didanosine (buffered tablets)

Atazanavir, simultaneous

Didanosine should be taken at

200 mg/stavudine 40 mg, both

administration with ddI+d4T (fasted)

the fasted state 2 hours after

single dose

Atazanavir AUC ↓87% (↓92% ↓79%)

REYATAZ taken with food.

(atazanavir 400 mg single dose)

Atazanavir Cmax ↓89% (↓94% ↓82%)

The co-administration of

 

Atazanavir Cmin ↓84% (↓90% ↓73%)

stavudine with REYATAZ is

 

 

not expected to significantly

 

Atazanavir, dosed 1 hr after ddI+d4T

alter the exposure of stavudine.

 

(fasted)

 

 

Atazanavir AUC ↔3% (↓36% ↑67%)

 

 

Atazanavir Cmax ↑12% (↓33% ↑18%)

 

 

Atazanavir Cmin ↔3% (↓39% ↑73%)

 

 

Atazanavir concentrations were greatly

 

 

decreased when co-administered with

 

 

didanosine (buffered tablets) and

 

 

stavudine. The mechanism of

 

 

interaction is a reduced solubility of

 

 

atazanavir with increasing pH related

 

 

to the presence of anti-acid agent in

 

 

didanosine buffered tablets.

 

 

No significant effect on didanosine

 

 

and stavudine concentrations was

 

 

observed.

 

Didanosine (enteric coated

Didanosine (with food)

 

capsules) 400 mg single dose

Didanosine AUC ↓34% (↓41% ↓27%)

 

(atazanavir 300 mg once daily

Didanosine Cmax ↓38% (↓48% ↓26%)

 

with ritonavir 100 mg once

Didanosine Cmin ↑25% (↓8% ↑69%)

 

daily)

No significant effect on atazanavir

 

 

 

 

concentrations was observed when

 

 

administered with enteric-coated

 

 

didanosine, but administration with

 

 

food decreased didanosine

 

 

concentrations.

 

Tenofovir disoproxil fumarate

Atazanavir AUC ↓22% (↓35% ↓6%) *

When co-administered with

300 mg once daily

Atazanavir Cmax ↓16% (↓30% ↔0%) *

tenofovir disoproxil fumarate, it

(atazanavir 300 mg once daily

Atazanavir Cmin ↓23% (↓43% ↑2%) *

is recommended that

with ritonavir 100 mg once

 

REYATAZ 300 mg be given

daily)

* In a combined analysis from several

with ritonavir 100 mg and

 

clinical studies, atazanavir/ritonavir

tenofovir disoproxil fumarate

Studies conducted in HIV-

300/100 mg co-administered with

300 mg (all as a single dose with

infected patients

tenofovir disoproxil fumarate 300 mg

food).

 

(n=39) was compared to

 

 

atazanavir/ritonavir 300/100 mg

 

 

(n=33).

 

 

The efficacy of REYATAZ/ritonavir

 

 

in combination with tenofovir

 

 

disoproxil fumarate in treatment-

 

 

experienced patients has been

 

 

demonstrated in clinical study 045 and

 

 

in treatment naive patients in clinical

 

 

study 138 (see sections 4.8 and 5.1).

 

 

The mechanism of interaction between

 

 

atazanavir and tenofovir disoproxil

 

 

fumarate is unknown.

 

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate AUC

Patients should be closely

300 mg once daily

↑37% (↑30% ↑45%)

monitored for tenofovir

(atazanavir 300 mg once daily

Tenofovir disoproxil fumarate Cmax

disoproxil fumarate-associated

with ritonavir 100 mg once

↑34% (↑20% ↑51%)

adverse reactions, including

daily)

Tenofovir disoproxil fumarate Cmin

renal disorders.

 

↑29% (↑21% ↑36%)

 

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

 

 

 

Efavirenz 600 mg once daily

Atazanavir (pm): all administered with

Co-administration of efavirenz

(atazanavir 400 mg once daily

food

and REYATAZ is not

with ritonavir 100 mg once

Atazanavir AUC ↔0%(↓9% ↑10%)*

recommended (see section 4.4)

daily)

Atazanavir Cmax ↑17%(↑8% ↑27%)*

 

 

Atazanavir Cmin ↓42%(↓51% ↓31%)*

 

 

 

 

Efavirenz 600 mg once daily

Atazanavir (pm): all administered with

 

(atazanavir 400 mg once daily

food

 

with ritonavir 200 mg once

Atazanavir AUC ↔6% (↓10% ↑26%)

 

daily)

*/**

 

 

Atazanavir Cmax ↔9% (↓5% ↑26%)

 

 

*/**

 

 

Atazanavir Cmin ↔12% (↓16% ↑49%)

 

 

*/**

 

 

* When compared to REYATAZ

 

 

300 mg/ritonavir 100 mg once daily in

 

 

the evening without efavirenz. This

 

 

decrease in atazanavir Cmin, might

 

 

negatively impact the efficacy of

 

 

atazanavir. The mechanism of

 

 

efavirenz/atazanavir interaction is

 

 

CYP3A4 induction.

 

 

** Based on historical comparison.

 

Nevirapine 200 mg twice daily

Nevirapine AUC ↑26% (↑17% ↑36%)

Co-administration of nevirapine

(atazanavir 400 mg once daily

Nevirapine Cmax ↑21% (↑11% ↑32%)

and REYATAZ is not

with ritonavir 100 mg once

Nevirapine Cmin ↑35% (↑25% ↑47%)

recommended (see section 4.4)

daily)

Atazanavir AUC ↓19% (↓35% ↑2%) *

 

Study conducted in HIV

 

Atazanavir Cmax ↔2% (↓15% ↑24%) *

 

infected patients

Atazanavir Cmin ↓59% (↓73% ↓40%) *

 

 

* When compared to REYATAZ

 

 

300 mg and ritonavir 100 mg without

 

 

nevirapine. This decrease in atazanavir

 

 

Cmin, might negatively impact the

 

 

efficacy of atazanavir. The mechanism

 

 

of nevirapine/atazanavir interaction is

 

 

CYP3A4 induction.

 

Integrase Inhibitors

 

 

 

 

 

Raltegravir 400 mg twice

Raltegravir AUC ↑41%

No dose adjustment required for

daily

Raltegravir Cmax ↑24%

raltegravir.

(atazanavir/ritonavir)

Raltegravir C12hr ↑77%

 

 

The mechanism is UGT1A1 inhibition.

 

HCV Protease Inhibitors

 

 

 

 

 

Boceprevir 800 mg three times

boceprevir AUC ↔5%

Co-administration of

daily

boceprevir Cmax ↔7%

atazanavir/ritonavir with

(atazanavir 300 mg/ritonavir

boceprevir Cmin ↔18%

boceprevir resulted in lower

100 mg once daily)

atazanavir AUC ↓ 35%

exposure of atazanavir which

 

may be associated with lower

 

atazanavir Cmax ↓ 25%

efficacy and loss of HIV control.

 

atazanavir Cmin ↓ 49%

This co-administration might be

 

 

considered on a case by case

 

ritonavir AUC ↓ 36%

basis if deemed necessary, in

 

ritonavir Cmax ↓ 27%

patients with suppressed HIV

 

ritonavir Cmin ↓ 45%

viral loads and with HIV viral

 

 

strain without any suspected

 

 

resistance to the HIV regimen.

 

 

Increased clinical and laboratory

 

 

monitoring for HIV suppression

 

 

is warranted.

ANTIBIOTICS

 

 

 

 

 

Clarithromycin 500 mg twice

Clarithromycin AUC ↑94% (↑75%

No recommendation regarding

daily

↑116%)

dose reduction can be made;

(atazanavir 400 mg once daily)

Clarithromycin Cmax ↑50% (↑32%

therefore, caution should be

 

↑71%)

exercised if REYATAZ is co-

 

Clarithromycin Cmin ↑160% (↑135%

administered with

 

↑188%)

clarithromycin.

 

14-OH clarithromycin

 

 

14-OH clarithromycin AUC ↓70%

 

 

(↓74% ↓66%)

 

 

14-OH clarithromycin Cmax ↓72%

 

 

(↓76% ↓67%)

 

 

14-OH clarithromycin Cmin ↓62%

 

 

(↓66% ↓58%)

 

 

Atazanavir AUC ↑28% (↑16% ↑43%)

 

 

Atazanavir Cmax ↔6% (↓7% ↑20%)

 

 

Atazanavir Cmin ↑91% (↑66% ↑121%)

 

 

A dose reduction of clarithromycin

 

 

may result in subtherapeutic

 

 

concentrations of 14-OH

 

 

clarithromycin. The mechanism of the

 

 

clarithromycin/atazanavir interaction is

 

 

CYP3A4 inhibition.

 

 

 

 

ANTIFUNGALS

 

 

 

 

 

Ketoconazole 200 mg once

No significant effect on atazanavir

Ketoconazole and itraconazole

daily

concentrations was observed.

should be used cautiously with

(atazanavir 400 mg once daily)

 

REYATAZ/ritonavir, high doses

Itraconazole

Itraconazole, like ketoconazole, is a

of ketoconazole and itraconazole

 

potent inhibitor as well as a substrate

(>200 mg/day) are not

 

of CYP3A4.

recommended.

 

 

 

 

Based on data obtained with other

 

 

boosted PIs and ketoconazole, where

 

 

ketoconazole AUC showed a 3-fold

 

 

increase, REYATAZ/ritonavir is

 

 

expected to increase ketoconazole or

 

 

itraconazole concentrations.

 

 

 

 

Voriconazole 200 mg twice

Voriconazole AUC ↓33% (↓42%

Co-administration of

daily (atazanavir

↓22%)

voriconazole and REYATAZ

300 mg/ritonavir 100 mg once

Voriconazole Cmax ↓10% (↓22% ↓4%)

with ritonavir is not

daily)

Voriconazole Cmin ↓39% (↓49% ↓28%)

recommended unless an

 

 

assessment of the benefit/risk to

Subjects with at least one

 

the patient justifies the use of

functional CYP2C19 allele.

Atazanavir AUC ↓12% (↓18% ↓5%)

voriconazole (see section 4.4).

 

Atazanavir Cmax ↓13% (↓20% ↓4%)

At the time voriconazole

 

Atazanavir Cmin ↓ 20 % (↓28 % ↓10%)

 

 

treatment is required, a patient's

 

 

CYP2C19 genotype should be

 

Ritonavir AUC ↓12% (↓17% ↓7%)

performed if feasible.

 

Ritonavir Cmax ↓9% (↓17% ↔0%)

Therefore if the combination is

 

Ritonavir Cmin ↓25% (↓35% ↓14%)

 

 

unavoidable, the following

 

In the majority of patients with at least

recomendations are made

 

one functional CYP2C19 allele, a

according to the CYP2C19

 

reduction in both voriconazole and

status:

 

atazanavir exposures are expected.

- in patients with at least one

 

 

Voriconazole 50 mg twice

Voriconazole AUC ↑561% (↑451%

functional CYP2C19 allele,

daily (atazanavir

↑699%)

close clinical monitoring for a

300 mg/ritonavir 100 mg once

Voriconazole Cmax ↑438% (↑355%

loss of both voriconazole

daily)

↑539%)

(clinical signs) and atazanavir

 

Voriconazole Cmin ↑765% (↑571%

(virologic response) efficacy is

Subjects without a functional

↑1,020%)

recommended.

CYP2C19 allele.

 

- in patients without a functional

 

 

 

Atazanavir AUC ↓20% (↓35% ↓3%)

CYP2C19 allele, close clinical

 

Atazanavir Cmax ↓19% (↓34% ↔0.2%)

and laboratory monitoring of

 

Atazanavir Cmin ↓ 31 % (↓46 % ↓13%)

voriconazole-associated adverse

 

 

events is recommended.

 

Ritonavir AUC ↓11% (↓20% ↓1%)

If genotyping is not feasible, full

 

Ritonavir Cmax ↓11% (↓24% ↑4%)

monitoring of safety and

 

Ritonavir Cmin ↓19% (↓35% ↑1%)

efficacy should be performed.

 

In a small number of patients without a

 

 

functional CYP2C19 allele,

 

 

significantly increased voriconazole

 

 

exposures are expected.

 

 

 

 

Fluconazole 200 mg once daily

Atazanavir and fluconazole

No dosage adjustments are

(atazanavir 300 mg and

concentrations were not significantly

needed for fluconazole and

ritonavir 100 mg once daily)

modified when REYATAZ/ritonavir

REYATAZ.

 

was co-administered with fluconazole.

 

ANTIMYCOBACTERIAL

 

 

 

 

 

Rifabutin 150 mg twice

Rifabutin AUC ↑48% (↑19% ↑84%)

When given with REYATAZ,

weekly

**

the recommended dose of

(atazanavir 300 mg and

Rifabutin Cmax ↑149% (↑103% ↑206%)

rifabutin is 150 mg 3 times per

ritonavir 100 mg once daily)

**

week on set days (for example

 

Rifabutin Cmin ↑40% (↑5% ↑87%) **

Monday-Wednesday-Friday).

 

 

Increased monitoring for

 

25-O-desacetyl-rifabutin AUC ↑990%

rifabutin-associated adverse

 

(↑714% ↑1361%) **

reactions including neutropenia

 

25-O-desacetyl-rifabutin Cmax ↑677%

and uveitis is warranted due to

 

(↑513% ↑883%) **

an expected increase in exposure

 

25-O-desacetyl-rifabutin Cmin ↑1045%

to rifabutin. Further dosage

 

(↑715% ↑1510%) **

reduction of rifabutin to 150 mg

 

 

twice weekly on set days is

 

** When compared to rifabutin

recommended for patients in

 

150 mg once daily alone. Total

whom the 150 mg dose 3 times

 

rifabutin and 25-O-desacetyl-rifabutin

per week is not tolerated. It

 

AUC ↑119% (↑78% ↑169%).

should be kept in mind that the

 

 

twice weekly dosage of 150 mg

 

In previous studies, the

may not provide an optimal

 

pharmacokinetics of atazanavir was

exposure to rifabutin thus

 

not altered by rifabutin.

leading to a risk of rifamycin

 

 

resistance and a treatment

 

 

failure. No dose adjustment is

 

 

needed for REYATAZ.

Rifampicin

Rifampicin is a strong CYP3A4

The combination of rifampicin

 

inducer and has been shown to cause a

and REYATAZ is

 

72% decrease in atazanavir AUC

contraindicated (see section 4.3).

 

which can result in virological failure

 

 

and resistance development. During

 

 

attempts to overcome the decreased

 

 

exposure by increasing the dose of

 

 

REYATAZ or other protease inhibitors

 

 

with ritonavir, a high frequency of

 

 

liver reactions was seen.

