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Evotaz (atazanavir sulfate / cobicistat) – Summary of product characteristics - J05AR

Updated on site: 06-Oct-2017

Medication nameEvotaz
ATC CodeJ05AR
Substanceatazanavir sulfate / cobicistat
ManufacturerBristol-Myers Squibb Pharma EEIG

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1.NAME OF THE MEDICINAL PRODUCT

EVOTAZ 300 mg/150 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains atazanavir sulphate corresponding to 300 mg atazanavir and 150 mg of cobicistat.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

Pink, oval, biconvex, film-coated tablet of approximate dimensions of 19 mm x 10.4 mm, debossed with "3641" on one side and plain on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults without known mutations associated with resistance to atazanavir (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 EVOTAZ is one tablet once daily taken orally with food (see section 5.2).

Advice on missed doses

If EVOTAZ is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of EVOTAZ with food as soon as possible. If this is noticed later than

12 hours of the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.

Special populations

Renal impairment

Based on the very limited renal elimination of cobicistat and atazanavir, no special precautions or dose adjustments of EVOTAZ are required for patients with renal impairment.

EVOTAZ is not recommended for patients undergoing haemodialysis (see sections 4.4 and 5.2).

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. EVOTAZ should not be initiated in patients with creatinine clearance less than 70 ml/min if any co-administered agent (e.g. emtricitabine, lamivudine, tenofovir disoproxil or adefovir) requires dose adjustment based on creatinine clearance (see sections 4.4, 4.8 and 5.2).

Hepatic impairment

There are no pharmacokinetic data regarding the use of EVOTAZ in patients with hepatic impairment.

Atazanavir and cobicistat are metabolised by the hepatic system. Atazanavir should be used with caution in patients with mild (Child-Pugh Class A) hepatic impairment. However, atazanavir must not be used in patients with moderate (Child-Pugh Class B) to severe (Child-Pugh Class C) hepatic impairment. No dose adjustment of cobicistat is required in patients with mild or moderate hepatic impairment. Cobicistat has not been studied in patients with severe hepatic impairment and is not recommended in these patients.

EVOTAZ should be used with caution in patients with mild hepatic impairment. EVOTAZ must not be used in patients with moderate to severe hepatic impairment (see section 4.3).

Paediatric population

EVOTAZ should not be used in children less than 3 months of age because of safety concerns especially taking into account the potential risk of kernicterus associated with the atazanavir component.

The safety and efficacy of EVOTAZ in children less than 18 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

EVOTAZ is to be taken orally with food (see section 5.2). The film-coated tablet should be swallowed whole and must not be chewed, broken, cut or crushed.

4.3Contraindications

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

Co-administration with the following medicinal products that are strong inducers of the CYP3A4 isoform of cytochrome P450 due to the potential for loss of therapeutic effect (see section 4.5):

carbamazepine, phenobarbital, phenytoin (antiepileptics)

St John's wort (Hypericum perforatum) (herbal product)

rifampicin (antimycobacterial)

Co-administration with the following medicinal products due to the potential for serious and/or life- threatening adverse reactions (see section 4.5):

colchicine, when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)

sildenafil - when used for the treatment of pulmonary arterial hypertension (see sections 4.4 and 4.5 for co-administration for the treatment of erectile dysfunction), avanafil (PDE5 inhibitors)

simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)

substrates of CYP3A4 or the UGT1A1 isoform of UDP-glucuronyltransferase and have narrow therapeutic windows:

alfuzosin (alpha-1-adrenoreceptor antagonist)

amiodarone, bepridil, dronedarone, quinidine, systemic lidocaine (antiarrhythmics/antianginals)

astemizole, terfenadine (antihistamines)

cisapride (gastrointestinal motility agent)

ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

pimozide, quetiapine (antipsychotics/neuroleptics) (see section 4.5)

ticagrelor (platelet aggregation inhibitor)

triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam, see section 4.5).

Moderate to severe hepatic impairment.

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.

The choice of EVOTAZ in adult patients should be based on individual viral resistance testing and the patient’s treatment history (see section 5.1).

Patients with co-existing conditions

Hepatic impairment

The use of EVOTAZ is contraindicated in patients with moderate to severe hepatic impairment. EVOTAZ should be used with caution in patients with mild hepatic impairment (see sections 4.2, 4.3 and 5.2).

Atazanavir

Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 5.2). The safety and efficacy of atazanavir have 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 (see section 4.8). 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.

Patients with previous liver dysfunction or patients with 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.

Cobicistat

Cobicistat has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Renal impairment

EVOTAZ is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

Effects on estimated creatinine clearance

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated creatine clearance, should be taken into consideration when EVOTAZ is administered to patients in whom the estimated creatinine clearance is used to guide aspects of their clinical management, including adjusting doses of co-administered medicinal products. For more information consult the cobicistat Summary of Product Characteristics.

EVOTAZ should not be initiated in patients with creatinine clearance less than 70 ml/min if one or more co-administered agent requires dose adjustment based on creatinine clearance (e.g. emtricitabine, lamivudine, tenofovir disoproxil or adefovir; see sections 4.2, 4.8 and 5.2).

As atazanavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat.

QT prolongation

Dose related asymptomatic prolongations in PR interval with atazanavir, a component of EVOTAZ 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), EVOTAZ should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing EVOTAZ 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 therapy. 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 clinically appropriate.

In clinical studies, atazanavir 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 atazanavir (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving EVOTAZ should be evaluated for alternative etiologies. Alternative antiretroviral therapy to EVOTAZ may be considered if jaundice or scleral icterus is unacceptable to a patient.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of EVOTAZ 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 atazanavir (see section 4.8). Some patients required hospitalisation for additional management and some had complications. If signs or symptoms of cholelithiasis occurs, temporary interruption or discontinuation of treatment may be considered.

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving atazanavir (see section 4.8). Some patients required hospitalisation 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 occurs, 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 occur 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 atazanavir, a component of EVOTAZ.

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 atazanavir. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. EVOTAZ or any other medicinal product containing atazanavir 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 EVOTAZ, EVOTAZ may not be restarted.

Co-administration with antiretroviral medicinal products

EVOTAZ is indicated for use with other antiretrovirals for the treatment of HIV-1 infection. EVOTAZ should not be used in combination with products containing the same active components including atazanavir, cobicistat or with fixed-dose products that contain cobicistat. EVOTAZ should not be used in combination with another antiretroviral that requires pharmacokinetic enhancement (i.e., another protease inhibitor or elvitegravir) since dosing recommendations for such combinations have not been established and may result in decreased plasma concentrations of atazanavir and/or the other antiretroviral leading to loss of therapeutic effect and development of resistance. Co-administration of EVOTAZ with other protease inhibitors is not recommended. Because atazanavir is a component of EVOTAZ, co-administration of EVOTAZ with nevirapine or efavirenz is not recommended (see section 4.5).

EVOTAZ should not be used in combination with ritonavir or medicinal products containing ritonavir due to similar pharmacological effects of cobicistat and ritonavir on CYP3A (see section 4.5).

Interactions with other medicinal products

Atazanavir is metabolised principally by CYP3A4. Cobicistat is a strong mechanism-based CYP3A inhibitor and is a CYP3A substrate. Co-administration of EVOTAZ and medicinal products that induce CYP3A4 is contraindicated or not recommended (see sections 4.3 and 4.5) because, in addition to decreased plasma concentrations of atazanavir due to induction of CYP3A4, decreased plasma concentrations of cobicistat could result in cobicistat plasma levels that are insufficient to achieve adequate pharmacoenhancement of atazanavir.

Increased plasma concentrations of medicinal products that are metabolised by CYP3A (including atazanavir) are observed on co-administration with cobicistat. Higher plasma concentrations of co- administered medicinal products can result in increased or prolonged therapeutic effects or adverse reactions. For medicinal products metabolised by CYP3A these higher plasma concentrations may potentially lead to severe, life-threatening or fatal events (see sections 4.3 and 4.5).

Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may decrease the clearance of atazanavir and cobicistat, resulting in increased atazanavir and cobicistat plasma concentrations (see section 4.5).

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching from atazanavir boosted with ritonavir to EVOTAZ, caution is required during the first two weeks of treatment with EVOTAZ, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer (see section 4.5).

Cobicistat is a weak CYP2D6 inhibitor and is metabolised to a minor extent by CYP2D6. Co-administration with EVOTAZ can increase plasma concentrations of medicinal products that are metabolised by CYP2D6 (see sections 4.3 and 4.5).

Because atazanavir is a component of EVOTAZ, the combination of EVOTAZ with atorvastatin is not recommended (see section 4.5).

PDE5 inhibitors used for the treatment of erectile dysfunction

Particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, vardenafil, or avanafil) for the treatment of erectile dysfunction in patients receiving EVOTAZ. Co-administration of EVOTAZ 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 EVOTAZ is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole (see section 4.5).

Concomitant use of EVOTAZ and fluticasone or other glucocorticoids that are metabolized 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).