 

ANTIPSYCHOTICS

 

 

 

 

 

Quetiapine

Due to CYP3A4 inhibition by

Co-administration of quetiapine

 

REYATAZ, concentrations of

with REYATAZ is

 

quetiapine are expected to increase.

contraindicated as REYATAZ

 

 

may increase quetiapine-related

 

 

toxicity. Increased plasma

 

 

concentrations of quetiapine

 

 

may lead to coma

 

 

(see section 4.3).

ACID REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir disoproxil fumarate

 

In HIV-infected patients with atazanavir/ritonavir at the recommended

For patients not taking

dose 300/100 mg once daily

tenofovir disoproxil fumarate,

Famotidine 20 mg twice daily

Atazanavir AUC ↓18% (↓25% ↑1%)

if REYATAZ 300 mg/ritonavir

 

Atazanavir Cmax ↓20% (↓32% ↓7%)

100 mg and H2-receptor

 

Atazanavir Cmin ↔1% (↓16% ↑18%)

antagonists are co-administered,

Famotidine 40 mg twice daily

Atazanavir AUC ↓23% (↓32% ↓14%)

a dose equivalent to famotidine

 

Atazanavir Cmax ↓23% (↓33% ↓12%)

20 mg twice daily should not be

 

Atazanavir Cmin ↓20% (↓31% ↓8%)

exceeded. If a higher dose of an

In Healthy volunteers with atazanavir/ritonavir at an increased dose

H2-receptor antagonist is

of 400/100 mg once daily

required (e.g., famotidine 40 mg

Famotidine 40 mg twice daily

Atazanavir AUC ↔3% (↓14% ↑22%)

twice daily or equivalent) an

 

Atazanavir Cmax ↔2% (↓13% ↑8%)

increase of the

 

Atazanavir Cmin ↓14% (↓32% ↑8%)

REYATAZ/ritonavir dose from

 

 

300/100 mg to 400/100 mg can

 

 

be considered.

With Tenofovir disoproxil fumarate 300 mg once daily

 

In HIV-infected patients with atazanavir/ritonavir at the recommended dose of 300/100 mg once daily

Famotidine 20 mg twice daily Atazanavir AUC ↓21% (↓34% ↓4%) *

Atazanavir Cmax ↓21% (↓36% ↓4%) *

Atazanavir Cmin ↓19% (↓37% ↑5%) *

Famotidine 40 mg twice daily Atazanavir AUC ↓24% (↓36% ↓11%)*

Atazanavir Cmax ↓23% (↓36% ↓8%) *

Atazanavir Cmin ↓25% (↓47% ↑7%) *

In HIV-infected patients with atazanavir/ritonavir at an increased dose of 400/100 mg once daily

Famotidine 20 mg twice daily

Atazanavir AUC ↑18% (↑6.5%

 

↑30%)*

 

Atazanavir Cmax ↑18% (↑6.7% ↑31%)*

 

Atazanavir Cmin ↑24 % (↑10% ↑39%)*

 

 

Famotidine 40 mg twice daily

Atazanavir AUC ↔2.3% (↓13%

 

↑10%)*

 

Atazanavir Cmax ↔5% (↓17% ↑8.4%)*

 

Atazanavir Cmin ↔1.3% (↓10% ↑15)*

 

 

 

* When compared to atazanavir

 

300 mg once daily with ritonavir

 

100 mg once daily and tenofovir

 

disoproxil fumarate 300 mg all as a

 

single dose with food. When compared

 

to atazanavir 300 mg with ritonavir

 

100 mg without tenofovir disoproxil

 

fumarate, atazanavir concentrations

 

are expected to be additionally

 

decreased by about 20%.

 

The mechanism of interaction is

 

decreased solubility of atazanavir as

 

intra-gastric pH increases with H2-

 

blockers.

For patients who are taking tenofovir disoproxil fumarate, if REYATAZ/ritonavir with both tenofovir disoproxil fumarate and an H2-receptor antagonist are co-administered, a dose increase of REYATAZ to 400 mg with 100 mg of ritonavir is recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.

Proton pump inhibitors

 

 

 

 

 

Omeprazole 40 mg once daily

Atazanavir (am): 2 hr after omeprazole

Co-administration of

(atazanavir 400 mg once daily

Atazanavir AUC ↓61% (↓65% ↓55%)

REYATAZ with ritonavir and

with ritonavir 100 mg once

Atazanavir Cmax ↓66% (↓62% ↓49%)

proton pump inhibitors is not

daily)

Atazanavir Cmin ↓65% (↓71% ↓59%)

recommended. If the

 

 

combination is judged

Omeprazole 20 mg once daily

Atazanavir (am): 1 hr after omeprazole

unavoidable, close clinical

(atazanavir 400 mg once daily

Atazanavir AUC ↓30% (↓43% ↓14%) *

monitoring is recommended in

with ritonavir 100 mg once

Atazanavir Cmax ↓31% (↓42% ↓17%) *

combination with an increase in

daily)

Atazanavir Cmin ↓31% (↓46% ↓12%) *

the dose of REYATAZ to

 

 

400 mg with 100 mg of

 

* When compared to atazanavir

ritonavir; doses of proton pump

 

300 mg once daily with ritonavir

inhibitors comparable to

 

100 mg once daily.

omeprazole 20 mg should not be

 

The decrease in AUC, Cmax, and Cmin

exceeded (see section 4.4).

 

was not mitigated when an increased

 

 

dose of REYATAZ/ritonavir

 

 

(400/100 mg once daily) was

 

 

temporally separated from omeprazole

 

 

by 12 hours. Although not studied,

 

 

similar results are expected with other

 

 

proton pump inhibitors. This decrease

 

 

in atazanavir exposure might

 

 

negatively impact the efficacy of

 

 

atazanavir. The mechanism of

 

 

interaction is decreased solubility of

 

 

atazanavir as intra-gastric pH increases

 

 

with proton pump inhibitors.

 

 

 

 

Antacids

 

 

 

 

 

Antacids and medicinal

Reduced plasma concentrations of

REYATAZ should be

products containing buffers

atazanavir may be the consequence of

administered 2 hours before or

 

increased gastric pH if antacids,

1 hour after antacids or buffered

 

including buffered medicinal products,

medicinal products.

 

are administered with REYATAZ.

 

ALPHA 1-ADRENORECEPTOR

ANTAGONIST

 

 

 

 

Alfuzosin

Potential for increased alfuzosin

Co-administration of alfuzosin

 

concentrations which can result in

with REYATAZ is

 

hypotension. The mechanism of

contraindicated (see section 4.3)

 

interaction is CYP3A4 inhibition by

 

 

REYATAZ and/or ritonavir.

 

ANTICOAGULANTS

 

 

 

 

 

Warfarin

Co-administration with REYATAZ

It is recommended that the

 

has the potential to increase or

International Normalised Ratio

 

decrease warfarin concentrations.

(INR) be monitored carefully

 

 

during treatment with

 

 

REYATAZ, especially when

 

 

commencing therapy.

ANTIEPILEPTICS

 

 

 

 

 

Carbamazepine

 

REYATAZ may increase plasma

Carbamazepine should be used

 

 

levels of carbamazepine due to

with caution in combination

 

 

CYP3A4 inhibition.

with REYATAZ. If necessary,

 

 

Due to carbamazepine inducing effect,

monitor carbamazepine serum

 

 

a reduction in REYATAZ exposure

concentrations and adjust the

 

 

cannot be ruled out.

dose accordingly. Close

 

 

 

monitoring of the patient's

 

 

 

virologic response should be

 

 

 

excercised.

Phenytoin, phenobarbital

 

Ritonavir may decrease plasma levels

Phenobarbital and phenytoin

 

 

of phenytoin and/or phenobarbital due

should be used with caution in

 

 

to CYP2C9 and CYP2C19 induction.

combination with

 

 

Due to phenytoin/phenobarbital

REYATAZ/ritonavir.

 

 

inducing effect, a reduction in

When REYATAZ/ritonavir is

 

 

REYATAZ exposure cannot be ruled

 

 

out.

co-administered with either

 

 

 

phenytoin or phenobarbital, a

 

 

 

dose adjustment of phenytoin or

 

 

 

phenobarbital may be required.

 

 

 

Close monitoring of patient's

 

 

 

virologic response should be

 

 

 

exercised.

Lamotrigine

 

Co-administration of lamotrigine and

Lamotrigine should be used with

 

 

REYATAZ/ritonavir may decrease

caution in combination with

 

 

lamotrigine plasma concentrations due

REYATAZ/ritonavir.

 

 

to UGT1A4 induction.

If necessary, monitor

 

 

 

 

 

 

lamotrigine concentrations and

 

 

 

adjust the dose accordingly.

ANTINEOPLASTICS AND

IMMUNOSUPRESSANTS

 

 

 

 

 

Antineoplastics

 

 

 

 

 

 

Irinotecan

 

Atazanavir inhibits UGT and may

If REYATAZ is co-administered

 

 

interfere with the metabolism of

with irinotecan, patients should be

 

 

irinotecan, resulting in increased

closely monitored for adverse

 

 

irinotecan toxicities.

events related to irinotecan.

Immunosuppressants

 

 

 

 

 

 

Cyclosporin

 

Concentrations of these

More frequent therapeutic

Tacrolimus

 

immunosuppressants may be increased

concentration monitoring of

Sirolimus

 

when co-administered with

these medicinal products is

 

 

REYATAZ due to CYP3A4 inhibition.

recommended until plasma

 

 

 

levels have been stabilised.

CARDIOVASCULAR AGENTS

 

 

 

 

 

 

Antiarrhythmics

 

 

 

 

 

Amiodarone,

 

Concentrations of these

Caution is warranted and

Systemic lidocaine,

 

antiarrhythmics may be increased

therapeutic concentration

Quinidine

 

when co-administered with

monitoring is recommended

 

 

REYATAZ. The mechanism of

when available. The

 

 

amiodarone or systemic

concomitant use of quinidine is

 

 

lidocaine/atazanavir interaction is

contraindicated (see section 4.3).

 

 

CYP3A inhibition. Quinidine has a

 

 

 

narrow therapeutic window and is

 

 

 

contraindicated due to potential

 

 

 

inhibition of CYP3A by REYATAZ.

 

Calcium channel blockers

 

 

 

 

 

 

 

Bepridil

REYATAZ should not be used in

Co-administration with bepridil is

 

combination with medicinal products

contraindicated (see section 4.3)

 

that are substrates of CYP3A4 and

 

 

have a narrow therapeutic index.

 

Diltiazem 180 mg once daily

Diltiazem AUC ↑125% (↑109%

An initial dose reduction of

(atazanavir 400 mg once daily)

↑141%)

diltiazem by 50% is

 

Diltiazem Cmax ↑98% (↑78% ↑119%)

recommended, with subsequent

 

Diltiazem Cmin ↑142% (↑114%

titration as needed and ECG

 

↑173%)

monitoring.

 

Desacetyl-diltiazem AUC ↑165%

 

 

(↑145% ↑187%)

 

 

Desacetyl-diltiazem Cmax ↑172%

 

 

(↑144% ↑203%)

 

 

Desacetyl-diltiazem Cmin ↑121%

 

 

(↑102% ↑142%)

 

 

No significant effect on atazanavir

 

 

concentrations was observed. There

 

 

was an increase in the maximum PR

 

 

interval compared to atazanavir alone.

 

 

Co-administration of diltiazem and

 

 

REYATAZ/ritonavir has not been

 

 

studied. The mechanism of

 

 

diltiazem/atazanavir interaction is

 

 

CYP3A4 inhibition.

 

Verapamil

Serum concentrations of verapamil

Caution should be exercised

 

may be increased by REYATAZ due

when verapamil is co-

 

to CYP3A4 inhibition.

administered with REYATAZ.

CORTICOSTEROIDS

 

 

 

 

 

Fluticasone propionate

The fluticasone propionate plasma

Co-administration of

intranasal 50 µg 4 times daily

levels increased significantly, whereas

REYATAZ/ritonavir and these

for 7 days

the intrinsic cortisol levels decreased

glucocorticoids is not

(ritonavir 100 mg capsules

by approximately 86% (90%

recommended unless the

twice daily)

confidence interval 82%-89%).

potential benefit of treatment

 

Greater effects may be expected when

outweighs the risk of systemic

 

fluticasone propionate is inhaled.

corticosteroid effects

 

Systemic corticosteroid effects

(see section 4.4). A dose

 

including Cushing’s syndrome and

reduction of the glucocorticoid

 

adrenal suppression have been

should be considered with close

 

reported in patients receiving ritonavir

monitoring of local and systemic

 

and inhaled or intranasally

effects or a switch to a

 

administered fluticasone propionate;

glucocorticoid, which is not a

 

this could also occur with other

substrate for CYP3A4 (e.g.,

 

corticosteroids metabolised via the

beclomethasone). Moreover, in

 

P450 3A pathway, e.g., budesonide.

case of withdrawal of

 

The effects of high fluticasone

glucocorticoids, progressive

 

systemic exposure on ritonavir plasma

dose reduction may have to be

 

levels are yet unknown. The

performed over a longer period.

 

mechanism of interaction is CYP3A4

 

 

inhibition.

 

ERECTILE DYSFUNCTION

 

 

 

 

 

PDE5 Inhibitors

 

 

 

 

 

Sildenafil, tadalafil, vardenafil

Sildenafil, tadalafil and vardenafil are

Patients should be warned about

 

metabolised by CYP3A4. Co-

these possible side effects when

 

administration with REYATAZ may

using PDE5 inhibitors for

 

result in increased concentrations of

erectile dysfunction with

 

the PDE5 inhibitor and an increase in

REYATAZ (see section 4.4).

 

PDE5-associated adverse events,

Also see PULMONARY

 

including hypotension, visual changes,

ARTERIAL HYPERTENSION

 

and priapism. The mechanism of this

in this table for futher

 

interaction is CYP3A4 inhibition.

information regarding co-

 

 

administration of REYATAZ

 

 

with sildenafil.

HERBAL PRODUCTS

 

 

 

 

 

St. John’s wort (Hypericum

Concomitant use of St. John's wort

Co-administration of

perforatum)

with REYATAZ may be expected to

REYATAZ with products

 

result in significant reduction in

containing St. John's wort is

 

plasma levels of atazanavir. This effect

contraindicated.

 

may be due to an induction of

 

 

CYP3A4. There is a risk of loss of

 

 

therapeutic effect and development of

 

 

resistance (see section 4.3).

 

HORMONAL CONTRACEPTIVES

 

 

 

 

 

Ethinyloestradiol 25 μg +

Ethinyloestradiol AUC ↓19% (↓25%

If an oral contraceptive is

norgestimate

↓13%)

administered with

(atazanavir 300 mg once daily

Ethinyloestradiol Cmax ↓16% (↓26%

REYATAZ/ritonavir, it is

with ritonavir 100 mg once

↓5%)

recommended that the oral

daily)

Ethinyloestradiol Cmin ↓37% (↓45%

contraceptive contain at least

 

↓29%)

30 μg of ethinyloestradiol and

 

 

that the patient be reminded of

 

Norgestimate AUC ↑85% (↑67%

strict compliance with this

 

↑105%)

contraceptive dosing regimen.

 

Norgestimate Cmax ↑68% (↑51%

Co-administration of

 

↑88%)

REYATAZ/ritonavir with other

 

Norgestimate Cmin ↑102% (↑77%

hormonal contraceptives or oral

 

↑131%)

contraceptives containing

 

 

progestogens other than

 

While the concentration of

norgestimate has not been

 

ethinyloestradiol was increased with

studied, and therefore should be

 

atazanavir given alone, due to both

avoided. An alternate reliable

 

UGT and CYP3A4 inhibition by

method of contraception is

 

atazanavir, the net effect of

recommended.

 

atazanavir/ritonavir is a decrease in

 

 

ethinyloestradiol levels because of the

 

 

inducing effect of ritonavir.

 

 

The increase in progestin exposure

 

 

may lead to related side-effects (e.g.

 

 

insulin resistance, dyslipidemia, acne

 

 

and spotting), thus possibly affecting

 

 

the compliance.

 

Ethinyloestradiol 35 µg +

Ethinyloestradiol AUC ↑48% (↑31%

 

norethindrone

↑68%)

 

(atazanavir 400 mg once daily)

Ethinyloestradiol Cmax ↑15% (↓1%

 

 

↑32%)

 

 

Ethinyloestradiol Cmin ↑91% (↑57%

 

 

↑133%)

 

 

Norethindrone AUC ↑110% (↑68%

 

 

↑162%)

 

 

Norethindrone Cmax ↑67% (↑42%

 

 

↑196%)

 

 

Norethindrone Cmin ↑262% (↑157%

 

 

↑409%)

 

 

The increase in progestin exposure

 

 

may lead to related side-effects (e.g.

 

 

insulin resistance, dyslipidemia, acne

 

 

and spotting), thus possibly affecting

 

 

the compliance.

 

LIPID LOWERING AGENTS

 

 

 

 

 

HMG-CoA reductase inhibitors

 

 

 

 

 

Simvastatin

Simvastatin and lovastatin are highly

Co-administration of simvastatin

Lovastatin

dependent on CYP3A4 for their

or lovastatin with REYATAZ is

 

metabolism and co-administration with

contraindicated due to an

 

REYATAZ may result in increased

increased risk of myopathy

 

concentrations.

including rhabdomyolysis

 

 

(see section 4.3).

Atorvastatin

The risk of myopathy including

Co-administration of

 

rhabdomyolysis may also be increased

atorvastatin with REYATAZ is

 

with atorvastatin, which is also

not recommended. If the use of

 

metabolised by CYP3A4.

atorvastatin is considered strictly

 

 

necessary, the lowest possible

 

 

dose of atorvastatin should be

 

 

administered with careful safety

 

 

monitoring (see section 4.4).

Pravastatin

Although not studied, there is a

Caution should be exercised.

Fluvastatin

potential for an increase in pravastatin

 

 

or fluvastatin exposure when co-

 

 

administered with protease inhibitors.

 

 

Pravastatin is not metabolised by

 

 

CYP3A4. Fluvastatin is partially

 

 

metabolised by CYP2C9.

 

INHALED BETA AGONISTS

 

 

Salmeterol

Co-administration with REYATAZ

 

may result in increased concentrations

 

of salmeterol and an increase in

 

salmeterol-associated adverse events.

 

The mechanism of interaction is

 

CYP3A4 inhibition by atazanavir

OPIOIDS

and/or ritonavir.

 

Co-administration of salmeterol with REYATAZ is not recommended (see section 4.4).

Buprenorphine, once daily,

Buprenorphine AUC ↑67%

Co-administration with

stable maintenance dose

Buprenorphine Cmax ↑37%

REYATAZ with ritonavir

(atazanavir 300 mg once daily

Buprenorphine Cmin ↑69%

warrants clinical monitoring for

with ritonavir 100 mg once

 

sedation and cognitive effects. A

daily)

Norbuprenorphine AUC ↑105%

dose reduction of buprenorphine

 

Norbuprenorphine Cmax ↑61%

may be considered.

 

Norbuprenorphine Cmin ↑101%

 

 

The mechanism of interaction is

 

 

CYP3A4 and UGT1A1 inhibition.

 

 

Concentrations of atazanavir (when

 

 

given with ritonavir) were not

 

 

significantly affected.

 

Methadone, stable

No significant effect on methadone

No dosage adjustment is

maintenance dose

concentrations was observed. Given

necessary if methadone is co-

(atazanavir 400 mg once daily)

that low dose ritonavir (100 mg twice

administered with REYATAZ.

 

daily) has been shown to have no

 

 

significant effect on methadone

 

 

concentrations, no interaction is

 

 

expected if methadone is co-

 

 

administered with REYATAZ, based

 

 

on these data.

 

PULMONARY ARTERIAL

HYPERTENSION

 

 

 

 

PDE5 Inhibitors

 

 

 

 

 

Sildenafil

Co-administration with REYATAZ

A safe and effective dose in

 

may result in increased concentrations

combination with REYATAZ

 

of the PDE5 inhibitor and an increase

has not been established for

 

in PDE5-inhibitor-associated adverse

sildenafil when used to treat

 

events.

pulmonary arterial hypertension.

 

 

Sildenafil, when used for the

 

The mechanism of interaction is

treatment of pulmonary arterial

 

CYP3A4 inhibition by atazanavir

hypertension, is contraindicated

 

and/or ritonavir.

(see section 4.3).

 

 

 

SEDATIVES

 

 

 

 

 

Benzodiazepines

 

 

 

 

 

Midazolam

Midazolam and triazolam are

Co-administration of

Triazolam

extensively metabolised by CYP3A4.

REYATAZ with triazolam or

 

Co-administration with REYATAZ

orally administered midazolam

 

may cause a large increase in the

is contraindicated

 

concentration of these

(see section 4.3), whereas

 

benzodiazepines. No drug interaction

caution should be used with co-

 

study has been performed for the co-

administration of REYATAZ

 

administration of REYATAZ with

and parenteral midazolam. If

 

benzodiazepines. Based on data for

REYATAZ is co-administered

 

other CYP3A4 inhibitors, plasma

with parenteral midazolam, it

 

concentrations of midazolam are

should be done in an intensive

 

expected to be significantly higher

care unit (ICU) or similar setting

 

when midazolam is given orally. Data

which ensures close clinical

 

from concomitant use of parenteral

monitoring and appropriate

 

midazolam with other protease

medical management in case of

 

inhibitors suggest a possible 3-4 fold

respiratory depression and/or

 

increase in midazolam plasma levels.

prolonged sedation. Dosage

 

 

adjustment for midazolam

 

 

should be considered, especially

 

 

if more than a single dose of

 

 

midazolam is administered.

In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen (see section 4.4)

The same recommendations for drug drug interactions would apply except:

that co-administration is not recommended with tenofovir, boceprevir, carbamazepine, phenytoin, phenobarbital, proton pump inhibitors, and buprenorphine.

that co-administration with famotidine is not recommended but if required, atazanavir without ritonavir should be administered either 2 hours after famotidine or 12 hours before. No single dose of famotidine should exceed 20 mg, and the total daily dose of famotidine should not exceed

40 mg.

the need to consider that

co-administration of voriconazole and REYATAZ without ritonavir may affect atazanavir concentrations

co-administration of fluticasone and REYATAZ without ritonavir may increase fluticasone concentrations relative to fluticasone given alone

if an oral contraceptive is administered with REYATAZ without ritonavir, it is recommended that the oral contraceptive contain no more than 30 µg of ethinyloestradiol

no dose adjustment of lamotrigine is required

Paediatric population

Interaction studies have only been performed in adults.

4.6Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity

(see section 5.3). The use of REYATAZ with ritonavir may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182 REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include REYATAZ) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with REYATAZ/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with REYATAZ/ritonavir

400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

It is not known whether REYATAZ with ritonavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.

Breast-feeding

Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

Fertility

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).

4.7Effects on ability to drive and use machines

Patients should be informed that dizziness has been reported during treatment with regimens containing REYATAZ (see section 4.8).

4.8Undesirable effects

Summary of the safety profile

REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received REYATAZ 400 mg once daily and patients who received REYATAZ 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with REYATAZ plus ritonavir.

Among patients who received REYATAZ 400 mg once daily or REYATAZ 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving REYATAZ 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

Tabulated list of adverse reactions

Assessment of adverse reactions for REYATAZ is based on safety data from clinical studies and post- marketing experience. Frequency is defined using the following convention: 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), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders:

uncommon: hypersensitivity

Metabolism and nutrition

uncommon: weight decreased, weight gain, anorexia,

disorders:

appetite increased

Psychiatric disorders:

uncommon: depression, disorientation, anxiety, insomnia,

 

sleep disorder, abnormal dream

Nervous system disorders:

common: headache;

 

uncommon: peripheral neuropathy, syncope, amnesia,

 

dizziness, somnolence, dysgeusia

Eye disorders:

common: ocular icterus

Cardiac disorders:

uncommon: torsades de pointesa

 

rare: QTc prolongationa, oedema, palpitation

Vascular disorders:

uncommon: hypertension

Respiratory, thoracic and

uncommon: dyspnoea

mediastinal disorders:

 

Gastrointestinal disorders:

common: vomiting, diarrhoea, abdominal pain, nausea,

 

dyspepsia;

 

uncommon: pancreatitis, gastritis, abdominal distension,

 

stomatitis aphthous, flatulence, dry mouth

Hepatobiliary disorders:

common: jaundice;

 

uncommon: hepatitis, cholelithiasisa, cholestasisa;

 

rare: hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue

common: rash;

disorders:

uncommon: erythemia multiformea,b, toxic skin

 

eruptionsa,b, drug rash with eosinophilia and systemic

 

symptoms (DRESS) syndromea,b, angioedemaa, urticaria,

 

alopecia, pruritus;

 

rare: Stevens-Johnson syndromea,b, vesiculobullous rash,

 

eczema, vasodilatation

Musculoskeletal and connective

uncommon: muscle atrophy, arthralgia, myalgia;

tissue disorders:

rare: myopathy

Renal and urinary disorders:

uncommon: nephrolithiasisa, haematuria, proteinuria,

 

pollakiuria, interstitial nephritis;

 

rare: kidney pain

Reproductive system and breast

uncommon: gynaecomastia

disorders:

 

General disorders and

common: fatigue;

administration site conditions:

uncommon: chest pain, malaise, pyrexia, asthenia;

 

rare: gait disturbance

aThese adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated from

astatistical calculation based on the total number of patients exposed to REYATAZ in randomised controlled and other available clinical trials (n = 2321).

bSee description of selected adverse reactions for more details.

Description of selected adverse reactions

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).

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).

Metabolic parameters

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

Rash and associated syndromes

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of REYATAZ (see section 4.4).

Laboratory abnormalities

The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations (see section 4.4).

Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

Two percent of patients treated with REYATAZ experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

In a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received either the oral powder or capsule formulation had a mean duration of treatment with REYATAZ of 115 weeks. The safety profile in this study was overall comparable to that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The most frequently reported laboratory abnormality in paediatric patients receiving REYATAZ was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4) which occurred in 45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had a mean duration of treatment with REYATAZ oral powder of 80 weeks. No deaths were reported. The safety profile in these studies was overall comparable to that seen in previous paediatric and adult studies. The most frequently reported laboratory abnormalities in paediatric patients receiving REYATAZ oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatric patients in these studies than in adults.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between REYATAZ and comparator regimens (see section 4.4).

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 of acute overdose with REYATAZ is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with REYATAZ should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE08

Mechanism of action

Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.

Resistance

Antiretroviral treatment naive adult patients

In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.

Table 3. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks)

Frequency

de novo PI substitution (n=26)a

>20%

none

10-20%

none

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

Antiretroviral treatment experienced adult patients

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.

Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks)

Frequency

de novo PI substitution (n=35)a,b

>20%

M36, M46, I54, A71, V82

10-20%

L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90

aNumber of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

bTen patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)

None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re- emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.

Clinical results

In antiretroviral naive adult patients

Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïve patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir

(400 mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg tablets once daily). The REYATAZ/ritonavir arm showed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

Table 5:

Efficacy Outcomes in Study 138 a

 

 

 

 

 

 

REYATAZ/ritonavirb

Lopinavir/ritonavirc

Parameter

 

(300 mg/100 mg once daily)

(400 mg/100 mg twice daily)

 

n=440

 

n=443

 

 

Week 48

 

 

Week 96

Week 48

Week 96

HIV RNA <50 copies/ml,

%

 

 

 

 

 

All patientsd

 

 

 

Difference estimate

 

 

 

Week 48: 1.7%

[-3.8%, 7.1%]

 

[95% CI]d

 

 

 

 

Week 96: 6.1% [0.3%, 12.0%]

 

Per protocol analysise

 

 

 

 

(n=392f)

 

 

(n=352)

(n=372)

(n=331)

Difference estimatee

 

 

 

Week 48: -3%

[-7.6%, 1.5%]

 

[95% CI]

 

 

 

 

Week 96: 2.2% [-2.3%, 6.7%]

 

HIV RNA <50 copies/ml,

% by Baseline Characteristicd

 

 

HIV RNA

 

 

 

 

 

 

 

<100,000 copies/ml

82 (n=217)

 

 

75 (n=217)

81 (n=218)

70 (n=218)

≥100,000 copies/ml

74 (n=223)

 

 

74 (n=223)

72 (n=225)

66 (n=225)

CD4 count

 

78 (n=58)

 

 

78 (n=58)

63 (n=48)

58 (n=48)

<50 cells/mm3

 

 

 

 

 

 

50 to <100 cells/mm3

76 (n=45)

 

 

71 (n=45)

69 (n=29)

69 (n=29)

100 to <200 cells/mm3

75 (n=106)

 

 

71 (n=106)

78 (n=134)

70 (n=134)

≥ 200 cells/mm3

80 (n=222)

 

 

76 (n=222)

80 (n=228)

69 (n=228)

HIV RNA Mean Change

from Baseline, log

10 copies/ml

 

 

All patients

-3.09 (n=397)

 

-3.21 (n=360)

-3.13 (n=379)

-3.19 (n=340)

CD4 Mean Change from

Baseline, cells/mm

 

 

 

 

All patients

203 (n=370)

 

 

268 (n=336)

219 (n=363)

290 (n=317)

CD4 Mean Change from

Baseline, cells/mm3

by Baseline Characteristic

 

HIV RNA

 

179 (n=183)

 

243 (n=163)

194 (n=183)

267 (n=152)

<100,000 copies/ml

 

 

 

 

 

 

≥100,000 copies/ml

227 (n=187)

 

291 (n=173)

245 (n=180)

310 (n=165)

aMean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml)

bREYATAZ/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

cLopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

dIntent-to-treat analysis, with missing values considered as failures.

ePer protocol analysis: Excluding non-completers and patients with major protocol deviations.

fNumber of patients evaluable.