Co-administration of EVOTAZ with warfarin has the potential to produce serious and/or life-threatening bleeding due to increased warfarin plasma concentrations, and it is recommended that the INR (International Normalized Ratio) be monitored (see section 4.5).

Co-administration of EVOTAZ with proton pump inhibitors (PPIs) is not recommended due to the decreased solubility of atazanavir as intra-gastric pH increase with PPIs (see section 4.5).

Contraception requirements

No dosing recommendations can be made regarding the use of EVOTAZ with oral contraceptives (see section 4.5). Alternative forms of contraception (non-hormonal) should be considered (see

section 4.6).

4.5Interaction with other medicinal products and other forms of interaction

Drug interaction trials were not conducted for EVOTAZ. As EVOTAZ contains atazanavir and cobicistat, any interactions that have been identified with these active substances individually may occur with EVOTAZ.

Complex or unknown mechanisms of drug interaction preclude extrapolation of ritonavir drug interactions to certain cobicistat drug interactions. The recommendations given for concomitant use of atazanavir and other medicinal products may, therefore, differ depending on whether atazanavir is boosted with ritonavir or cobicistat. In particular, atazanavir boosted with cobicistat is more sensitive for CYP3A induction (see section 4.3 and the interaction table). Caution is also required during the first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Medicinal products that affect atazanavir/cobicistat exposure Atazanavir is metabolised in the liver through CYP3A4.

Cobicistat is a CYP3A substrate and is metabolised to a minor extent by CYP2D6.

Concomitant use contraindicated

Co-administration of EVOTAZ with medicinal products that are strong inducers of CYP3A (such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort [Hypericum perforatum]) may result in decreased plasma concentrations of atazanavir and/or cobicistat, leading to loss of therapeutic effect and possible development of resistance to atazanavir (see section 4.3 and Table 1).

Concomitant use not recommended

Co-administration of EVOTAZ with medicinal products containing ritonavir or cobicistat, which are strong inhibitors of CYP3A, may result in additional boosting and increased plasma concentration of atazanavir.

Co-administration of EVOTAZ with medicinal products that inhibit CYP3A may result in increased plasma concentration of atazanavir and/or cobicistat. Some examples include, but are not limited to, itraconazole, ketoconazole and voriconazole (see Table 1).

Co-administration of EVOTAZ with medicinal products that are moderate to weak inducers of CYP3A may result in decreased plasma concentration of atazanavir and/or cobicistat, leading to loss of therapeutic effect and possible development of resistance to atazanavir. Some examples include, but are not limited to etravirine, nevirapine, efavirenz, boceprevir, fluticasone and bosentan (see Table 1).

Medicinal products that may be affected by atazanavir/cobicistat

Atazanavir is an inhibitor of CYP3A4 and UGT1A1. Atazanavir is a weak to moderate inhibitor of CYP2C8. Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some medicinal products metabolised by CYP3A4.

Cobicistat is a strong mechanism-based CYP3A inhibitor and a weak CYP2D6 inhibitor. Cobicistat inhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP3A4 or P-gp. Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1.

Concomitant use contraindicated

Co-administration of medicinal products that are substrates of CYP3A and have narrow therapeutic indeces and for which elevated plasma concentrations are associated with serious and/or life-threatening events are contraindicated with EVOTAZ. These medicinal products include alfuzosin, amiodarone, astemizole, bepridil, cisapride, colchicine, dronedarone, ergot deriviatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine), lovastatin, orally administered

midazolam, pimozide, quetiapine, quinidine, simvastatin, sildenafil (when used to treat pulmonary arterial hypertension), avanafil, systemic lidocaine, ticagrelor, terfenadine and triazolam (see section 4.3 and Table 1).

Increased plasma concentrations of medicinal products that are metabolised by CYP3A, CYP2C8, CYP2D6 and/or UGT1A1 are expected when co-administered with EVOTAZ. Co-administration of EVOTAZ in patients receiving medicinal products that are substrates of the transporters P-gp, BCRP, MATE1, OATP1B1 and OATP1B3 may result in increased plasma concentrations of the co-administered medicinal products (see section 4.4). Clinically significant interactions between EVOTAZ and substrates of CYP1A2, CYP2B6, CYP2C9 or CYP2C19 are not expected.

Interaction table

Interactions between EVOTAZ and other medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). The recommendations shown in Table 1 are based on either drug interaction trials of unboosted atazanavir, atazanavir boosted with ritonavir, cobicistat or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse reactions or loss of therapeutic effect of EVOTAZ. If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 1 were conducted in healthy subjects unless otherwise noted.

Table 1: Interactions between EVOTAZ and other medicinal products

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

ANTI-RETROVIRALS

Protease inhibitors: EVOTAZ in combination with other protease inhibitors is not recommended because co-administration may not provide adequate protease inhibitor exposure.

Indinavir

Indinavir is associated with

Co-administration of EVOTAZ and

 

indirect unconjugated

indinavir is not recommended

 

hyperbilirubinaemia due to

(see section 4.4).

 

inhibition of UGT.

 

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

 

 

 

 

Lamivudine 150 mg twice daily +

No significant effect on

Based on these data and because

zidovudine 300 mg twice daily

lamivudine and zidovudine

cobicistat is not expected to have a

(atazanavir 400 mg once daily)

concentrations was observed

significant impact on the

 

when co-administered with

pharmacokinetics of NRTIs, the

 

atazanavir.

co-administration of EVOTAZ with

 

 

these medicinal products is not

 

 

expected to significantly alter the

 

 

exposure of the co-administered

 

 

medicinal products.

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Didanosine (buffered tablets)

Atazanavir, simultaneous

Didanosine should be taken in the

200 mg/stavudine 40 mg, both

administration with ddI+d4T

fasted state 2 hours after EVOTAZ

single dose

(fasted)

taken with food. The

(atazanavir 400 mg single dose)

Atazanavir AUC ↓87% (↓92%

co-administration of EVOTAZ with

 

↓79%)

stavudine is not expected to

 

Atazanavir Cmax ↓89% (↓94%

significantly alter the exposure of

 

↓82%)

stavudine.

 

Atazanavir Cmin ↓84% (↓90%

 

 

↓73%)

 

 

Atazanavir, dosed 1 hr after

 

 

ddI+d4T (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% (↓40%

 

(atazanavir 400 mg once daily)

↓26%)

 

 

Didanosine Cmax ↓36% (↓45%

 

 

↓26%)

 

 

Didanosine Cmin ↑13% (↓9%

 

 

↑41%)

 

 

No significant effect on

 

 

atazanavir concentrations was

 

 

observed when administered with

 

 

enteric-coated didanosine, but

 

 

administration with food

 

 

decreased didanosine

 

 

concentrations.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Tenofovir disoproxil fumarate

Atazanavir AUC ↓25% (↓30%

Tenofovir DF may decrease the

(tenofovir DF) 300 mg once daily

↓19%)

AUC and Cmin of atazanavir. When

(atazanavir 400 mg once daily)

Atazanavir Cmax ↓21% (↓27%

co-administered with tenofovir DF,

 

↓14%)

it is recommended that EVOTAZ

 

Atazanavir Cmin ↓40% (↓48%

and tenofovir DF 300 mg be given

 

↓32%)

together with food. Atazanavir

 

Tenofovir:

increases tenofovir concentrations.

 

Higher concentrations could

 

AUC: ↑24% (↑21% ↑28%)

potentiate tenofovir-associated

 

Cmax: ↑14% (↑8% ↑20%)

adverse reactions, including renal

 

Cmin: ↑22% (↑15% ↑30%)

disorders. Patients receiving

 

Co-administration of tenofovir

tenofovir disoproxil should be

 

monitored for tenofovir-associated

 

DF with cobicistat is expected to

adverse reactions.

 

increase tenofovir plasma

 

 

concentrations.

 

 

Tenofovir:

 

 

AUC: ↑23%

 

 

Cmin: ↑55%

 

 

The mechanism of interaction

 

 

between atazanavir and tenofovir

 

 

DF is unknown.

 

Tenofovir alafenamide 10 mg once

Tenofovir alafenamide

When co-administering tenofovir

daily/emtricitabine 200 mg once

AUC ↑75% (↑55% ↑98%)

alafenamide/emtricitabine and

daily

Cmax ↑80% (↑48% ↑118%)

EVOTAZ, the recommended dose

(atazanavir 300 mg once daily with

 

of tenofovir

cobicistat 150 mg once daily)

Tenofovir:

alafenamide/emtricitabine is

 

AUC ↑247% (↑229% ↑267%)

10/200 mg once daily.

 

Cmax ↑216% (↑200% ↑233%)

 

Tenofovir alafenamide 10 mg once

Cmin ↑273% (↑254% ↑293%)

Co-administration of EVOTAZ and

daily

Cobicistat:

tenofovir alafenamide 25 mg for

(atazanavir 300 mg once daily with

treatment of HBV infection is not

cobicistat 150 mg once daily)

AUC ↑5% (↔0% ↑9%)

recommended

 

Cmax ↓4% (↓8% ↔0%)

 

 

Cmin ↑35% (↑21% ↑51%)

 

 

Co-administration of tenofovir

 

 

alafenamide with cobicistat is

 

 

expected to increase tenofovir

 

 

alafenamide and tenofovir plasma

 

 

concentrations.