Data on withdrawal of ritonavir from atazanavir boosted regimen (see also section 4.4) Study 136 (INDUMA)

In an open-label, randomised, comparative study following a 26- to 30-week induction phase with REYATAZ 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted REYATAZ 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with REYATAZ + ritonavir and two NRTIs (n=85) in HIV infected subjects with fully suppressed HIV replication, as assessed by the proportion of subjects with

HIV RNA < 50 copies/ml: 78% of subjects on unboosted REYATAZ and two NRTIs compared with 75% on REYATAZ + ritonavir and two NRTIs.

Eleven subjects (13%) in the unboosted REYATAZ group and 6 (7%) in the REYATAZ + ritonavir group, had virologic rebound. Four subjects in the unboosted REYATAZ group and 2 in the REYATAZ + ritonavir group had HIV RNA > 500 copies/ml during the maintenance phase. No subject in either group showed emergence of protease inhibitor resistance. The M184V substitution in reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in

2 subjects in the unboosted REYATAZ and 1 subject in the REYATAZ + ritonavir group.

There were fewer treatment discontinuations in the unboosted REYATAZ group (1 vs. 4 subjects in the REYATAZ + ritonavir group). There was less hyperbilirubinaemia and jaundice in the unboosted REYATAZ group compared with the REYATAZ + ritonavir group (18 and 28 subjects, respectively).

In antiretroviral experienced adult patients

Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks (Table 6).

Table 6:

Efficacy Outcomes at Week 48a and at Week 96 (Study 045)

 

 

Parameter

 

ATV/RTVb (300 mg/

LPV/RTVc (400 mg/

 

Time-averaged difference

 

100 mg once daily)

100 mg twice daily)

 

ATV/RTV-LPV/RTV

 

 

n=120

n=123

 

[97.5% CId]

 

 

Week 48

Week 96

Week 48

Week 96

 

Week 48

Week 96

HIV RNA Mean Change from Baseline, log10 copies/ml

 

 

 

 

All patients

 

-1.93

-2.29

-1.87

-2.08

 

0.13

0.14

 

(n=90 e)

(n=64)

(n=99)

(n=65)

 

[-0.12, 0.39]

[-0.13, 0.41]

HIV RNA <50

copies/ml, %f

(responder/evaluable)

 

 

 

 

All patients

 

36 (43/120)

32 (38/120)

42 (52/123)

35 (41/118)

 

NA

NA

HIV RNA <50

copies/ml by

select baseline

PI substitutions,

f, g % (responder/evaluable)

 

44 (28/63)

41 (26/63)

56 (32/57)

48 (26/54)

 

NA

NA

 

18 (2/11)

9 (1/11)

38 (6/16)

33 (5/15)

 

NA

NA

≥ 4

 

27 (12/45)

24 (11/45)

28 (14/50)

20 (10/49)

 

NA

NA

CD4 Mean Change from Baseline, cells/mm3

 

 

 

 

All patients

 

110 (n=83)

122 (n=60)

121 (n=94)

154 (n=60)

NA

NA

aThe mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml).

bATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

cLPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

dConfidence interval.

eNumber of patients evaluable.

fIntent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.

gSelect substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for REYATAZ + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall remained on study.

REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.

Paediatric population

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to

21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and

101 antiretroviral-experienced) received once daily REYATAZ (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received REYATAZ capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients, the mean baseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment- experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to 1157 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 log10 copies/ml).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study AI424-020)

 

 

Treatment-

 

Treatment-Naive

Experienced

Parameter

REYATAZ

REYATAZ

Capsules/ritonavir

Capsules/ritonavir

 

 

(300 mg/100 mg once

(300 mg/100 mg once

 

daily) n=16

daily) n=25

HIV RNA <50 copies/ml, % a

 

 

All patients

81 (13/16)

24 (6/25)

HIV RNA <400 copies/ml, % a

 

 

All patients

88 (14/16)

32 (8/25)

CD4 Mean Change from Baseline, cells/mm3

 

All patients

293 (n=14b)

229 (n=14b)

HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled)

NA

(4/15)

NA

 

-

≥ 4

NA

(0/3)

aIntent-to-treat analysis, with missing values considered as failures.

bNumber of patients evaluable.

cPI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

dIncludes patients with baseline resistance data.

NA = not applicable.

5.2Pharmacokinetic properties

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non-linear disposition.

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) ng/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.

In HIV-infected patients (n=13), multiple dosing of REYATAZ 400 mg (without ritonavir) once daily with food produced a geometric mean (CV%) for atazanavir Cmax of 2298 (71) ng/ml, with time to Cmax of approximately 2.0 hours. The geometric mean (CV%) for atazanavir Cmin and AUC were

120 (109) ng/ml and 14874 (91) ng•h/ml, respectively.

Food effect: co-administration of REYATAZ and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of REYATAZ and 100 mg dose of ritonavir

with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24 hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal

did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24 hour concentration following a high fat meal was increased by approximately

33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, REYATAZ is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a multiple-dose study in HIV- infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was

12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

Special populations

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for REYATAZ with ritonavir in patients with renal insufficiency. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. REYATAZ (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ capsules with ritonavir are presented in Table 8.

Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State

 

atazanavir 300 mg with ritonavir 100 mg

 

 

 

 

Pharmacokinetic Parameter

2nd Trimester

3rd Trimester

postpartuma

(n=9)

(n=20)

(n=36)

 

Cmax ng/mL

3729.09

3291.46

5649.10

Geometric mean (CV%)

(39)

(48)

(31)

AUC ng•h/mL

34399.1

34251.5

60532.7

Geometric mean (CV%)

(37)

(43)

(33)

Cmin ng/mLb

663.78

668.48

1420.64

Geometric mean (CV%)

(36)

(50)

(47)

aAtazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV infected non-pregnant patients.

bCmin is concentration 24 hours post-dose.

Paediatric population

There is a trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed, however at recommended doses, geometric mean atazanavir exposures (Cmin, Cmax and AUC) in paediatric patients are expected to be similar to those observed in adults.

5.3Preclinical safety data

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single- cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30 fold the free drug concentration at Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9 month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose

(see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo- development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

REYATAZ 100 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

Capsule shells: gelatine, indigocarmin (E132) and titanium dioxide (E171)

Blue ink containing: shellac, propylene glycol, ammonium hydroxide and indigocarmin (E132)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol and simethicone

REYATAZ 150 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

Capsule shells: gelatine, indigocarmin (E132) and titanium dioxide (E171)

Blue ink containing: shellac, propylene glycol, ammonium hydroxide and indigocarmin (E132)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol and simethicone

REYATAZ 200 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

Capsule shells: gelatine, indigocarmin (E132) and titanium dioxide (E171)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol and simethicone

REYATAZ 300 mg hard capsules

Capsule contents: crospovidone, lactose monohydrate and magnesium stearate

Capsule shells: gelatine, red iron oxide, black iron oxide, yellow iron oxide, indigocarmin (E132) and titanium dioxide (E171)

White ink containing: shellac, titanium dioxide (E171), ammonium hydroxide, propylene glycol and simethicone

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

Do not store above 25°C.

6.5Nature and contents of container

REYATAZ 100 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistant polypropylene closure. Each bottle contains 60 hard capsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unit dose blisters.

REYATAZ 150 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle closed with child-resistant polypropylene closure. Each bottle contains 60 hard capsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unit dose blisters.

REYATAZ 200 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle or three high-density polyethylene (HDPE) bottles closed with child-resistant polypropylene closure. Each bottle contains 60 hard capsules.

Each carton contains 60 x 1 capsules; 10 blister cards of 6 x 1 capsules each in Alu/Alu perforated unit dose blisters.

REYATAZ 300 mg hard capsules

Each carton contains one high-density polyethylene (HDPE) bottle or three high-density polyethylene (HDPE) bottles closed with child-resistant polypropylene closure. Each bottle contains 30 hard capsules.

Each carton contains 30 x 1 capsules; 5 blister cards of 6 x 1 capsules each in Alu/Alu perforated unit dose blisters.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.MARKETING AUTHORISATION HOLDER

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/03/267/001-006; 008-011

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 02 March 2004

Date of latest renewal: 02 March 2009

10.DATE OF REVISION OF THE TEXT

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

1. NAME OF THE MEDICINAL PRODUCT

REYATAZ 50 mg oral powder

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet of 1.5 g oral powder contains 50 mg of atazanavir (as sulphate).

Excipient with known effect: 63 mg of aspartame; 1305.15 mg of sucrose per sachet (1.5 g oral powder).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral powder

Off white to pale yellow powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

REYATAZ oral powder, co-administered with low dose ritonavir, is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected paediatric patients at least 3 months of age and weighing at least 5 kg (see section 4.2).

Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). The choice of REYATAZ in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient’s treatment history (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

Paediatric patients (at least 3 months of age and weighing at least 5 kg)

The doses of atazanavir oral powder and ritonavir for paediatric patients are based on body weight as shown in Table 1. REYATAZ oral powder must be taken with ritonavir and has to be taken with food.

Table 1: Dose of REYATAZ oral powder with ritonavir for paediatric patientsa (at least 3 months of age and weighing at least 5 kg)

Body weight (kg)

REYATAZ once daily dose

ritonavir once daily dose

at least 5 to less than 15

200 mg (4 sachetsb)

80 mgc

at least 15 to less than 35

250 mg (5 sachetsb)

80 mgc

at least 35

300 mg (6 sachetsb)

100 mgd

aThe same recommendations regarding the timing and maximum doses of concomitant proton pump inhibitors and H2- receptor antagonists in adults also apply to paediatric patients (see section 4.5).

bEach sachet contains 50 mg of atazanavir.

cRitonavir oral solution.

dRitonavir oral solution or capsule/tablet.

REYATAZ capsules are available for paediatric patients at least 6 years of age who weigh at least 15 kg and who are able to swallow capsules (see Summary of Product Characteristics for REYATAZ

capsules). Switching from REYATAZ oral powder to REYATAZ capsules is encouraged as soon as patients are able to consistenly swallow capsules.

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation (see Summary of Product Characteristics for REYATAZ capsules).

Special populations

Renal impairment

No dosage adjustment is needed. REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).

Hepatic impairment

REYATAZ with ritonavir has not been studied in patients with hepatic impairment. REYATAZ with ritonavir should be used with caution in patients with mild hepatic impairment. REYATAZ must not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4, and 5.2).

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g., tenofovir or H2-receptor antagonists).

If tenofovir or an H2-receptor antagonist is needed, a dose increase to REYATAZ 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

It is not recommended to use REYATAZ with ritonavir for pregnant patients who are receiving both tenofovir and an H2-receptor antagonist.

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

During this time, postpartum patients should follow the same dose recommendation as for non- pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

REYATAZ has not been studied in children less than 3 months of age and is not recommended because of the potential risk of kernicterus.

Method of administration For oral use.

REYATAZ oral powder should be taken/given with food (e.g. applesauce or yogurt) or drinks (e.g. milk, infant formula or water) for infants who can drink from a cup. For young infants (less than

6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral syringe, which can be obtained from a pharmacist. Administration of REYATAZ and infant formula using an infant bottle is not recommended because the full dose may not be delivered.

For details on preparation and administration of the REYATAZ oral powder and Instructions for Use, see section 6.6.

4.3 Contraindications

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

Patients with moderate to severe hepatic insufficiency (see sections 4.2 and 4.4).

Co-administration with simvastatin or lovastatin (see section 4.5).

Combination of rifampicin with concomitant low-dose ritonavir (see section 4.5).

Co-administration of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see sections 4.4 and 4.5.

Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5).

Co-administration with products containing St. John’s wort (Hypericum perforatum) (see section 4.5).

4.4 Special warnings and precautions for use

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.

Co-administration of REYATAZ with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).

Patients with coexisting conditions

Hepatic impairment

Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The safety and efficacy of REYATAZ has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

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

Renal impairment

No dosage adjustment is needed in patients with renal impairment. However, REYATAZ with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

QT prolongation

Dose related asymptomatic prolongations in PR interval with REYATAZ have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk

(see section 5.1). Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre- existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8

and 5.3).

Haemophiliac patients

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients 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 suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Weight and metabolic parameters

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

In clinical studies, REYATAZ (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators.

Hyperbilirubinaemia

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving REYATAZ (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving REYATAZ should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of REYATAZ and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Cholelithiasis

Cholelithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving REYATAZ (see section 4.8). Some patients required hospitalization for additional management and some had complications. In some cases, nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

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 carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occurs many months after initiation of treatment.

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.

Rash and associated syndromes

Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving REYATAZ. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. REYATAZ should be discontinued if severe rash develops.

The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of REYATAZ, REYATAZ may not be restarted.

Interactions with other medicinal products

The combination of REYATAZ with atorvastatin is not recommended (see section 4.5).

Co-administration of REYATAZ with nevirapine or efavirenz is not recommended (see section 4.5). If the co-administration of REYATAZ with an NNRTI is required, an increase in the dose of both REYATAZ and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of REYATAZ with ritonavir and medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile dysfunction in patients receiving REYATAZ with concomitant low-dose ritonavir. Co-administration of REYATAZ with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and REYATAZ with ritonavir is not recommended, unless an assessment of the benefit/risk justifies the use of voriconazole.

In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected (see section 4.5).

Concomitant use of REYATAZ/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).

Concomitant use of salmeterol and REYATAZ/ritonavir may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and REYATAZ is not recommended (see section 4.5).

The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.

Co-administration of REYATAZ with proton pump inhibitors is not recommended (see section 4.5). If the combination of REYATAZ with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of REYATAZ to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.

Co-administration of REYATAZ/ritonavir with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate has not been studied, and therefore should be avoided (see section 4.5).

Paediatric population

Safety

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Efficacy

Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance.

Excipients

Phenylketonuria

REYATAZ oral powder contains aspartame as a sweetening agent. Aspartame provides a source of phenylalanine and, therefore, may not be suitable for persons with phenylketonuria.

Diabetic population

REYATAZ oral powder contains 1305.15 mg of sucrose per sachet. For the recommended paediatric dosage, REYATAZ oral powder contains 3915.45 mg sucrose per 150 mg atazanavir, 5220.60 mg sucrose per 200 mg atazanavir, 6525.75 mg sucrose per 250 mg atazanavir, and 7830.90 mg sucrose per 300 mg atazanavir. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

When REYATAZ and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with REYATAZ and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, REYATAZ with ritonavir is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Other interactions

Interactions between atazanavir/ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and other non-antiretroviral medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the approved regimen of atazanavir.

Table 2: Interactions between REYATAZ and other medicinal products

 

 

 

 

 

Medicinal products by

Interaction

 

Recommendations concerning

therapeutic area

 

 

co-administration

 

 

 

 

ANTI-RETROVIRALS

 

 

 

Protease inhibitors: The co-administration of REYATAZ/ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors. Therefore, such co- administration is not recommended.

Ritonavir 100 mg once daily

Atazanavir AUC: ↑250% (↑144%

Ritonavir 100 mg once daily is

(atazanavir 300 mg once daily)

↑403%)*

used as a booster of atazanavir

 

Atazanavir Cmax: ↑120% (↑56%

pharmacokinetics.

Studies conducted in HIV-

↑211%)*

 

infected patients.

Atazanavir Cmin: ↑713% (↑359%

 

 

↑1339%)*

 

 

* In a combined analysis, atazanavir

 

 

300 mg and ritonavir 100 mg (n=33)

 

 

was compared to atazanavir 400 mg

 

 

without ritonavir (n=28).

 

 

The mechanism of interaction between

 

 

atazanavir and ritonavir is CYP3A4

 

 

inhibition.

 

Indinavir

Indinavir is associated with indirect

Co-administration of

 

unconjugated hyperbilirubinaemia due

REYATAZ/ritonavir and

 

to inhibition of UGT.

indinavir is not recommended

 

 

(see section 4.4).

Nucleoside/nucleotide reverse

transcriptase inhibitors (NRTIs)

 

 

 

 

Lamivudine 150 mg twice

No significant effect on lamivudine

Based on these data and because

daily + zidovudine 300 mg

and zidovudine concentrations was

ritonavir is not expected to have

twice daily

observed.

a significant impact on the

(atazanavir 400 mg once daily)

 

pharmacokinetics of NRTIs, the

 

 

co-administration of

 

 

REYATAZ/ritonavir with these

 

 

medicinal products is not

 

 

expected to significantly alter

 

 

the exposure of the co-

 

 

administered medicinal

 

 

products.

Abacavir

The co-administration of REYATAZ/

 

 

ritonavir with abacavir is not expected

 

 

to significantly alter the exposure of

 

 

abacavir.

 

Didanosine (buffered tablets)

Atazanavir, simultaneous

Didanosine should be taken at

200 mg/stavudine 40 mg, both

administration with ddI+d4T (fasted)

the fasted state 2 hours after

single dose

Atazanavir AUC ↓87% (↓92% ↓79%)

REYATAZ/ritonavir taken with

(atazanavir 400 mg single dose)

Atazanavir Cmax ↓89% (↓94% ↓82%)

food. The co-administration of

 

Atazanavir Cmin ↓84% (↓90% ↓73%)

REYATAZ/ritonavir with

 

 

stavudine is not expected to

 

Atazanavir, dosed 1 hr after ddI+d4T

significantly alter the exposure

 

(fasted)

of stavudine.

 

Atazanavir AUC ↔3% (↓36% ↑67%)

 

 

Atazanavir Cmax ↑12% (↓33% ↑18%)

 

 

Atazanavir Cmin ↔3% (↓39% ↑73%)

 

 

Atazanavir concentrations were greatly

 

 

decreased when co-administered with

 

 

didanosine (buffered tablets) and

 

 

stavudine. The mechanism of

 

 

interaction is a reduced solubility of

 

 

atazanavir with increasing pH related

 

 

to the presence of anti-acid agent in

 

 

didanosine buffered tablets.

 

 

No significant effect on didanosine

 

 

and stavudine concentrations was

 

 

observed.

 

Didanosine (enteric coated

Didanosine (with food)

 

capsules) 400 mg single dose

Didanosine AUC ↓34% (↓41% ↓27%)

 

(atazanavir 300 mg once daily

Didanosine Cmax ↓38% (↓48% ↓26%)

 

with ritonavir 100 mg once

Didanosine Cmin ↑25% (↓8% ↑69%)

 

daily)

No significant effect on atazanavir

 

 

 

 

concentrations was observed when

 

 

administered with enteric-coated

 

 

didanosine, but administration with

 

 

food decreased didanosine

 

 

concentrations.

 

Tenofovir disoproxil fumarate

Atazanavir AUC ↓22% (↓35% ↓6%) *

 

300 mg once daily

Atazanavir Cmax ↓16% (↓30% ↔0%) *

 

(atazanavir 300 mg once daily

Atazanavir Cmin ↓23% (↓43% ↑2%) *

 

with ritonavir 100 mg once

* In a combined analysis from several

 

daily)

 

 

clinical studies, atazanavir/ritonavir

 

Studies conducted in HIV-

300/100 mg co-administered with

 

infected patients

tenofovir disoproxil fumarate 300 mg

 

 

(n=39) was compared to

 

 

atazanavir/ritonavir 300/100 mg

 

 

(n=33).

 

 

The efficacy of REYATAZ/ritonavir

 

 

in combination with tenofovir

 

 

disoproxil fumarate in treatment-

 

 

experienced patients has been

 

 

demonstrated in clinical study 045 and

 

 

in treatment naive patients in clinical

 

 

study 138 (see sections 4.8 and 5.1).

 

 

The mechanism of interaction between

 

 

atazanavir and tenofovir disoproxil

 

 

fumarate is unknown.

 

Tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate AUC

Patients should be closely

300 mg once daily

↑37% (↑30% ↑45%)

monitored for tenofovir-

(atazanavir 300 mg once daily

Tenofovir disoproxil fumarate Cmax

associated adverse reactions,

with ritonavir 100 mg once

↑34% (↑20% ↑51%)

including renal disorders.

daily)

Tenofovir disoproxil fumarate Cmin

 

 

↑29% (↑21% ↑36%)

 

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

 

 

 

Efavirenz 600 mg once daily

Atazanavir (pm): all administered with

Co-administration of efavirenz

(atazanavir 400 mg once daily

food

with REYATAZ/ritonavir is not

with ritonavir 100 mg once

Atazanavir AUC ↔0%(↓9% ↑10%)*

recommended (see section 4.4)

daily)

Atazanavir Cmax ↑17%(↑8% ↑27%)*

 

 

Atazanavir Cmin ↓42%(↓51% ↓31%)*

 

 

 

 

Efavirenz 600 mg once daily

Atazanavir (pm): all administered with

 

(atazanavir 400 mg once daily

food

 

with ritonavir 200 mg once

Atazanavir AUC ↔6% (↓10% ↑26%)

 

daily)

*/**

 

 

Atazanavir Cmax ↔9% (↓5% ↑26%)

 

 

*/**

 

 

Atazanavir Cmin ↔12% (↓16% ↑49%)

 

 

*/**

 

 

* When compared to REYATAZ

 

 

300 mg/ritonavir 100 mg once daily in

 

 

the evening without efavirenz. This

 

 

decrease in atazanavir Cmin, might

 

 

negatively impact the efficacy of

 

 

atazanavir. The mechanism of

 

 

efavirenz/atazanavir interaction is

 

 

CYP3A4 induction.

 

 

** Based on historical comparison.

 

Nevirapine 200 mg twice daily

Nevirapine AUC ↑26% (↑17% ↑36%)

Co-administration of nevirapine

(atazanavir 400 mg once daily

Nevirapine Cmax ↑21% (↑11% ↑32%)

with REYATAZ/ritonavir is not

with ritonavir 100 mg once

Nevirapine Cmin ↑35% (↑25% ↑47%)

recommended (see section 4.4)

daily)

Atazanavir AUC ↓19% (↓35% ↑2%) *

 

Study conducted in HIV

 

Atazanavir Cmax ↔2% (↓15% ↑24%) *

 

infected patients

Atazanavir Cmin ↓59% (↓73% ↓40%) *

 

 

* When compared to REYATAZ

 

 

300 mg and ritonavir 100 mg without

 

 

nevirapine. This decrease in atazanavir

 

 

Cmin, might negatively impact the

 

 

efficacy of atazanavir. The mechanism

 

 

of nevirapine/atazanavir interaction is

 

 

CYP3A4 induction.

 

Integrase Inhibitors

 

 

 

 

 

Raltegravir 400 mg twice

Raltegravir AUC↑ 41%

No dose adjustment required for

daily

Raltegravir Cmax↑ 24%

raltegravir.

(atazanavir/ritonavir)

Raltegravir C12hr↑ 77%

 

 

The mechanism is UGT1A1 inhibition.

 

HCV Protease Inhibitors

 

 

 

 

 

Boceprevir 800 mg three times

boceprevir AUC ↔5%

Co-administration of

daily

boceprevir Cmax ↔7%

atazanavir/ritonavir with

(atazanavir 300 mg/ritonavir

boceprevir Cmin ↔18%

boceprevir resulted in lower

100 mg once daily)

atazanavir AUC ↓ 35%

exposure of atazanavir which

 

may be associated with lower

 

atazanavir Cmax ↓ 25%

efficacy and loss of HIV control.

 

atazanavir Cmin ↓ 49%

This co-administration might be

 

 

considered on a case by case

 

ritonavir AUC ↓ 36%

basis if deemed necessary, in

 

ritonavir Cmax ↓ 27%

patients with suppressed HIV

 

ritonavir Cmin ↓ 45%

viral loads and with HIV viral

 

 

strain without any suspected

 

 

resistance to the HIV regimen.

 

 

Increased clinical and laboratory

 

 

monitoring for HIV suppression

 

 

is warranted.

 

 

 

ANTIBIOTICS

 

 

 

 

 

Clarithromycin 500 mg twice

Clarithromycin AUC ↑94% (↑75%

No recommendation regarding

daily

↑116%)

dose reduction can be made;

(atazanavir 400 mg once daily)

Clarithromycin Cmax ↑50% (↑32%

therefore, caution should be

 

↑71%)

exercised if

 

Clarithromycin Cmin ↑160% (↑135%

REYATAZ/ritonavir is co-

 

↑188%)

administered with

 

14-OH clarithromycin

clarithromycin.

 

 

 

14-OH clarithromycin AUC ↓70%

 

 

(↓74% ↓66%)

 

 

14-OH clarithromycin Cmax ↓72%

 

 

(↓76% ↓67%)

 

 

14-OH clarithromycin Cmin ↓62%

 

 

(↓66% ↓58%)

 

 

Atazanavir AUC ↑28% (↑16% ↑43%)

 

 

Atazanavir Cmax ↔6% (↓7% ↑20%)

 

 

Atazanavir Cmin ↑91% (↑66% ↑121%)

 

 

A dose reduction of clarithromycin

 

 

may result in subtherapeutic

 

 

concentrations of 14-OH

 

 

clarithromycin. The mechanism of the

 

 

clarithromycin/atazanavir interaction is

 

 

CYP3A4 inhibition.

 

 

 

 

ANTIFUNGALS

 

 

 

 

 

Ketoconazole 200 mg once

No significant effect on atazanavir

Ketoconazole and itraconazole

daily

concentrations was observed.

should be used cautiously with

(atazanavir 400 mg once daily)

 

REYATAZ/ritonavir. High

Itraconazole

Itraconazole, like ketoconazole, is a

doses of ketoconazole and

 

potent inhibitor as well as a substrate

itraconazole (>200 mg/day) are

 

of CYP3A4.

not recommended.

 

 

 

 

Based on data obtained with other

 

 

boosted PIs and ketoconazole, where

 

 

ketoconazole AUC showed a 3-fold

 

 

increase, REYATAZ/ritonavir is

 

 

expected to increase ketoconazole or

 

 

itraconazole concentrations.

 

 

 

 

Voriconazole 200 mg twice

Voriconazole AUC ↓33% (↓42%

Co-administration of

daily (atazanavir

↓22%)

voriconazole and

300 mg/ritonavir 100 mg once

Voriconazole Cmax ↓10% (↓22% ↓4%)

REYATAZ/ritonavir is not

daily)

Voriconazole Cmin ↓39% (↓49% ↓28%)

recommended unless an

 

 

assessment of the benefit/risk to

Subjects with at least one

 

the patient justifies the use of

functional CYP2C19 allele.

Atazanavir AUC ↓12% (↓18% ↓5%)

voriconazole (see section 4.4).

 

Atazanavir Cmax ↓13% (↓20% ↓4%)

At the time voriconazole

 

Atazanavir Cmin ↓ 20 % (↓28 % ↓10%)

 

 

treatment is required, a patient's

 

 

CYP2C19 genotype should be

 

Ritonavir AUC ↓12% (↓17% ↓7%)

performed if feasible.

 

Ritonavir Cmax ↓9% (↓17% ↔0%)

Therefore if the combination is

 

Ritonavir Cmin ↓25% (↓35% ↓14%)

 

 

unavoidable, the following

 

In the majority of patients with at least

recomendations are made

 

one functional CYP2C19 allele, a

according to the CYP2C19

 

reduction in both voriconazole and

status:

 

atazanavir exposures are expected.

- in patients with at least one

 

 

Voriconazole 50 mg twice

Voriconazole AUC ↑561% (↑451%

functional CYP2C19 allele,

daily (atazanavir

↑699%)

close clinical monitoring for a

300 mg/ritonavir 100 mg once

Voriconazole Cmax ↑438% (↑355%

loss of both voriconazole

daily)

↑539%)

(clinical signs) and atazanavir

 

Voriconazole Cmin ↑765% (↑571%

(virologic response) efficacy is

Subjects without a functional

↑1,020%)

recommended.

CYP2C19 allele.

 

- in patients without a functional

 

 

 

Atazanavir AUC ↓20% (↓35% ↓3%)

CYP2C19 allele, close clinical

 

Atazanavir Cmax ↓19% (↓34% ↔0.2%)

and laboratory monitoring of

 

Atazanavir Cmin ↓ 31 % (↓46 % ↓13%)

voriconazole-associated adverse

 

 

events is recommended

 

Ritonavir AUC ↓11% (↓20% ↓1%)

If genotyping is not feasible, full

 

Ritonavir Cmax ↓11% (↓24% ↑4%)

monitoring of safety and

 

Ritonavir Cmin ↓19% (↓35% ↑1%)

efficacy should be performed.