 

 

Atazanavir:

 

 

AUC ↑6% (↑1% ↑11%)

 

 

Cmax ↓2% (↓4% ↑2%)

 

 

Cmin ↑18% (↑6% ↑31%)

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

 

 

 

 

Efavirenz 600 mg once daily

Atazanavir

EVOTAZ is not recommended for

(atazanavir 400 mg once daily)

Atazanavir AUC ↓74% (↓78%

co-administration with efavirenz.

 

↓68%)

Efavirenz decreases atazanavir

 

Atazanavir Cmax ↓59% (↓77%

concentrations and is expected to

 

↓49%)

decrease cobicistat plasma

 

Atazanavir Cmin ↓93% (↓95%

concentrations. This may result in

 

↓90%)

loss of therapeutic effect of

 

 

EVOTAZ and development of

Efavirenz 600 mg single dose

Efavirenz:

resistance to atazanavir (see

(cobicistat 150 mg once daily)

AUC: ↔7% (↓11% ↓3%)

section 4.4).

 

Cmax: ↓13% (↓20% ↓6%)

 

 

Cmin: Not determined

 

 

The mechanism of interaction

 

 

between efavirenz and atazanavir,

 

 

or efavirenz and cobicistat is

 

 

CYP3A4 induction by efavirenz.

 

Etravirine

Co-administration of etravirine

EVOTAZ is not recommended for

 

and EVOTAZ is expected to

co-administration with etravirine

 

decrease atazanavir and cobicistat

because it may result in the loss of

 

plasma concentrations.

therapeutic effect and development

 

The mechanism of interaction is

of resistance to atazanavir.

 

 

 

CYP3A4 induction by etravirine.

 

Nevirapine 200 mg twice daily

Nevirapine AUC ↑25% (↑17%

Co-administration of EVOTAZ and

(atazanavir 300 mg once daily with

↑34%)

nevirapine is not recommended and

ritonavir 100 mg once daily)

Nevirapine Cmax ↑17% (↑9%

may result in a loss of therapeutic

 

↑25%)

effect of EVOTAZ and

Study conducted in HIV infected

Nevirapine Cmin ↑32% (↑22%

development of resistance to

patients

↑43%)

atazanavir. Co-administration of

 

Atazanavir AUC ↓42% (↓52%

nevirapine and EVOTAZ is

 

expected to increase nevirapine

 

↓29%)

plasma concentrations which may

 

Atazanavir Cmax ↓28% (↓40%

increase the risk of

 

↓14%)

nevirapine-associated toxicity (see

 

Atazanavir Cmin ↓72% (↓80%

section 4.4).

 

↓60%)

 

 

Co-administration of nevirapine

 

 

and cobicistat is expected to

 

 

decrease cobicistat plasma

 

 

concentrations while nevirapine

 

 

plasma concentrations may be

 

 

increased.

 

 

The mechanism of interaction is

 

 

CYP3A4 induction by nevirapine

 

 

and CYP3A4 inhibition by

 

 

atazanavir and cobicistat.

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Rilpivirine

EVOTAZ is expected to increase

Co-administration of EVOTAZ and

 

rilpivirine plasma concentrations.

rilpivirine can be used without dose

 

The mechanism of interaction is

adjustments, as the expected

 

increase in rilpivirine concentrations

 

CYP3A inhibition.

is not considered clinically relevant.

Integrase Inhibitors

 

 

 

 

 

Dolutegravir

Co-administration with EVOTAZ

EVOTAZ and dolutegravir can be

 

is expected to increase

used without dose adjustments.

 

dolutegravir plasma

 

 

concentrations. Dolutegravir is

 

 

not expected to affect the

 

 

pharmacokinetics of EVOTAZ.

 

 

The mechanism of interaction is

 

 

inhibition of UGT1A1 by

 

 

atazanavir.

 

Raltegravir 400 mg twice daily

Raltegravir AUC ↑72%

No dose adjustment is required for

(atazanavir 400 mg)

Raltegravir Cmax ↑53%

raltegravir if co-administered with

 

Raltegravir C12hr ↑95%

EVOTAZ.

 

The mechanism is UGT1A1

 

 

inhibition by atazanavir.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

CCR5 Antagonists

 

 

 

 

 

Maraviroc

Maraviroc is a substrate of

When co-administering maraviroc

 

CYP3A and its plasma

and EVOTAZ, patients should

 

concentration increases when

receive maraviroc 150 mg

 

co-administered with potent

twice daily. For further details,

 

CYP3A inhibitors.

consult the Summary of Product

 

Maraviroc is not expected to have

Characteristics for maraviroc.

 

 

 

an impact on concentrations of

 

 

atazanavir and cobicistat.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

HCV Protease Inhibitors

 

 

 

 

 

Boceprevir 800 mg three times

boceprevir AUC ↔5%

Co-administration of boceprevir and

daily

boceprevir Cmax ↔7%

EVOTAZ is not recommended.

(atazanavir 300 mg/ritonavir 100 mg

boceprevir Cmin ↔18%

 

once daily)

atazanavir AUC ↓35%

 

 

 

 

atazanavir Cmax ↓25%

 

 

atazanavir Cmin ↓49%

 

 

Concomitant administration of

 

 

boceprevir and

 

 

atazanavir/ritonavir resulted in

 

 

reduced exposures to atazanavir

 

 

and ritonavir.

 

 

The mechanism of interaction is

 

 

unknown.

 

Simeprevir

EVOTAZ is expected to increase

It is not recommended to

 

simeprevir plasma

co-administer EVOTAZ with

 

concentrations. Simeprevir may

simeprevir.

 

increase atazanavir and/or

 

 

cobicistat plasma concentrations.

 

 

The mechanism of interaction is

 

 

CYP3A inhibition.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Telaprevir 750 mg three times

Telaprevir AUC ↓20% (↓24%

No dose adjustment is required for

daily

↓15%)

telaprevir if co-administered with

(atazanavir/ritonavir 300/100 mg

Telaprevir Cmax ↓21% (↓26%

EVOTAZ.

once daily)

↓16%)

Clinical and laboratory monitoring

 

Telaprevir Cmin ↓15% (↓25%

 

↓2%)

for hyperbilirubinaemia is

 

 

recommended.

 

Atazanavir AUC ↑17% (↓3%

 

 

↑43%)

 

 

Atazanavir Cmax ↓15% (↓27%

 

 

↓2%)

 

 

Atazanavir Cmin ↑85% (↑40%

 

 

↑144%)

 

 

 

 

Telaprevir 750 mg three times

Telaprevir AUC ↔

 

daily

Telaprevir Cmax

 

(cobicistat 150 mg once daily in

Telaprevir Cmin

 

combination with elvitegravir)

Cobicistat AUC ↔

 

 

 

 

Cobicistat Cmax

 

 

Cobicistat Cmin ↑232%

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

ANTIBIOTICS

 

 

 

 

 

Clarithromycin 500 mg twice daily

Clarithromycin AUC ↑94%

Alternative antibiotics should be

(atazanavir 400 mg once daily)

(↑75% ↑116%)

considered.

 

Clarithromycin Cmax ↑50% (↑32%

 

 

↑71%)

 

 

Clarithromycin Cmin ↑160%

 

 

(↑135% ↑188%)

 

 

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%)

 

 

Clarithromycin may increase

 

 

concentrations of atazanavir and

 

 

cobicistat. Exposure to

 

 

clarithromycin is expected to

 

 

increase if co-administered with

 

 

EVOTAZ.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and/or cobicistat and

 

 

clarithromycin.

 

ANTIDIABETICS

 

 

 

 

 

Metformin

Cobicistat reversibly inhibits

Careful patient monitoring and dose

 

MATE1, and concentrations of

adjustment of metformin is

 

metformin may be increased

recommended in patients who are

 

when co-administered with

taking EVOTAZ.

 

EVOTAZ.

 

 

 

 

ANTIFUNGALS

 

 

 

 

 

Ketoconazole 200 mg once daily

No significant effect on

Caution is warranted. Specific

(atazanavir 400 mg once daily)

atazanavir concentrations was

dosing recommendations are not

 

observed.

available for co-administration of

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Itraconazole

Itraconazole, like ketoconazole, is

EVOTAZ with either ketoconazole

 

a potent inhibitor as well as a

or itraconazole.

 

substrate of CYP3A4.

If co-administration is required, the

 

Concentrations of ketoconazole,

daily dose of ketoconazole or

 

itraconazole should not exceed

 

itraconazole, and/or cobicistat

200 mg.

 

may be increased with

 

 

co-administration of

 

 

ketoconazole or itraconazole with

 

 

EVOTAZ.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by

 

 

atazanavir, cobicistat and

 

 

ketoconazole or itraconazole.