 

In a small number of patients without a

 

 

functional CYP2C19 allele,

 

 

significantly increased voriconazole

 

 

exposures are expected.

 

 

 

 

Fluconazole 200 mg once daily

Atazanavir and fluconazole

No dosage adjustments are

(atazanavir 300 mg and

concentrations were not significantly

needed for REYATAZ/ritonavir

ritonavir 100 mg once daily)

modified when REYATAZ/ritonavir

and fluconazole.

 

was co-administered with fluconazole.

 

ANTIMYCOBACTERIAL

 

 

 

 

 

Rifabutin 150 mg twice

Rifabutin AUC ↑48% (↑19% ↑84%)

When given with

weekly

**

REYATAZ/ritonavir, the

(atazanavir 300 mg and

Rifabutin Cmax ↑149% (↑103% ↑206%)

recommended dose of rifabutin

ritonavir 100 mg once daily)

**

is 150 mg 3 times per week on

 

Rifabutin Cmin ↑40% (↑5% ↑87%) **

set days (for example Monday-

 

 

Wednesday-Friday). Increased

 

25-O-desacetyl-rifabutin AUC ↑990%

monitoring for rifabutin-

 

(↑714% ↑1361%) **

associated adverse reactions

 

25-O-desacetyl-rifabutin Cmax ↑677%

including neutropenia and

 

(↑513% ↑883%) **

uveitis is warranted due to an

 

25-O-desacetyl-rifabutin Cmin ↑1045%

expected increase in exposure to

 

(↑715% ↑1510%) **

rifabutin. Further dosage

 

 

reduction of rifabutin to 150 mg

 

** When compared to rifabutin

twice weekly on set days is

 

150 mg once daily alone. Total

recommended for patients in

 

rifabutin and 25-O-desacetyl-rifabutin

whom the 150 mg dose 3 times

 

AUC ↑119% (↑78% ↑169%).

per week is not tolerated. It

 

 

should be kept in mind that the

 

In previous studies, the

twice weekly dosage of 150 mg

 

pharmacokinetics of atazanavir was

may not provide an optimal

 

not altered by rifabutin.

exposure to rifabutin thus

 

 

leading to a risk of rifamycin

 

 

resistance and a treatment

 

 

failure. No dose adjustment is

 

 

needed for REYATAZ/ritonavir.

Rifampicin

Rifampicin is a strong CYP3A4

The combination of rifampicin

 

inducer and has been shown to cause a

and REYATAZ with

 

72% decrease in atazanavir AUC

concomitant low-dose ritonavir

 

which can result in virological failure

is contraindicated (see

 

and resistance development. During

section 4.3).

 

attempts to overcome the decreased

 

 

exposure by increasing the dose of

 

 

REYATAZ or other protease inhibitors

 

 

with ritonavir, a high frequency of

 

 

liver reactions was seen.

 

ANTIPSYCHOTICS

 

 

 

 

 

Quetiapine

Due to CYP3A4 inhibition by

Co-administration of

 

REYATAZ, concentrations of

REYATAZ/ritonavir with

 

quetiapine are expected to increase.

quetiapine is contraindicated as

 

 

may increase quetiapine-related

 

 

toxicity. Increased plasma

 

 

concentrations of quetiapine

 

 

may lead to coma

 

 

(see section 4.3).

ACID REDUCING AGENTS

 

 

 

 

 

H2-Receptor antagonists

 

 

 

 

 

Without Tenofovir

 

 

In HIV-infected patients with atazanavir/ritonavir at the recommended

For patients not taking

dose 300/100 mg once daily

 

tenofovir, if REYATAZ

Famotidine 20 mg twice daily

Atazanavir AUC ↓18% (↓25% ↑1%)

300 mg/ritonavir 100 mg and

 

Atazanavir Cmax ↓20% (↓32% ↓7%)

H2-receptor antagonists are co-

 

Atazanavir Cmin ↔1% (↓16% ↑18%)

administered, a dose equivalent

Famotidine 40 mg twice daily

Atazanavir AUC ↓23% (↓32% ↓14%)

to famotidine 20 mg twice daily

 

Atazanavir Cmax ↓23% (↓33% ↓12%)

should not be exceeded. If a

 

Atazanavir Cmin ↓20% (↓31% ↓8%)

higher dose of an H2-receptor

In Healthy volunteers with atazanavir/ritonavir at an increased dose

antagonist is required (eg,

of 400/100 mg once daily

 

famotidine 40 mg twice daily or

Famotidine 40 mg twice daily

Atazanavir AUC ↔3% (↓14% ↑22%)

equivalent) an increase of the

 

Atazanavir Cmax ↔2% (↓13% ↑8%)

REYATAZ/ritonavir dose from

 

Atazanavir Cmin ↓14% (↓32% ↑8%)

300/100 mg to 400/100 mg can

 

 

be considered.

With Tenofovir 300 mg once daily

 

 

 

 

In HIV-infected patients with atazanavir/ritonavir at the recommended

For patients who are taking

dose of 300/100 mg once daily

 

tenofovir, if

Famotidine 20 mg twice daily

Atazanavir AUC ↓21% (↓34% ↓4%) *

REYATAZ/ritonavir with both

 

Atazanavir Cmax ↓21% (↓36% ↓4%) *

tenofovir and an H2-receptor

 

Atazanavir Cmin ↓19% (↓37% ↑5%) *

antagonist are co-administered,a

 

 

dose increase of REYATAZ to

Famotidine 40 mg twice daily

Atazanavir AUC ↓24% (↓36% ↓11%)*

400 mg with 100 mg of ritonavir

 

Atazanavir Cmax ↓23% (↓36% ↓8%) *

is recommended. A dose

 

Atazanavir Cmin ↓25% (↓47% ↑7%) *

equivalent to famotidine 40 mg

 

 

twice daily should not be

 

 

exceeded.

In HIV-infected patients with

atazanavir/ritonavir at an increased dose

of 400/100 mg once daily

 

 

Famotidine 20 mg twice daily

Atazanavir AUC ↑18% (↑6.5%

 

 

↑30%)*

 

 

Atazanavir Cmax ↑18% (↑6.7% ↑31%)*

 

 

Atazanavir Cmin ↑24 % (↑10% ↑39%)*

 

 

 

 

Famotidine 40 mg twice daily

Atazanavir AUC ↔2.3% (↓13%

 

 

↑10%)*

 

 

Atazanavir Cmax ↔5% (↓17% ↑8.4%)*

 

 

Atazanavir Cmin ↔1.3% (↓10% ↑15)*

 

 

 

 

 

* When compared to atazanavir

 

 

300 mg once daily with ritonavir

 

 

100 mg once daily and tenofovir

 

 

disoproxil fumarate 300 mg all as a

 

 

single dose with food. When compared

 

 

to atazanavir 300 mg with ritonavir

 

 

100 mg without tenofovir, atazanavir

 

 

concentrations are expected to be

 

 

additionally decreased by about 20%.

 

 

The mechanism of interaction is

 

 

decreased solubility of atazanavir as

 

 

intra-gastric pH increases with H2-

 

 

blockers.

 

Proton pump inhibitors

 

 

 

 

 

Omeprazole 40 mg once daily

Atazanavir (am): 2 hr after omeprazole

Co-administration of

(atazanavir 400 mg once daily

Atazanavir AUC ↓61% (↓65% ↓55%)

REYATAZ/ritonavir with

with ritonavir 100 mg once

Atazanavir Cmax ↓66% (↓62% ↓49%)

proton pump inhibitors is not

daily)

Atazanavir Cmin ↓65% (↓71% ↓59%)

recommended. If the

 

 

combination of

Omeprazole 20 mg once daily

Atazanavir (am): 1 hr after omeprazole

REYATAZ/ritonavir with a

(atazanavir 400 mg once daily

Atazanavir AUC ↓30% (↓43% ↓14%) *

proton pump inhibitor is judged

with ritonavir 100 mg once

Atazanavir Cmax ↓31% (↓42% ↓17%) *

unavoidable, close clinical

daily)

Atazanavir Cmin ↓31% (↓46% ↓12%) *

monitoring is recommended in

 

 

combination with an increase in

 

* When compared to atazanavir

the dose of REYATAZ to

 

300 mg once daily with ritonavir

400 mg with 100 mg of

 

100 mg once daily.

ritonavir; doses of proton pump

 

The decrease in AUC, Cmax, and Cmin

inhibitors comparable to

 

was not mitigated when an increased

omeprazole 20 mg should not be

 

dose of REYATAZ/ritonavir

exceeded (see section 4.4).

 

(400/100 mg once daily) was

 

 

temporally separated from omeprazole

 

 

by 12 hours. Although not studied,

 

 

similar results are expected with other

 

 

proton pump inhibitors. This decrease

 

 

in atazanavir exposure might

 

 

negatively impact the efficacy of

 

 

atazanavir. The mechanism of

 

 

interaction is decreased solubility of

 

 

atazanavir as intra-gastric pH increases

 

 

with proton pump inhibitors.

 

 

 

 

Antacids

 

 

 

 

 

Antacids and medicinal

Reduced plasma concentrations of

REYATAZ/ritonavir should be

products containing buffers

atazanavir may be the consequence of

administered 2 hours before or 1

 

increased gastric pH if antacids,

hour after antacids or buffered

 

including buffered medicinal products,

medicinal products.

 

are administered with

 

 

REYATAZ/ritonavir.

 

ALPHA 1-ADRENORECEPTOR

ANTAGONIST

 

 

 

 

Alfuzosin

Potential for increased alfuzosin

Co-administration of

 

concentrations which can result in

REYATAZ/ritonavir with

 

hypotension. The mechanism of

alfuzosin is contraindicated (see

 

interaction is CYP3A4 inhibition by

section 4.3)

 

atazanavir/ritonavir.

 

ANTICOAGULANTS

 

 

 

 

 

Warfarin

Co-administration with

It is recommended that the INR

 

REYATAZ/ritonavir has the potential

be monitored carefully during

 

to produce a decrease or, less often, an

treatment with

 

increase in INR (International

REYATAZ/ritonavir, especially

 

Normalised Ratio).

when commencing therapy.

ANTIEPILEPTICS

 

 

 

 

 

Carbamazepine

REYATAZ/ritonavir may increase

Carbamazepine should be used

 

plasma levels of carbamazepine due to

with caution in combination

 

CYP3A4 inhibition.

with REYATAZ/ritonavir. If

 

Due to carbamazepine inducing effect,

necessary, monitor

 

a reduction in REYATAZ/ritonavir

carbamazepine serum

 

exposure cannot be ruled out.

concentrations and adjust the

 

 

dose accordingly. Close

 

 

monitoring of the patient's

 

 

virologic response should be

 

 

excercised.

Phenytoin, phenobarbital

 

Ritonavir may decrease plasma levels

Phenobarbital and phenytoin

 

 

of phenytoin and/or phenobarbital due

should be used with caution in

 

 

to CYP2C9 and CYP2C19 induction.

combination with

 

 

Due to phenitoine/phenobarbital

REYATAZ/ritonavir.

 

 

inducing effect, a reduction in

When REYATAZ/ritonavir is

 

 

REYATAZ/ritonavir exposure cannot

 

 

be ruled out

co-administered with either

 

 

 

phenytoin or phenobarbital, a

 

 

 

dose adjustment of phenytoin or

 

 

 

phenobarbital may be required.

 

 

 

Close monitoring of patient's

 

 

 

virologic response should be

 

 

 

exercised.

Lamotrigine

 

Co-administration of lamotrigine and

Lamotrigine should be used with

 

 

REYATAZ/ritonavir may decrease

caution in combination with

 

 

lamotrigine plasma concentrations due

REYATAZ/ritonavir.

 

 

to UGT1A4 induction.

If necessary, monitor

 

 

 

 

 

 

lamotrigine concentrations and

 

 

 

adjust the dose accordingly.

ANTINEOPLASTICS AND

IMMUNOSUPRESSANTS

 

 

 

 

 

Antineoplastics

 

 

 

 

 

 

Irinotecan

 

Atazanavir inhibits UGT and may

If REYATAZ/ritonavir is co-

 

 

interfere with the metabolism of

administered with irinotecan,

 

 

irinotecan, resulting in increased

patients should be closely

 

 

irinotecan toxicities.

monitored for adverse events

 

 

 

related to irinotecan.

Immunosuppressants

 

 

 

 

 

 

Cyclosporin

 

Concentrations of these

More frequent therapeutic

Tacrolimus

 

immunosuppressants may be increased

concentration monitoring of

Sirolimus

 

when co-administered with

these medicinal products is

 

 

REYATAZ/ritonavir due to CYP3A4

recommended until plasma

 

 

inhibition.

levels have been stabilised.

CARDIOVASCULAR AGENTS

 

 

 

 

 

 

Antiarrhythmics

 

 

 

 

 

Amiodarone,

 

Concentrations of these

Caution is warranted and

Systemic lidocaine,

 

antiarrhythmics may be increased

therapeutic concentration

Quinidine

 

when co-administered with

monitoring is recommended

 

 

REYATAZ/ritonavir. The mechanism

when available. The

 

 

of amiodarone or systemic

concomitant use of quinidine is

 

 

lidocaine/atazanavir interaction is

contraindicated (see section 4.3).

 

 

CYP3A inhibition. Quinidine has a

 

 

 

narrow therapeutic window and is

 

 

 

contraindicated due to potential

 

 

 

inhibition of CYP3A by

 

 

 

REYATAZ/ritonavir.

 

Calcium channel blockers

 

 

 

 

 

 

Bepridil

 

REYATAZ/ritonavir should not be

Co-administration with bepridil is

 

 

used in combination with medicinal

contraindicated (see section 4.3)

 

 

products that are substrates of

 

 

 

CYP3A4 and have a narrow

 

 

 

therapeutic index.

 

Diltiazem 180 mg once daily

Diltiazem AUC ↑125% (↑109%

An initial dose reduction of

(atazanavir 400 mg once daily)

↑141%)

diltiazem by 50% is

 

Diltiazem Cmax ↑98% (↑78% ↑119%)

recommended, with subsequent

 

Diltiazem Cmin ↑142% (↑114%

titration as needed and ECG

 

↑173%)

monitoring.

 

Desacetyl-diltiazem AUC ↑165%

 

 

(↑145% ↑187%)

 

 

Desacetyl-diltiazem Cmax ↑172%

 

 

(↑144% ↑203%)

 

 

Desacetyl-diltiazem Cmin ↑121%

 

 

(↑102% ↑142%)

 

 

No significant effect on atazanavir

 

 

concentrations was observed. There

 

 

was an increase in the maximum PR

 

 

interval compared to atazanavir alone.