 

Voriconazole

Effects unknown

Voriconazole should not be

 

 

co-administered with EVOTAZ

 

 

unless the benefit/risk assessment

 

 

justifies the use of voriconazole (see

 

 

section 4.4). Clinical monitoring

 

 

may be needed upon

 

 

co-administration with EVOTAZ.

Fluconazole 200 mg once daily

Atazanavir and fluconazole

Clinical monitoring is

(atazanavir 300 mg and ritonavir

concentrations were not

recommended upon

100 mg once daily)

significantly modified when

co-administration with EVOTAZ.

 

atazanavir/ritonavir was

 

 

co-administered with fluconazole.

 

 

Concentration of fluconazole may

 

 

be increased if co-administered

 

 

with cobicistat.

 

ANTIGOUT

 

 

 

 

 

Colchicine

Colchicine plasma concentrations

EVOTAZ must not be

 

may be increased when

co-administered with colchicine to

 

co-administered with EVOTAZ.

patients with renal or hepatic

 

The mechanism of interaction is

impairment.

 

Recommended dosage of

 

CYP3A4 inhibition by atazanavir

 

colchicine when administered

 

and cobicistat.

 

with EVOTAZ in patients without

 

 

 

 

renal or hepatic impairment: a

 

 

dose reduction in colchicine dosage

 

 

or an interruption of colchicine

 

 

treatment is recommended in

 

 

patients with normal renal or

 

 

hepatic function if treatment with

 

 

EVOTAZ is required.

 

 

 

ANTIMYCOBACTERIALS

 

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Rifabutin 150 mg twice weekly

Rifabutin AUC ↑48% (↑19%

Co-administration of EVOTAZ and

(atazanavir 300 mg once daily with

↑84%)*

rifabutin is not recommended. If the

ritonavir 100 mg once daily)

Rifabutin Cmax ↑149% (↑103%

combination is needed, the

 

↑206%)*

recommended dose of rifabutin is

 

Rifabutin Cmin ↑40% (↑5%

150 mg 3 times per week on set

 

↑87%)*

days (for example

 

25-O-desacetyl-rifabutin AUC

Monday-Wednesday-Friday).

 

Increased monitoring for

 

↑990% (↑714% ↑1361%)*

rifabutin-associated adverse

 

25-O-desacetyl-rifabutin Cmax

reactions including neutropenia and

 

↑677% (↑513% ↑883%)*

uveitis is warranted due to an

 

25-O-desacetyl-rifabutin Cmin

expected increase in exposure to

 

↑1045% (↑715% ↑1510%)*

rifabutin. Further dosage reduction

 

*When compared to rifabutin

of rifabutin to 150 mg twice weekly

 

on set days is recommended for

 

150 mg once daily alone. Total

patients in whom the 150 mg dose

 

rifabutin and

3 times per week is not tolerated. It

 

25-O-desacetyl-rifabutin AUC

should be kept in mind that the

 

↑119% (↑78% ↑169%).

twice weekly dosage of 150 mg may

Rifabutin 150 mg every other

Cobicistat:

not provide an optimal exposure to

day/elvitegravir 150 mg

AUC: ↔

rifabutin thus leading to a risk of

once daily/cobicistat 150 mg

Cmax: ↔

rifamycin resistance and a treatment

once daily

Cmin: ↓66%

failure.

 

Rifabutin:

Consideration should be given to

 

official guidance on the appropriate

 

AUC: ↔8%

treatment of tuberculosis in HIV

 

Cmax: ↔9%

infected patients.

 

Cmin: ↔6%

 

 

25-O-desacetyl-rifabutin:

 

 

AUC: ↑525%

 

 

Cmax: ↑384%

 

 

Cmin: ↑394%

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

Rifampicin 600 mg once daily

Rifampicin is a strong CYP3A4

Rifampicin substantially decreases

(atazanavir 300 mg once daily with

inducer and has been shown to

plasma concentrations of atazanavir,

ritonavir 100 mg once daily)

cause a 72% decrease in

which may result in loss of

 

atazanavir AUC which can result

therapeutic effect of EVOTAZ and

 

in virological failure and

development of resistance to

 

resistance development.

atazanavir. The combination of

 

The mechanism of interaction is

rifampicin and EVOTAZ is

 

contraindicated (see section 4.3).

 

CYP3A4 induction by rifampicin.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

ACID REDUCING AGENTS

 

 

 

 

 

H2-Receptor antagonists

 

 

 

 

 

Without Tenofovir

 

 

Famotidine 20 mg twice daily

Atazanavir AUC ↓18% (↓25%

For patients not taking tenofovir,

(atazanavir 300 mg/ritonavir 100 mg

↑1%)

EVOTAZ once daily with food

once daily) in HIV-infected patients

Atazanavir Cmax ↓20% (↓32%

should be administered

 

↓7%)

simultaneously with, and/or at least

 

Atazanavir Cmin ↔1% (↓16%

10 hours after, a dose of the

 

↑18%)

H2-receptor antagonist. The dose of

 

 

the H2-receptor antagonist should

 

 

not exceed a dose comparable to

 

 

famotidine 20 mg twice daily.

With Tenofovir DF 300 mg once daily

 

 

 

 

Famotidine 20 mg twice daily

Atazanavir AUC ↓10% (↓18%

For patients who are taking

(atazanavir 300 mg/ritonavir

↓2%)

tenofovir DF, it is not

100 mg/tenofovir DF 300 mg once

Atazanavir Cmax ↓9% (↓16%

recommended to co-administer

daily, simultaneous administration)

↓1%)

EVOTAZ with an H2-receptor

 

Atazanavir Cmin ↓19% (↓31%

antagonist.

 

↓6%)

 

 

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 AUC ↓94% (↓95%

Co-administration of EVOTAZ with

(atazanavir 400 mg once daily,

↓93%)

proton pump inhibitors is not

2 hours after omeprazole)

Atazanavir Cmax ↓96% (↓96%

recommended.

 

↓95%)

 

 

Atazanavir Cmin ↓95% (↓97%

 

 

↓93%)

 

Omeprazole 40 mg once daily

Atazanavir AUC ↓76% (↓78%

 

(atazanavir 300 mg once daily with

↓73%)

 

ritonavir 100 mg once daily, 2 hours

Atazanavir Cmax ↓72% (↓76%

 

after omeprazole)

↓68%)

 

 

Atazanavir Cmin ↓78% (↓81%

 

 

↓74%)

 

Omeprazole 20 mg once daily am

Atazanavir AUC ↓42% (↓66%

 

(atazanavir 300 mg once daily with

↓25%)

 

ritonavir 100 mg once daily pm,

Atazanavir Cmax ↓39% (↓64%

 

12 hours after omeprazole)

↓19%)

 

 

Atazanavir Cmin ↓46% (↓59%

 

 

↓29%)

 

 

The mechanism of interaction is

 

 

decreased solubility of atazanavir

 

 

as intra-gastric pH increases with

 

 

proton pump inhibitors.

 

Antacids

 

 

 

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Antacids and medicinal products

Reduced plasma concentrations

EVOTAZ should be administered

containing buffers

of atazanavir may be the

2 hours before or 1 hour after

 

consequence of increased gastric

antacids or buffered medicinal

 

pH if antacids, including buffered

products.

 

medicinal products, are

 

 

administered with EVOTAZ.

 

ALPHA 1-ADRENORECEPTOR

ANTAGONIST

 

 

 

 

Alfuzosin

Potential for increased alfuzosin

Co-administration of EVOTAZ with

 

concentrations which can result

alfuzosin is contraindicated (see

 

in hypotension.

section 4.3)

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

ANTICOAGULANTS

 

 

 

 

 

Warfarin

Co-administration with EVOTAZ

Co-administration with EVOTAZ

 

has the potential to increase

has the potential to produce serious

 

warfarin plasma concentrations.

and/or life-threatening bleeding due

 

The mechanism of interaction is

to increased exposure to warfarin

 

and has not been studied. It is

 

CYP3A4 inhibition by atazanavir

recommended that the INR

 

and cobicistat.

(International Normalized Ratio) be

 

 

monitored.

Rivaroxaban

Co-administration of EVOTAZ

Avoid concomitant use of EVOTAZ

 

and rivaroxaban may result in

and rivaroxaban.

 

increased exposure to

 

 

rivaroxaban and may lead to

 

 

increased bleeding.

 

 

The mechanism of interaction is

 

 

CYP3A4 and P-gp inhibition by

 

 

cobicistat.

 

Dabigatran

Concentrations of dabigatran may

Clinical monitoring is

 

be affected upon

recommended when dabigatran is

 

co-administration with EVOTAZ.

co-administered with P-gp

 

The mechanism of interaction is

inhibitors.

 

 

 

P-gp inhibition by atazanavir and

A coagulation test helps to identify

 

cobicistat.

patients with an increased bleeding

 

 

risk due to increased dabigatran

 

 

exposure.