 

 

Co-administration of diltiazem and

 

 

REYATAZ/ritonavir has not been

 

 

studied. The mechanism of

 

 

diltiazem/atazanavir interaction is

 

 

CYP3A4 inhibition.

 

Verapamil

Serum concentrations of verapamil

Caution should be exercised

 

may be increased by

when verapamil is co-

 

REYATAZ/ritonavir due to CYP3A4

administered with

 

inhibition.

REYATAZ/ritonavir.

CORTICOSTEROIDS

 

 

 

 

 

Fluticasone propionate

The fluticasone propionate plasma

Co-administration of

intranasal 50 µg 4 times daily

levels increased significantly, whereas

REYATAZ/ritonavir and these

for 7 days

the intrinsic cortisol levels decreased

glucocorticoids is not

(ritonavir 100 mg capsules

by approximately 86% (90%

recommended unless the

twice daily)

confidence interval 82%-89%).

potential benefit of treatment

 

Greater effects may be expected when

outweighs the risk of systemic

 

fluticasone propionate is inhaled.

corticosteroid effects (see

 

Systemic corticosteroid effects

section 4.4). A dose reduction of

 

including Cushing’s syndrome and

the glucocorticoid should be

 

adrenal suppression have been

considered with close

 

reported in patients receiving ritonavir

monitoring of local and systemic

 

and inhaled or intranasally

effects or a switch to a

 

administered fluticasone propionate;

glucocorticoid, which is not a

 

this could also occur with other

substrate for CYP3A4 (e.g.,

 

corticosteroids metabolised via the

beclomethasone). Moreover, in

 

P450 3A pathway, e.g., budesonide.

case of withdrawal of

 

The effects of high fluticasone

glucocorticoids, progressive

 

systemic exposure on ritonavir plasma

dose reduction may have to be

 

levels are yet unknown. The

performed over a longer period.

 

mechanism of interaction is CYP3A4

 

 

inhibition.

 

ERECTILE DYSFUNCTION

 

 

 

 

 

PDE5 Inhibitors

 

 

 

 

 

Sildenafil, tadalafil, vardenafil

Sildenafil, tadalafil, and vardenafil are

Patients should be warned about

 

metabolised by CYP3A4. Co-

these possible side effects when

 

administration with

using PDE5 inhibitors for

 

REYATAZ/ritonavir may result in

erectile dysfunction with

 

increased concentrations of the PDE5

REYATAZ/ritonavir (see

 

inhibitor and an increase in PDE5-

section 4.4).

 

associated adverse events, including

Also see PULMONARY

 

hypotension, visual changes, and

ATERIAL HYPERTENSION in

 

priapism. The mechanism of this

this table for futher information

 

interaction is CYP3A4 inhibition.

regarding co-administration of

 

 

REYATAZ/ritonavir with

 

 

sildenafil.

HERBAL PRODUCTS

 

 

 

 

 

St. John’s wort (Hypericum

Concomitant use of St. John's wort

Co-administration of

perforatum)

with REYATAZ/ritonavir may be

REYATAZ/ritonavir with

 

expected to result in significant

products containing St. John's

 

reduction in plasma levels of

wort is contraindicated.

 

atazanavir. This effect may be due to

 

 

an induction of CYP3A4. There is a

 

 

risk of loss of therapeutic effect and

 

 

development of resistance (see

 

 

section 4.3).

 

HORMONAL CONTRACEPTIVES

 

 

 

 

 

Ethinyloestradiol 25 μg +

Ethinyloestradiol AUC ↓19% (↓25%

If an oral contraceptive is

norgestimate

↓13%)

administered with

(atazanavir 300 mg once daily

Ethinyloestradiol Cmax ↓16% (↓26%

REYATAZ/ritonavir, it is

with ritonavir 100 mg once

↓5%)

recommended that the oral

daily)

Ethinyloestradiol Cmin ↓37% (↓45%

contraceptive contain at least

 

↓29%)

30 μg of ethinyloestradiol and

 

 

that the patient be reminded of

 

Norgestimate AUC ↑85% (↑67%

strict compliance with this

 

↑105%)

contraceptive dosing regimen.

 

Norgestimate Cmax ↑68% (↑51%

Co-administration of

 

↑88%)

REYATAZ/ritonavir with other

 

Norgestimate Cmin ↑102% (↑77%

hormonal contraceptives or oral

 

↑131%)

contraceptives containing

 

 

progestogens other than

 

While the concentration of

norgestimate has not been

 

ethinyloestradiol was increased with

studied, and therefore should be

 

atazanavir given alone, due to both

avoided. An alternate reliable

 

UGT and CYP3A4 inhibition by

method of contraception is

 

atazanavir, the net effect of

recommended.

 

atazanavir/ritonavir is a decrease in

 

 

ethinyloestradiol levels because of the

 

 

inducing effect of ritonavir.

 

 

The increase in progestin exposure

 

 

may lead to related side-effects (e.g.

 

 

insulin resistance, dyslipidemia, acne

 

 

and spotting), thus possibly affecting

 

 

the compliance.

 

LIPID LOWERING AGENTS

 

 

 

 

 

HMG-CoA reductase inhibitors

 

 

 

 

 

Simvastatin

Simvastatin and lovastatin are highly

Co-administration of simvastatin

Lovastatin

dependent on CYP3A4 for their

or lovastatin with REYATAZ is

 

metabolism and co-administration with

contraindicated due to an

 

REYATAZ/ritonavir may result in

increased risk of myopathy

 

increased concentrations.

including rhabdomyolysis (see

 

 

section 4.3).

Atorvastatin

The risk of myopathy including

Co-administration of

 

rhabdomyolysis may also be increased

atorvastatin with REYATAZ is

 

with atorvastatin, which is also

not recommended. If the use of

 

metabolised by CYP3A4.

atorvastatin is considered strictly

 

 

necessary, the lowest possible

 

 

dose of atorvastatin should be

 

 

administered with careful safety

 

 

monitoring (see section 4.4).

Pravastatin

Although not studied, there is a

Caution should be exercised.

Fluvastatin

potential for an increase in pravastatin

 

 

or fluvastatin exposure when co-

 

 

administered with protease inhibitors.

 

 

Pravastatin is not metabolised by

 

 

CYP3A4. Fluvastatin is partially

 

 

metabolised by CYP2C9.

 

INHALED BETA AGONISTS

 

 

 

 

 

Salmeterol

Co-administration with

Co-administration of salmeterol

 

REYATAZ/ritonavir may result in

with REYATAZ/ritonavir is not

 

increased concentrations of salmeterol

recommended (see section 4.4).

 

and an increase in salmeterol-

 

 

associated adverse events.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by

 

 

atazanavir/ritonavir.

 

OPIOIDS

 

 

 

 

 

Buprenorphine, once daily,

Buprenorphine AUC ↑67%

Co-administration warrants

stable maintenance dose

Buprenorphine Cmax ↑37%

clinical monitoring for sedation

(atazanavir 300 mg once daily

Buprenorphine Cmin ↑69%

and cognitive effects. A dose

with ritonavir 100 mg once

 

reduction of buprenorphine may

daily)

Norbuprenorphine AUC ↑105%

be considered.

 

Norbuprenorphine Cmax ↑61%

 

 

Norbuprenorphine Cmin ↑101%

 

 

The mechanism of interaction is

 

 

CYP3A4 and UGT1A1 inhibition.

 

 

Concentrations of atazanavir were not

 

 

significantly affected.

 

Methadone, stable

No significant effect on methadone

No dosage adjustment is

maintenance dose

concentrations was observed. Given

necessary if methadone is co-

(atazanavir 400 mg once daily)

that low dose ritonavir (100 mg twice

administered with REYATAZ

 

daily) has been shown to have no

and ritonavir.

 

significant effect on methadone

 

 

concentrations, no interaction is

 

 

expected if methadone is co-

 

 

administered with REYATAZ and

 

 

ritonavir, based on these data.

 

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with

A safe and effective dose in

 

REYATAZ/ritonavir may result in

combination with

 

increased concentrations of the PDE5

REYATAZ/ritonavir has not

 

inhibitor and an increase in PDE5-

been established for sildenafil

 

inhibitor-associated adverse events.

when used to treat pulmonary

 

 

arterial hypertension. Sildenafil,

 

The mechanism of interaction is

when used for the treatment of

 

CYP3A4 inhibition by

pulmonary arterial hypertension,

 

atazanavir/ritonavir.

is contraindicated (see

 

 

section 4.3).

SEDATIVES

 

 

 

 

 

Benzodiazepines

 

 

 

 

 

Midazolam

Midazolam and triazolam are

REYATAZ/ritonavir should not

Triazolam

extensively metabolised by CYP3A4.

be co-administered with

 

Co-administration with

triazolam or orally administered

 

REYATAZ/ritonavir may cause a

midazolam (see section 4.3),

 

large increase in the concentration of

whereas caution should be used

 

these benzodiazepines. No drug

with co-administration of

 

interaction study has been performed

REYATAZ/ritonavir and

 

for the co-administration of

parenteral midazolam. If

 

REYATAZ/ritonavir with

REYATAZ is co-administered

 

benzodiazepines. Based on data for

with parenteral midazolam, it

 

other CYP3A4 inhibitors, plasma

should be done in an intensive

 

concentrations of midazolam are

care unit (ICU) or similar setting

 

expected to be significantly higher

which ensures close clinical

 

when midazolam is given orally. Data

monitoring and appropriate

 

from concomitant use of parenteral

medical management in case of

 

midazolam with other protease

respiratory depression and/or

 

inhibitors suggest a possible 3-4 fold

prolonged sedation. Dosage

 

increase in midazolam plasma levels.

adjustment for midazolam

 

 

should be considered, especially

 

 

if more than a single dose of

 

 

midazolam is administered.

Paediatric population

 

 

Interaction studies have only been performed in adults.

 

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of REYATAZ may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182 REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinaemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include REYATAZ) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with REYATAZ/ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with REYATAZ/ritonavir

400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of

40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

It is not known whether REYATAZ administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.

Breast-feeding

Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

Fertility

In a non-clinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be informed that dizziness has been reported during treatment with regimens containing REYATAZ (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

REYATAZ has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving REYATAZ 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or REYATAZ 300 mg with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received REYATAZ 400 mg once daily and patients who received REYATAZ 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with REYATAZ plus ritonavir.

Among patients who received REYATAZ 400 mg once daily or REYATAZ 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing REYATAZ and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving REYATAZ 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

Tabulated list of adverse reactions

Assessment of adverse reactions for REYATAZ is based on safety data from clinical studies and post- marketing experience. Frequency is defined using the following convention: 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), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders:

uncommon: hypersensitivity

Metabolism and nutrition

uncommon: weight decreased, weight gain, anorexia,

disorders:

appetite increased

Psychiatric disorders:

uncommon: depression, disorientation, anxiety, insomnia,

 

sleep disorder, abnormal dream

Nervous system disorders:

common: headache;

 

uncommon: peripheral neuropathy, syncope, amnesia,

 

dizziness, somnolence, dysgeusia

Eye disorders:

common: ocular icterus

Cardiac disorders:

uncommon: torsades de pointesa

 

rare: QTc prolongationa, oedema, palpitation

Vascular disorders:

uncommon: hypertension

Respiratory, thoracic and

uncommon: dyspnoea

mediastinal disorders:

 

Gastrointestinal disorders:

common: vomiting, diarrhoea, abdominal pain, nausea,

 

dyspepsia;

 

uncommon: pancreatitis, gastritis, abdominal distension,

 

stomatitis aphthous, flatulence, dry mouth

Hepatobiliary disorders:

common: jaundice;

 

uncommon: hepatitis, cholelithiasisa, cholestasisa;

 

rare: hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue

common: rash;

disorders:

uncommon: erythemia multiformea,b, toxic skin

 

eruptionsa,b, drug rash with eosinophilia and systemic

 

symptoms (DRESS) syndromea,b, angioedemaa, urticaria,

 

alopecia, pruritus;

 

rare: Stevens-Johnson syndromea,b, vesiculobullous rash,

 

eczema, vasodilatation

Musculoskeletal and connective

uncommon: muscle atrophy, arthralgia, myalgia;

tissue disorders:

rare: myopathy

Renal and urinary disorders:

uncommon: nephrolithiasisa, haematuria, proteinuria,

 

pollakiuria, interstitial nephritis;

 

rare: kidney pain

Reproductive system and breast

uncommon: gynaecomastia

disorders:

 

General disorders and

common: fatigue;

administration site conditions:

uncommon: chest pain, malaise, pyrexia, asthenia;

 

rare: gait disturbance

aThese adverse reactions were identified through post-marketing surveillance, however, the frequencies were estimated from

astatistical calculation based on the total number of patients exposed to REYATAZ in randomised controlled and other available clinical trials (n = 2321).

bSee description of selected adverse reactions for more details.

Description of selected adverse reactions

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).

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).

Metabolic parameters

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

Rash and associated syndromes

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with REYATAZ.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of REYATAZ (see section 4.4).

Laboratory abnormalities

The most frequently reported laboratory abnormality in patients receiving regimens containing REYATAZ and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (6% Grade 4). Among experienced patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 total bilirubin elevations. Among naive patients treated with REYATAZ 300 mg once daily with 100 mg ritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations (see section 4.4).

Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing REYATAZ and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

Two percent of patients treated with REYATAZ experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

In a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received either the oral powder or capsule formulation had a mean duration of treatment with REYATAZ of 115 weeks. The safety profile in this study was overall comparable to that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The most frequently reported laboratory abnormalities in paediatric patients receiving REYATAZ was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4) which occurred in 45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had a mean duration of treatment with REYATAZ oral powder of 80 weeks. No deaths were reported. The safety profile in these studies was overall comparable to that seen in previous paediatric and adult studies. The most frequently reported laboratory abnormalities in paediatric patients receiving REYATAZ oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatric patients in these studies than in adults.

Other special populations

Patients co-infected with hepatitis B and/or hepatitis C virus

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-infected

patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between REYATAZ and comparator regimens (see section 4.4).

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 of acute overdose with REYATAZ is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinaemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with REYATAZ should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE08

Mechanism of action

Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.

Resistance

Antiretroviral treatment naive adult patients

In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.

Table 3. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks)

Frequency

de novo PI substitution (n=26)a

>20%

none

10-20%

none

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

The M184I/V substitution emerged in 5/26 REYATAZ/ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

Antiretroviral treatment experienced adult patients

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.

Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks)

Frequency

de novo PI substitution (n=35)a,b

>20%

M36, M46, I54, A71, V82

10-20%

L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90

aNumber of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

bTen patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture relative to the wild-type reference was assayed using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)

None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re- emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.