Ticagrelor

Co- administration of

Concomitant administration of

 

EVOTAZ and ticagrelor may

EVOTAZ with ticagrelor is

 

increase concentrations of the

contraindicated.

 

anticoagulant.

Use of other antiplatelets not

 

 

affected by CYP inhibition or

 

The mechanism of interaction is

induction (e.g. prasugrel) is

 

CYP3A and/or P-glycoprotein

recommended (see section 4.3).

 

inhibition by atazanavir and

 

 

cobicistat.

 

ANTIEPILEPTICS

 

 

 

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Carbamazepine

These antiepileptics are expected

Co-administration of EVOTAZ and

Phenobarbital

to decrease atazanavir and/or

these antiepileptics is

Phenytoin

cobicistat plasma concentrations.

contraindicated (see section 4.3).

 

The mechanism of interaction is

 

 

CYP3A induction by the

 

 

antiepileptic.

 

ANTIHISTAMINE AGENTS

 

 

 

 

 

Astemizole

EVOTAZ must not be used in

Co-administration of EVOTAZ with

Terfenadine

combination with medicinal

astemizole and terfenadine is

 

products that are substrates of

contraindicated (see section 4.3).

 

CYP3A4 and have a narrow

 

 

therapeutic index.

 

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

 

 

 

 

Antineoplastics

 

 

 

 

 

Irinotecan

Atazanavir inhibits UGT and may

If EVOTAZ is co-administered with

 

interfere with the metabolism of

irinotecan, patients should be closely

 

irinotecan, resulting in increased

monitored for adverse reactions

 

irinotecan toxicities.

related to irinotecan.

Dasatinib

Concentrations of these medicinal

Concentrations of these medicinal

Nilotinib

products may be increased when

products may be increased when

Vinblastine

co-administered with EVOTAZ.

co-administered with EVOTAZ

Vincristine

 

resulting in the potential for

 

The mechanism of interaction is

increased adverse events usually

 

CYP3A4 inhibition by cobicistat.

associated with these anticancer

 

 

medicinal products.

Immunosuppressants

 

 

 

 

 

Ciclosporin

Concentrations of these

More frequent therapeutic

Tacrolimus

immunosuppressants may be

concentration monitoring is

Sirolimus

increased when co-administered

recommended for

 

with EVOTAZ.

immunosuppressant agents when

 

The mechanism of interaction is

co-administered with EVOTAZ.

 

 

 

inhibition of CYP3A4 by

 

 

atazanavir and cobicistat.

 

ANTIPSYCHOTICS

 

 

 

 

 

Pimozide

Concentrations of these medicinal

The combination of pimozide or

Quetiapine

products may be increased when

quetiapine and EVOTAZ is

 

co-administered with EVOTAZ.

contraindicated (see section 4.3).

 

The mechanism of interaction is

 

 

CYP3A inhibition by atazanavir

 

 

and cobicistat.

 

CARDIOVASCULAR AGENTS

 

 

 

 

 

Antiarrhythmics

 

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Disopyramide

Concentrations of these

Co-administration with EVOTAZ

Flecainide

antiarrhythmics may be increased

has the potential to produce serious

Mexiletine

when co-administered with

and/or life-threatening adverse

Propafenone

EVOTAZ.

reactions. Caution is warranted and

 

The mechanism of interaction is

therapeutic concentration

 

monitoring of these medicinal

 

CYP3A inhibition by atazanavir

products is recommended if they are

 

and cobicistat.

used concomitantly with EVOTAZ.

Amiodarone

Concentrations of these

Amiodarone, dronedarone,

Dronedarone

antiarrhythmics may be increased

quinidine and systemic lidocaine

Quinidine

when co-administered with

have a narrow therapeutic window

Systemic lidocaine

EVOTAZ.

and are contraindicated due to

 

The mechanism of interaction is

potential inhibition of CYP3A by

 

EVOTAZ (see section 4.3).

 

CYP3A inhibition by atazanavir

 

 

and cobicistat.

 

Digoxin (0.5 mg

Plasma concentrations of digoxin

The peak concentration of digoxin

single dose)/cobicistat (150 mg

may be increased when

is increased when co-administered

multiple doses)

co-administered with EVOTAZ.

with cobicistat. When

 

 

co-administering with EVOTAZ,

 

Digoxin:

titrate the digoxin dose and monitor

 

AUC: ↔

digoxin concentrations. The lowest

 

Cmax: ↑41%

dose of digoxin should initially be

 

Cmin: not determined

prescribed.

 

The mechanism of interaction is

 

 

inhibition of P-gp by cobicistat.

 

Antihypertensives

 

 

 

 

 

Metoprolol

Concentrations of beta-blockers

Clinical monitoring is

Timolol

may be increased when

recommended when

 

co-administered with EVOTAZ.

co-administered with EVOTAZ and

 

 

a dose reduction of the beta-blocker

 

The mechanism of interaction is

may be necessary.

 

inhibition of CYP2D6 by

 

 

cobicistat.

 

Calcium channel blockers

 

 

 

 

 

Bepridil

EVOTAZ must not be used in

Co-administration with bepridil is

 

combination with medicinal

contraindicated (see section 4.3).

 

products that are substrates of

 

 

CYP3A4 and have a narrow

 

 

therapeutic index.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Diltiazem 180 mg once daily

Diltiazem AUC ↑125% (↑109%

Exposure to diltiazem and a

(atazanavir 400 mg once daily)

↑141%)

metabolite, desacetyl-diltiazem, is

 

Diltiazem Cmax ↑98% (↑78%

increased when diltiazem is

 

↑119%)

co-administered with atazanavir, a

 

Diltiazem Cmin ↑142% (↑114%

component of EVOTAZ. An initial

 

↑173%)

dose reduction of diltiazem by 50%

 

Desacetyl-diltiazem AUC ↑165%

should be considered, and

 

electrocardiogram monitoring is

 

(↑145% ↑187%)

recommended.

 

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.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

Amlodipine

Concentrations of these calcium

Caution is warranted. Dose titration

Felodipine

channel blockers may be

of the calcium channel blockers

Nicardipine

increased when co-administered

should be considered.

Nifedipine

with EVOTAZ.

Electrocardiogram monitoring is

Verapamil

The mechanism of interaction is

recommended.

 

 

 

inhibition of CYP3A4 by

Clinical monitoring of therapeutic

 

atazanavir and cobicistat.

effect and adverse events is

 

 

recommended when these medicinal

 

 

products are co-administered with

 

 

EVOTAZ.

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Endothelin Receptor Antagonists

 

 

 

 

 

Bosentan

Co-administration of bosentan

Atazanavir plasma concentrations

 

with cobicistat may lead to

may decrease as a consequence of a

 

decreased cobicistat plasma

reduction in cobicistat plasma

 

concentrations.

concentrations, which may result in

 

 

loss of therapeutic effect and

 

The mechanism of interaction is

development of resistance.

 

induction of CYP3A4 by

 

 

bosentan.

Co-administration is not

 

 

recommended (see section 4.4).

CORTICOSTEROIDS

 

 

 

 

 

Corticosteroids primarily

Interaction not studied with any

Concomitant use of EVOTAZ and

metabolised by CYP3A (including

of the components of EVOTAZ.

corticosteroids that are metabolised

betamethasone, budesonide,

Plasma concentrations of these

by CYP3A (e.g. fluticasone

fluticasone, mometasone,

propionate or other inhaled or nasal

prednisone, triamcinolone).

medicinal products may be

corticosteroids) may increase the

 

increased when co–administered

risk of development of systemic

 

with EVOTAZ, resulting in

corticosteroid effects, including

 

reduced serum cortisol

Cushing’s syndrome and adrenal

 

concentrations.

suppression.

 

 

Co-administration with CYP3A-

 

 

metabolised corticosteroids is not

 

 

recommended unless the potential

 

 

benefit to the patient outweighs the

 

 

risk, in which case patients should

 

 

be monitored for systemic

 

 

corticosteroid effects. Alternative

 

 

corticosteroids which are less

 

 

dependent on CYP3A metabolism,

 

 

e.g. beclomethasone for intranasal

 

 

or inhalational use, should be

 

 

considered, particularly for long

 

 

term use.

ANTIDEPRESSANTS

 

 

 

 

 

Other antidepressants:

 

 

 

 

 

Trazodone

Plasma concentrations of

If trazodone is co-administered with

 

trazodone may be increased when

EVOTAZ, the combination should

 

co-administered with EVOTAZ.

be used with caution and a lower

 

The mechanism of interaction is

dose of trazodone should be

 

considered.

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

 

 

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

ERECTILE DYSFUNCTION

 

 

 

 

 

PDE5 Inhibitors

 

 

 

 

 

Sildenafil

Sildenafil, tadalafil, and

Patients should be warned about

Tadalafil

vardenafil are metabolised by

these possible side effects when

Vardenafil

CYP3A4. Co-administration with

using PDE5 inhibitors for erectile

Avanafil

EVOTAZ may result in increased

dysfunction with EVOTAZ (see

 

concentrations of the PDE5

section 4.4).

 

inhibitor and an increase in

For the treatment of erectile

 

PDE5-associated adverse events,

 

including hypotension, visual

dysfunction, it is recommended that

 

changes, and priapism.

when co-administered with

 

 

EVOTAZ, sildenafil should be used

 

The mechanism of this

with caution at reduced doses of

 

25 mg every 48 hours; tadalafil

 

interaction is CYP3A4 inhibition

 

should be used with caution at

 

by atazanavir and cobicistat.

 

reduced doses of 10 mg every

 

 

 

 

72 hours; vardenafil should be used

 

 

with caution at reduced doses of no

 

 

more than 2.5 mg every 72 hours.

 

 

Increase monitoring for adverse

 

 

reactions.

 

 

The combination of avanafil and

 

 

EVOTAZ is contraindicated (see

 

 

section 4.3).

 

 

Also see PULMONARY ATERIAL

 

 

HYPERTENSION in this table for

 

 

further information regarding

 

 

co-administration of EVOTAZ with

 

 

sildenafil.

HERBAL PRODUCTS

 

 

 

 

 

St. John’s wort (Hypericum

Concomitant use of St. John's

Co-administration of EVOTAZ with

perforatum)

wort with EVOTAZ may be

products containing St. John's wort

 

expected to result in significant

is contraindicated (see section 4.3).

 

reduction in plasma levels of

 

 

cobicistat and atazanavir. This

 

 

effect may be due to an induction

 

 

of CYP3A4. There is a risk of

 

 

loss of therapeutic effect and

 

 

development of resistance to

 

 

atazanavir (see section 4.3).

 

Medicinal products by therapeutic

 

Interaction

Recommendations concerning

area

 

 

co-administration

 

 

 

 

HORMONAL CONTRACEPTIVES

 

 

 

 

 

Progestin/estrogen

 

Concentrations of ethinyl

Co-administration of EVOTAZ and

 

 

estradiol and norethindrone are

hormonal contraceptives should be

 

 

increased when a combined oral

avoided. An alternate

 

 

contraceptive containing those

(non-hormonal) reliable method of

 

 

agents is co-administered with

contraception is recommended.

 

 

atazanavir. The mechanism of

 

 

 

interaction is inhibition of

 

 

 

metabolism by atazanavir.

 

 

 

Effects of co-administration of

 

 

 

EVOTAZ on progestin and

 

 

 

estrogen are unknown.

 

LIPID LOWERING AGENTS

 

 

 

 

 

HMG-CoA reductase inhibitors

 

 

 

 

 

Simvastatin

 

Simvastatin and lovastatin are

Co-administration of simvastatin or

Lovastatin

 

highly dependent on CYP3A4 for

lovastatin with EVOTAZ is

 

 

their metabolism and

contraindicated due to an increased

 

 

co-administration with EVOTAZ

risk of myopathy including

 

 

may result in increased

rhabdomyolysis (see section 4.3).

 

 

concentrations.

 

Atorvastatin

 

The risk of myopathy including

Co-administration of atorvastatin

 

 

rhabdomyolysis may also be

with EVOTAZ is not recommended.

 

 

increased with atorvastatin,

If the use of atorvastatin is

 

 

which is also metabolised by

considered strictly necessary, the

 

 

CYP3A4.

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

 

Pitavastatin

 

pravastatin or fluvastatin

 

 

 

exposure when co-administered

 

 

 

with protease inhibitors.

 

 

 

Pravastatin is not metabolised by

 

 

 

CYP3A4. Fluvastatin is partially

 

 

 

metabolised by CYP2C9.

 

 

 

Plasma concentrations of

 

 

 

pitavastatin may be increased if

 

 

 

co-administered with EVOTAZ.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

Rosuvastatin (10 mg

Rosuvastatin:

Rosuvastatin dose should not

single dose)/Elvitegravir (150 mg

AUC: ↑38%

exceed 10 mg/day. The risk of

once daily)/Cobicistat (150 mg

Cmax: ↑89%

myopathy, including

once daily)

Cmin: ↑43%

rhabdomyolysis, may be increased.

 

Cobicistat:

 

 

AUC: ↔

 

 

Cmax: ↔

 

 

Cmin: ↔

 

 

The mechanism of interaction is

 

 

potential inhibition of the

 

 

transporter OATP1B1 by

 

 

cobicistat.

 

INHALED BETA AGONISTS

 

 

 

 

 

Salmeterol

Co-administration with EVOTAZ

Co-administration of salmeterol

 

may result in increased

with EVOTAZ is not recommended

 

concentrations of salmeterol and

(see section 4.4).

 

an increase in

 

 

salmeterol-associated adverse

 

 

events.

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

ERGOT DERIVATES

 

 

 

 

 

Dihydroergotamine

EVOTAZ must not be used in

Co-administration of EVOTAZ and

Ergometrine

combination with medicinal

these ergot derivates is

Ergotamine

products that are substrates of

contraindicated (see section 4.3).

Methylergonovine

CYP3A4 and have a narrow

 

 

therapeutic index.

 

NEUROLEPTICS

 

 

 

 

 

Perphenazine

Co-administration of neuroleptics

A decrease in the dose of

Risperidone

with EVOTAZ may result in

neuroleptics metabolized by

Thioridazine

increased plasma concentrations

CYP3A or CYP2D6 may be

 

of neuroleptics.

required when co-administered with

 

The mechanism of interaction is

EVOTAZ.

 

 

 

inhibition of CYP3A4 and/or

 

 

CYP2D6 by atazanavir and/or

 

 

cobicistat.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

OPIOIDS

 

 

 

 

 

Buprenorphine, once daily, stable

Buprenorphine AUC ↑67%

Co-administration warrants clinical

maintenance dose

Buprenorphine Cmax ↑37%

monitoring for sedation and

(atazanavir 300 mg once daily with

Buprenorphine Cmin ↑69%

cognitive effects. A dose reduction

ritonavir 100 mg once daily)

Norbuprenorphine AUC ↑105%

of buprenorphine may be

 

considered.

 

Norbuprenorphine Cmax ↑61%

 

 

Norbuprenorphine Cmin ↑101%

 

 

The mechanism of interaction is

 

 

CYP3A4 and UGT1A1 inhibition

 

 

by atazanavir.

 

 

Concentrations of atazanavir

 

 

were not significantly affected.

 

Buprenorphine/naloxone in

Buprenorphine AUC: ↑35%

 

combination with cobicistat

Buprenorphine Cmax: ↑66%

 

 

Buprenorphine Cmin: ↑12%

 

 

Naloxone AUC: ↓28%

 

 

Naloxone Cmax: ↓28%

 

 

The mechanism of interaction is

 

 

CYP3A4 inhibition by cobicistat.

 

Methadone, stable maintenance

No significant effect on

No dosage adjustment is necessary

dose

methadone concentrations was

if methadone is co-administered

(atazanavir 400 mg once daily)

observed when co-administered

with EVOTAZ.

 

with atazanavir. Given that

 

 

cobicistat has been shown to have

 

 

no significant effect on

 

 

methadone concentrations, no

 

 

interaction is expected if

 

 

methadone is co-administered

 

 

with EVOTAZ.

 

PULMONARY ARTERIAL HYPERTENSION

 

 

 

 

PDE5 Inhibitors

 

 

 

 

 

Sildenafil

Co-administration with EVOTAZ

A safe and effective dose in

 

may result in increased

combination with EVOTAZ has not

 

concentrations of the PDE5

been established for sildenafil when

 

inhibitor and an increase in

used to treat pulmonary arterial

 

PDE5 inhibitor-associated

hypertension. Sildenafil, when used

 

adverse events.

for the treatment of pulmonary

 

The mechanism of interaction is

arterial hypertension, is

 

contraindicated (see section 4.3).

 

CYP3A4 inhibition by atazanavir

 

 

and cobicistat.

 

Medicinal products by therapeutic

Interaction

Recommendations concerning

area

 

co-administration

 

 

 

SEDATIVES/HYPNOTICS

 

 

 

 

 

Midazolam

Midazolam and triazolam are

EVOTAZ should not be

Triazolam

extensively metabolized by

co-administered with triazolam or

 

CYP3A4. Co-administration with

orally administered midazolam (see

 

EVOTAZ may cause a large

section 4.3), whereas caution should

 

increase in the concentration of

be used with co-administration of

 

these benzodiazepines. Based on

EVOTAZ and parenteral

 

data for other CYP3A4 inhibitors,

midazolam. If EVOTAZ is

 

plasma concentrations of

co-administered with parenteral

 

midazolam are expected to be

midazolam, it should be done in an

 

significantly higher when

intensive care unit (ICU) or similar

 

midazolam is given orally. Data

setting which ensures close clinical

 

from concomitant use of

monitoring and appropriate medical

 

parenteral midazolam with other

management in case of respiratory

 

protease inhibitors suggest a

depression and/or prolonged

 

possible 3-4 fold increase in

sedation. Dosage adjustment for

 

midazolam plasma levels.

midazolam should be considered,

 

 

especially if more than a single dose

 

 

of midazolam is administered.