Clinical results

In antiretroviral naive adult patients

Study 138 is an international randomised, open-label, multicenter, prospective trial of

883 antiretroviral treatment naive patients comparing REYATAZ/ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir/emtricitabine (300 mg/200 mg tablets once daily). The REYATAZ/ritonavir arm showed similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

The mean baseline CD4 cell count was 214 cells/mm3 (range: 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml). The REYATAZ/ritonavir arm has similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48: 78% of patients on REYATAZ/ritonavir compared to 76% on lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: 1.7% [95% CI, -3.8%, 7.1%] according to the Confirmed Virologic Response (CVR) Non-Completer = Failure (NC = F) definition of response.

In a per protocol analysis which excluded non-completers (i.e. patients who discontinued before the week 48 HIV RNA assessment) and patients with major protocol deviations, the proportion of patients with HIV RNA < 50 copies/ml at week 48 was 86% (338/392) for REYATAZ/ritonavir and 89% (332/372) for lopinavir/ritonavir (difference estimate of ATV/RTV-LPV/RTV: -3% [95% CI, -7.6%, 1.5%].

Table 5:

Efficacy Outcomes in Study 138 a

 

 

 

 

 

 

REYATAZ/ritonavirb

Lopinavir/ritonavirc

Parameter

 

(300 mg/100 mg once daily)

(400 mg/100 mg twice daily)

 

n=440

 

n=443

 

 

Week 48

 

 

Week 96

Week 48

Week 96

HIV RNA <50 copies/ml,

%

 

 

 

 

 

All patientsd

 

 

 

Difference estimate

 

 

 

Week 48: 1.7%

[-3.8%, 7.1%]

 

[95% CI]d

 

 

 

 

Week 96: 6.1% [0.3%, 12.0%]

 

Per protocol analysise

 

 

 

 

(n=392f)

 

 

(n=352)

(n=372)

(n=331)

Difference estimatee

 

 

 

Week 48: -3%

[-7.6%, 1.5%]

 

[95% CI]

 

 

 

 

Week 96: 2.2% [-2.3%, 6.7%]

 

HIV RNA <50 copies/ml,

% by Baseline Characteristicd

 

 

HIV RNA

 

 

 

 

 

 

 

<100,000 copies/ml

82 (n=217)

 

 

75 (n=217)

81 (n=218)

70 (n=218)

≥100,000 copies/ml

74 (n=223)

 

 

74 (n=223)

72 (n=225)

66 (n=225)

CD4 count

 

78 (n=58)

 

 

78 (n=58)

63 (n=48)

58 (n=48)

<50 cells/mm3

 

 

 

 

 

 

50 to <100 cells/mm3

76 (n=45)

 

 

71 (n=45)

69 (n=29)

69 (n=29)

100 to <200 cells/mm3

75 (n=106)

 

 

71 (n=106)

78 (n=134)

70 (n=134)

≥ 200 cells/mm3

80 (n=222)

 

 

76 (n=222)

80 (n=228)

69 (n=228)

HIV RNA Mean Change

from Baseline, log

10 copies/ml

 

 

All patients

-3.09 (n=397)

 

-3.21 (n=360)

-3.13 (n=379)

-3.19 (n=340)

CD4 Mean Change from

Baseline, cells/mm

 

 

 

 

All patients

203 (n=370)

 

 

268 (n=336)

219 (n=363)

290 (n=317)

CD4 Mean Change from

Baseline, cells/mm3

by Baseline Characteristic

 

HIV RNA

 

179 (n=183)

 

243 (n=163)

194 (n=183)

267 (n=152)

<100,000 copies/ml

 

 

 

 

 

 

≥100,000 copies/ml

227 (n=187)

 

291 (n=173)

245 (n=180)

310 (n=165)

aMean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml)

bREYATAZ/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

cLopinavir/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

dIntent-to-treat analysis, with missing values considered as failures.

ePer protocol analysis: Excluding non-completers and patients with major protocol deviations.

fNumber of patients evaluable.

In antiretroviral experienced adult patients

Study 045 is a randomised, multicenter trial comparing REYATAZ/ritonavir (300/100 mg once daily) and REYATAZ/saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the REYATAZ + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks (Table 6).

Table 6:

Efficacy Outcomes at Week 48a and at Week 96 (Study 045)

 

 

Parameter

 

ATV/RTVb (300 mg/

LPV/RTVc (400 mg/

 

Time-averaged difference

 

100 mg once daily)

100 mg twice daily)

 

ATV/RTV-LPV/RTV

 

 

n=120

n=123

 

[97.5% CId]

 

 

Week 48

Week 96

Week 48

Week 96

 

Week 48

Week 96

HIV RNA Mean Change from Baseline, log10 copies/ml

 

 

 

 

All patients

 

-1.93

-2.29

-1.87

-2.08

 

0.13

0.14

 

(n=90 e)

(n=64)

(n=99)

(n=65)

 

[-0.12, 0.39]

[-0.13, 0.41]

HIV RNA <50

copies/ml, %f

(responder/evaluable)

 

 

 

 

All patients

 

36 (43/120)

32 (38/120)

42 (52/123)

35 (41/118)

 

NA

NA

HIV RNA <50

copies/ml by

select baseline

PI substitutions,

f, g % (responder/evaluable)

 

44 (28/63)

41 (26/63)

56 (32/57)

48 (26/54)

 

NA

NA

 

18 (2/11)

9 (1/11)

38 (6/16)

33 (5/15)

 

NA

NA

≥ 4

 

27 (12/45)

24 (11/45)

28 (14/50)

20 (10/49)

 

NA

NA

CD4 Mean Change from Baseline, cells/mm3

 

 

 

 

All patients

 

110 (n=83)

122 (n=60)

121 (n=94)

154 (n=60)

NA

NA

aThe mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml).

bATV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

cLPV/RTV with tenofovir/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

dConfidence interval.

eNumber of patients evaluable.

fIntent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.

gSelect substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for REYATAZ + ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the REYATAZ + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for REYATAZ + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for REYATAZ + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall remained on study.

REYATAZ + saquinavir was shown to be inferior to lopinavir + ritonavir.

Paediatric population

Paediatric trials with REYATAZ capsules

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to

21 years of age. Overall in this study, 182 paediatric patients (81 antiretroviral-naive and

101 antiretroviral-experienced) received once daily REYATAZ (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir capsules (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received REYATAZ capsules with ritonavir are presented in Table 7. For treatment-naive paediatric patients,

the mean baseline CD4 cell count was 344 cells/mm3 (range: 2 to 800 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment- experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to 1157 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 log10 copies/ml).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study AI424-020)

 

 

Treatment-

 

Treatment-Naive

Experienced

Parameter

REYATAZ

REYATAZ

Capsules/ritonavir

Capsules/ritonavir

 

 

(300 mg/100 mg once

(300 mg/100 mg once

 

daily) n=16

daily) n=25

HIV RNA <50 copies/ml, % a

 

 

All patients

81 (13/16)

24 (6/25)

HIV RNA <400 copies/ml, % a

 

 

All patients

88 (14/16)

32 (8/25)

CD4 Mean Change from Baseline, cells/mm3

 

All patients

293 (n=14b)

229 (n=14b)

HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled)

NA

(4/15)

NA

 

-

≥ 4

NA

(0/3)

aIntent-to-treat analysis, with missing values considered as failures.

bNumber of patients evaluable.

cPI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY, I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

dIncludes patients with baseline resistance data.

NA = not applicable.

Paediatric trials with REYATAZ oral powder

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.

AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age

AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age

In these studies, 155 patients (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors, protease inhibitor resistance or evidence of pre-existing cardiac abnormalities were excluded from the trials. Protease inhibitor resistance was defined as genotypic resistance to atazanavir or either component of the local NRTI backbone based on the criteria of 1) any major mutations: I50L, I84V, N88S and 2) ≥ 2 of the following minor or cross resistant mutations: M46I/L, G48V, I54L/V/M/T/A, V82A/T/FI, L90M, V32I.

At Week 48 there were 134 paediatric patients aged 3 months to less than 11 years that received REYATAZ oral powder with ritonavir that were evaluated for efficacy. These data are presented in Table 8. For treatment-naive paediatric patients, the mean baseline CD4 cell count was 930 cells/mm3 (range: 46 to 2291 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.81 log10 copies/ml (range: 3.4 to 5.9 log10 copies/ml). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 1441 cells/mm3 (range: 84 to 5703 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 2.0 to 5.9 log10 copies/ml).

Table 8: Efficacy Outcomes for oral powder (paediatric patients at least 3 months of age and weighing at least 5 kg) at Week 48 (Studies AI424-397 and AI424-451)

 

Treatment-Naive

Treatment-Experienced

Parameter

REYATAZ

REYATAZ

 

Powder/ritonavir n=52

Powder/ritonavir n=82

HIV RNA <50 copies/ml, %a

 

 

at least 5 to < 10 kg (REYATAZ

33 (4/12)

52 (17/33)

150 and 200 mg)

59 (13/22)

35 (6/17)

at least 10 to < 15 kg

at least 15 to < 25 kg

61 (11/18)

57 (17/30)

at least 25 to < 35 kg

-

50.0 (1/2)

HIV RNA <400 copies/ml, %a

 

 

at least 5 to < 10 kg (REYATAZ

75 (9/12)

61 (20/33)

150 and 200 mg)

82 (18/22)

59 (10/17)

at least 10 to < 15 kg

at least 15 to < 25 kg

78 (14/18)

67 (20/30)

at least 25 to < 35 kg

-

50.0 (1/2)

CD4 Mean Change from Baseline, cells/mm3

 

at least 5 to < 10 kg (REYATAZ

293 (n=7)

63 (n=16)

150 and 200 mg)

293 (n=11)

307 (n=8)

at least 10 to < 15 kg

at least 15 to < 25 kg

305 (n=9)

374 (n=12)

at least 25 to < 35 kg

-

213 (n=1)

a Intent-to-treat analysis, with missing values considered as failures.

5.2 Pharmacokinetic properties

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of REYATAZ 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) ng/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) ng•h/ml, respectively.

Food effect: co-administration of REYATAZ and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of REYATAZ and 100 mg dose of ritonavir

with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24 hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal

did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24 hour concentration following a high fat meal was increased by approximately

33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, REYATAZ is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a multiple-dose study in HIV- infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

Linearity/non-linearity: the pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non-linear disposition.

Special populations

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for REYATAZ with ritonavir in patients with renal insufficiency. REYATAZ (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown (see sections 4.2 and 4.4.).

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ capsules with ritonavir are presented in Table 9.

Table 9: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State

 

atazanavir 300 mg with ritonavir 100 mg

 

 

 

 

Pharmacokinetic Parameter

2nd Trimester

3rd Trimester

postpartuma

(n=9)

(n=20)

(n=36)

 

Cmax ng/mL

3729.09

3291.46

5649.10

Geometric mean (CV%)

(39)

(48)

(31)

AUC ng•h/mL

34399.1

34251.5

60532.7

Geometric mean (CV%)

(37)

(43)

(33)

Cmin ng/mLb

663.78

668.48

1420.64

Geometric mean (CV%)

(36)

(50)

(47)

a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period when compared to those observed historically in HIV infected non-pregnant patients.

 

atazanavir 300 mg with ritonavir 100 mg

 

 

 

 

Pharmacokinetic Parameter

2nd Trimester

3rd Trimester

postpartuma

(n=9)

(n=20)

(n=36)

 

b Cmin is concentration 24 hours post-dose.

Paediatric population

There is a trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed; however at recommended doses, geometric mean atazanavir exposures (Cmin, Cmax and AUC) in paediatric patients are expected to be similar to those observed in adults.

5.3 Preclinical safety data

In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single- cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30 fold the free drug concentration at Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9 month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose

(see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo- development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aspartame (E951)

Sucrose

Orange vanilla flavour

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After mixing with food or beverage, mixture may be stored for up to 1 hour at temperatures not above 30°C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

REYATAZ oral powder should be stored in the original sachet and should not be opened until ready to use.

For storage conditions after mixing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Polyester film/Aluminum/Polyethylene sealant film sachet.

Each carton contains 30 sachets.

6.6 Special precautions for disposal and other handling

Instructions for use:

The dose and the number of REYATAZ oral powder sachets needed is determined based on weight (see section 4.2.).

1.Prior to mixing, the sachet is tapped to settle the powder. A clean pair of scissors is used to cut each sachet along the dotted line.

2.The appropriate option listed below is chosen for mixing and administration with liquid infant formula, beverage or food. Larger volumes or quantities of liquid infant formula, beverage or food may be used for dosing. It should be ensured that the patient eats or drinks all the infant formula, beverage or food that contains the powder.

A:To mix the recommended number of REYATAZ oral powder sachets with liquid infant formula in a small medicine cup or small container and to administer with an oral syringe, which can be obtained from a pharmacist:

A spoon is used to mix the content of the appropriate number of sachets (4 or 5 sachets depending on infant weight) with 10 ml of prepared liquid infant formula in the medicine cup or small container. The full amount of the mixture is drawn up into an oral syringe and administered into either right or left inner cheek of the infant. Another 10 ml of formula is poured into the medicine cup or small container to rinse off remaining REYATAZ oral powder in the cup or container. The residual mixture is

drawn up into the syringe and administered into either the right or left inner cheek of the infant.

B:To mix the recommended number of REYATAZ oral powder sachets with a beverage such as milk or water in a small drinking cup:

A spoon is used to mix the content of the sachets with 30 ml of the beverage. The child is to drink the mixture. An additional 15 ml of beverage is added to the drinking cup for thorough rinsing of the cup and contents are mixed. The child is to drink the entire residual mixture.

If water is used, food should also be taken at the same time.

C:To mix the recommended number of REYATAZ oral powder sachets with food such as applesauce or yogurt in a small container:

One tablespoon of food is used to mix the content of the sachets. The mixture is fed to the infant or young child. An additional tablespoon of food is added to the small container for thorough delivery of the powder from the container and contents are mixed.The entire residual mixture is fed to the child.

3.The entire dosage of REYATAZ oral powder (mixed in the liquid infant formula, beverage or food) is administered within one hour of preparation (the mixture can be left at room stored at temperatures not above 30°C during this period).

4.Additional infant formula, beverage or food may be given after consumption of the entire mixture.

5.Ritonavir is administered immediately following REYATAZ powder administration.

For further details on the preparation and administration of the REYATAZ oral powder, see the Patient Information Leaflet, Instructions for Use section

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/03/267/012

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 02 March 2004

Date of latest renewal: 02 March 2009

10. DATE OF REVISION OF THE TEXT

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

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