Buspirone

Concentrations of these

For these sedatives/hypnotics, dose

Clorazepate

sedatives/hypnotics may be

reduction may be necessary and

Diazepam

increased when co-administered

concentration monitoring is

Estazolam

with EVOTAZ.

recommended.

Flurazepam

The mechanism of interaction is

 

Zolpidem

 

 

inhibition of CYP3A4 by

 

 

cobicistat.

 

GASTROINTESTINAL MOTILITY AGENTS

 

 

 

 

Cisapride

EVOTAZ must not be used in

Co-administration of EVOTAZ and

 

combination with medicinal

cisapride is contraindicated (see

 

products that are substrates of

section 4.3).

 

CYP3A4 and have a narrow

 

 

therapeutic index.

 

Paediatric population

 

 

Interaction studies have only been performed in adults.

 

4.6Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of EVOTAZ in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). The use of EVOTAZ may be considered during pregnancy only if the potential benefit justifies the potential risk.

Atazanavir

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

section 5.3).

It is not known whether atazanavir 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.

Cobicistat

There are no or limited clinical data with cobicistat in pregnant women.

Animal studies do not indicate direct or indirect harmful effects of cobicistat with respect to reproductive toxicity (see section 5.3).

Breast-feeding

Atazanavir, an active component of EVOTAZ, has been detected in human milk. It is unknown if cobicistat/metabolites are excreted in human milk. Studies in animals have been shown excretion of cobicistat/metabolites in milk Because of both the potential for HIV transmission and the potential for serious adverse reactions in breast-feeding infants, women should be instructed not to breast-feed if they are receiving EVOTAZ.

Fertility

The effect of EVOTAZ on fertility in humans has not been studied. 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). No human data on the effect of cobicistat on fertility are available. Animal studies do not indicate harmful effects of cobicistat on fertility.

4.7Effects on ability to drive and use machines

EVOTAZ has no or negligible influence on the ability to drive or use machines. However, patients should be informed that dizziness has been reported during treatment with regimens containing atazanavir or cobicistat (see section 4.8).

4.8Undesirable effects

Summary of the safety profile

The overall safety profile of EVOTAZ is based on available data from clinical trials conducted with atazanavir, atazanavir boosted with either cobicistat or ritonavir, and post-marketing data.

As EVOTAZ contains atazanavir and cobicistat, the adverse reactions associated with each of the individual components may be expected.

In clinical study GS-US-216-0114, a phase 3 randomised, active-controlled clinical study, in which 692 treatment-naïve patients received at least one dose of atazanavir boosted with cobicistat (n = 344) or atazanavir boosted with ritonavir (n = 348) administered with other antiretroviral medicinal products, the most frequently reported adverse reactions in the atazanavir boosted with cobicistat group during 144 weeks were associated with elevated bilirubin levels (see Table 2).

Of these 692 patients, 613 (300 atazanavir with cobicistat and 313 atazanavir with ritonavir) and 496 (250 atazanavir with cobicistat and 246 atazanavir with ritonavir) received at least 48 and 144 weeks of treatment, respectively.

In 2 controlled clinical studies for combination therapy with other antiretroviral medicinal products 1,806 adult patients receiving atazanavir 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or atazanavir 300 mg boosted with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration), the most frequently reported adverse reactions were nausea, diarrhoea and jaundice. 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

Adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2: Tabulated summary of adverse reactions

System Organ Class

 

Adverse Reactions

Frequency

 

 

 

Immune system disorders

 

uncommon

 

hypersensitivity

Metabolism and nutrition disorders

common

 

increased appetite

uncommon

 

weight decreased, weight gain, anorexia

Psychiatric disorders

 

common

 

insomnia, abnormal dreams

uncommon

 

depression, sleep disorder, disorientation, anxiety

Nervous system disorders

common

 

headache, dizziness, somnolence, dysgeusia

uncommon

 

peripheral neuropathy, syncope, amnesia

Eye disorders

 

very common

 

ocular icterus

Cardiac disorders

 

uncommon

 

torsades de pointesa

rare

 

QTc prolongationa, oedema, palpitation

Vascular disorders

 

uncommon

 

hypertension

Respiratory, thoracic and mediastinal disorders

uncommon

 

dyspnoea

Gastrointestinal disorders

very common

 

nausea

common

 

vomiting, diarrhoea, dyspepsia, abdominal pain, abdominal distension,

 

 

flatulence, dry mouth

uncommon

 

pancreatitis, gastritis, stomatitis aphthous

Hepatobiliary disorders

 

very common

 

jaundice

common

 

hyperbilirubinaemia

uncommon

 

hepatitis, cholelithiasisa, cholestasisa

rare

 

hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue disorders

common

 

rash

uncommon

 

pruritus, erythema multiformea,b, toxic skin eruptionsa,b, drug rash with

 

 

eosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa,

 

 

urticaria, alopecia

 

 

 

rare

 

Stevens-Johnson syndromea,b, vesiculobullous rash, eczema, vasodilatation

Musculoskeletal and connective tissue disorders

uncommon

 

myalgia, muscle atrophy, arthralgia

rare

 

myopathy

Renal and urinary disorders

uncommon

 

nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis

rare

 

kidney pain

Reproductive system and breast disorders

uncommon

 

gynaecomastia

 

 

System Organ Class

 

Adverse Reactions

Frequency

 

 

 

General disorders and administration site conditions

 

common

fatigue

uncommon

pyrexia, asthenia, chest pain, malaise

rare

gait disturbance

aThese adverse reactions were identified through post-marketing surveillance; however, the frequencies were estimated from a statistical calculation based on the total number of patients exposed to atazanavir (with and without ritonavir) in randomised controlled and other available clinical trials (n = 2321).

bSee section Description of selected adverse reactions for more details.

Description of selected adverse reactions

Immune reactivation syndrome and autoimmune disorders

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).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to 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 atazanavir.

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 atazanavir (see section 4.4).

Renal impairment

Cobicistat, a component of EVOTAZ, has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. An increase from baseline in serum creatinine solely due to cobicistat’s inhibitory effect generally does not exceed 0.4 mg/dl.

In study GS-US-216-0114, decreases in estimated creatinine clearance occurred early in treatment with cobicistat, after which they stabilised. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -15.1 ± 16.5 ml/min in the atazanavir boosted with cobicistat plus emtricitabine and tenofovir DF fixed-dose combination group and -8.0 ± 16.8 ml/min in the atazanavir boosted with ritonavir plus emtricitabine and tenofovir DF fixed-dose combination group.

Effects on the liver

In study GS-US-216-0114, through 144 weeks of treatment hyperbilirubinaemia (> 1 x ULN) was common: 97.7% in the atazanavir boosted with cobicistat plus emtricitabine and tenofovir DF fixed-dose combination group, and 97.4% in the atazanavir boosted with ritonavir plus emtricitabine and tenofovir DF fixed-dose combination group. However, a higher percentage of subjects in the atazanavir boosted with cobicistat group had increases in total bilirubin > 2 x ULN than those in the

atazanavir boosted with ritonavir group (88.0% versus 80.9%). The rates of study drug discontinuation due to bilirubin-related adverse events were low and similar in both groups (4.9% in the cobicistat-boosted group and 4.0% in the ritonavir-boosted group). An increase of > 3 x ULN in alanine aminotransferase or aspartate aminotransferase was recorded in 12.8% of subjects in the cobicistat-boosted group and 9.0% in the ritonavir-boosted group.

Laboratory abnormalities

The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavir 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 atazanavir 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 naïve patients treated with atazanavir 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 atazanavir 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 atazanavir experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

In clinical studies, paediatric patients 3 months to less than 18 years of age had a mean duration of treatment with atazanavir of 115 weeks. The safety profile in these studies 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 atazanavir was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4) which occurred in 45% of patients.

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 atazanavir and comparator regimens (see section 4.4).

Patients with chronic hepatitis B or hepatitis C virus co-infection:

In GS-US-216-0114, 3.6% of subjects were hepatitis B virus surface antigen positive and 5.3% were hepatitis C virus seropositive. Subjects with significant liver function test abnormalities generally had abnormal baseline transaminases (AST or ALT), underlying chronic or acute hepatitis B or C co-infection, concomitant hepatotoxic medications (e.g., isoniazid), or a medical history of alcoholism or alcohol abuse.

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 EVOTAZ is limited.

There is no specific antidote for overdose with EVOTAZ. If overdose occurs with EVOTAZ, the patient must be monitored for evidence of toxicity. Treatment should consist of general supportive measures including monitoring of vital signs and ECG as well as observation of the patient’s clinical status. Since atazanavir and cobicistat are extensively metabolised by the liver and 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; antivirals for treatment of HIV infections, combinations. ATC code: J05AR15

Mechanism of action

EVOTAZ is a fixed-dose combination of the antiviral drug atazanavir boosted by the pharmacokinetic enhancer cobicistat.

Atazanavir

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.

Cobicistat

Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as atazanavir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Antiviral activity in vitro

Atazanavir

Atazanavir exhibits anti-HIV-1 (including all clades tested) and anti-HIV-2 activity in cell culture.

Cobicistat

Cobicistat has no antiviral activity.

Pharmacodynamic effects

Effect of cobicistat on atazanavir pharmacokinetics

The antiretroviral effect of EVOTAZ is due to the atazanavir component. The activity of cobicistat as a pharmacokinetic enhancer to atazanavir has been demonstrated in pharmacokinetic trials. In these pharmacokinetic trials, the exposure of atazanavir 300 mg with cobicistat 150 mg was consistent with that observed when boosted with ritonavir 100 mg. EVOTAZ is bioequivalent to atazanavir 300 mg once daily in combination with cobicistat 150 mg once daily coadministered as single agents (see section 5.2).

Clinical efficacy and safety

In treatment-naïve HIV-1 infected patients

The safety and efficacy of atazanavir with cobicistat in HIV-1 infected patients were evaluated in the randomised, double-blind, active-controlled phase 3 study GS-US-216-0114 in HIV-1 infected patients with baseline estimated creatinine clearance above 70 ml/min who were treatment-naïve

(n = 692).

Patients were randomised in a 1:1 ratio to receive either atazanavir 300 mg with cobicistat 150 mg once daily or atazanavir 300 mg with ritonavir 100 mg once daily, each administered with a fixed background regimen containing tenofovir DF 300 mg and emtricitabine 200 mg administered as a fixed-dose combination tablet. Randomisation was stratified by screening HIV-1 RNA level (≤100,000 copies/ml or >100,000 copies/ml). Virologic response rate was evaluated in both treatment arms and virologic response was defined as achieving an undetectable viral load (<50 HIV-1

RNA copies/ml). Viruses were known to be susceptible to atazanavir, emtricitabine and tenofovir DF at baseline.

The demographic and baseline characteristics were similar between the atazanavir with cobicistat and atazanavir with ritonavir groups. The median age of subjects was 36 years (range: 19-70). The median baseline plasma HIV-1 RNA was 4.81 log10 copies/ml (range: 3.21-6.44). The median baseline CD4+ cell count was 352 cells/mm3 (range: 1-1455) and 16.9% had CD4+ cell counts ≤200 cells/mm3. The percentage of subjects with baseline viral loads >100,000 copies/ml was 39.7%. Treatment outcomes at weeks 48 and 144 for study GS-US-216-0114 are presented in Table 3.

Table 3: Virologic outcome of randomised treatment of study GS-US-216-0114 at weeks 48a and 144b

 

Week 48

Week 144

 

Atazanavir

Atazanavir

Atazanavir

Atazanavir

 

with

with

with

with

 

cobicistatf

ritonavirf

cobicistatf

ritonavirf

 

(n = 344)

(n = 348)

(n = 344)

(n = 348)

Virologic success

85%

87%

72%

74%

HIV-1 RNA <50 copies/ml

 

 

 

 

Treatment difference

-2.2% (95% CI

= -7.4%, 3.0%)

-2.1% (95% CI = -8.7%, 4.5%)

Virologic failurec

6%

4%

8%

5%

No virologic data in week 48

9%

9%

20%

21%

or week 144 window

 

 

 

 

Discontinued study drug due

6%

7%

11%

11%

to AE or deathd

 

 

 

 

Discontinued study drug due

3%

2%

8%

10%

to other reasons and last

 

 

 

 

available HIV-1 RNA

 

 

 

 

<50 copies/mle

 

 

 

 

Missing data during window

0%

0%

< 1%

< 1%

but on study drug

 

 

 

 

aWeek 48 window is between day 309 and 378 (inclusive)

bWeek 144 window is between day 967 and 1,050 (inclusive)

cIncludes subjects who had ≥50 copies/ml in the week 48 or 144 windows, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/ml.

dIncludes patients who discontinued due to adverse event (AE) or death at any time point from day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

eIncludes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up.

fPlus background regimen of emtricitabine 200 mg and tenofovir DF 300 mg fixed-dose combination.

Atazanavir with cobicistat and emtricitabine and tenofovir DF fixed-dose combination was non-inferior in achieving HIV-1 RNA <50 copies/ml when compared to atazanavir with ritonavir and emtricitabine and tenofovir DF fixed-dose combination.

In study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at weeks 48 and 144 were 213 and 310 cells/mm3 in patients receiving atazanavir boosted with cobicistat and 219 and 332 cells/mm3 in patients receiving atazanavir boosted with ritonavir, respectively.

Resistance

The resistance profile of EVOTAZ is driven by atazanavir. Cobicistat does not select any HIV resistance mutations, due to its lack of antiviral activity.

Atazanavir

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. For more information consult the REYATAZ Summary of Product Characteristics.

Atazanavir with cobicistat

Limited data are available on the development of resistance to atazanavir boosted with cobicistat.

In an analysis of treatment-failure subjects who received atazanavir 300 mg co-administered with cobicistat 150 mg in study GS-US-216-0114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates were available for all 21 virologic failures in this group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or K70E or any primary resistance substitution associated with protease inhibitors. In the group receiving atazanavir 300 mg co-administered with ritonavir 100 mg, evaluable genotypic data was available for all

19 virologic failures (5%, 19/348). Among the 19 patients, 1 developed the emtricitabine-associated resistance substitution M184V with no tenofovir or protease inhibitor associated resistance substitutions.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with EVOTAZ in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).

5.2Pharmacokinetic properties

One EVOTAZ tablet is bioequivalent to one atazanavir capsule (300 mg) plus one cobicistat tablet (150 mg) following single oral dose administration with a light meal in healthy subjects (n=62).

The following statements reflect the pharmacokinetic properties of atazanavir in combination with cobicistat or the individual components of EVOTAZ.

Absorption

In a trial where HIV-infected subjects (n=22) were instructed to take atazanavir 300 mg with cobicistat 150 mg once daily with food, the steady-state atazanavir Cmax, AUCtau and Ctau (mean ± SD) values were 3.9 ± 1.9 μg/ml, 46.1 ± 26.2 μg•hr/ml and 0.80 ± 0.72 μg/ml, respectively. Steady-state cobicistat

Cmax, AUCtau and Ctau (mean ± SD) values were 1.5 ± 0.5 μg/ml, 11.1 ± 4.5 μg•hr/ml and

0.05 ± 0.07 μg/ml, respectively (n=22).

Food effect

Administration of a single dose of EVOTAZ with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 42% increase in atazanavir Cmax, a 28% increase in atazanavir AUC, a 31% increase in cobicistat Cmax, and a 24% increase in cobicistat AUC relative to the fasting state. Administration of a single dose of EVOTAZ with a high fat meal (1,038 kcal, 59 g fat, 37 g protein) resulted in a 14% reduction in atazanavir Cmax with no change in atazanavir AUC or cobicistat exposures (Cmax, AUC) relative to the fasting state. The 24-hour atazanavir concentration following a high-fat meal was increased approximately 23% due to delayed absorption; the median Tmax increased from 2.0 to

3.5 hours. Cmax and AUCs after a high fat meal decreased 36% and 25% in comparison to a light meal, respectively; however, the 24-hour atazanavir concentration was similar when EVOTAZ was given with a light meal and a high fat meal. To enhance bioavailability, EVOTAZ is to be taken with food.

Distribution

Atazanavir

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.

Cobicistat

Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.

Biotransformation

Atazanavir

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.

Cobicistat

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat.

Elimination

Atazanavir

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.

Cobicistat

Following oral administration of [14C]cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of cobicistat is approximately 3-4 hours.

Linearity/non-linearity

Atazanavir

Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 mg to 800 mg once daily.

Cobicistat

Cobicistat exposures are non-linear and greater than dose-proportional over the range of 50 mg to 400 mg, consistent with a mechanism-based CYP3A inhibitor.

Special populations

Renal impairment Atazanavir

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for atazanavir in combination with cobicistat in patients with renal insufficiency. Atazanavir 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.)

Cobicistat

A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 ml/min). No meaningful differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Hepatic impairment Atazanavir

Atazanavir is metabolised and eliminated primarily by the liver. The effects of hepatic impairment on the pharmacokinetics of atazanavir given with cobicistat have not been studied. Concentrations of atazanavir given with cobicistat are expected to be increased in patients with impaired hepatic function (see sections 4.2 and 4.4).

Cobicistat

Cobicistat is primarily metabolised and eliminated by the liver. A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

Elderly

The pharmacokinetics of atazanavir and cobicistat, alone or in combination, have not been evaluated in an elderly population (65 years of age and older).

Paediatric population

No data are available on the pharmacokinetics of atazanavir and cobicistat in combination in paediatric patients.

Gender

No clinically relevant pharmacokinetic differences due to gender have been identified for atazanavir or cobicistat.

Race

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for atazanavir or cobicistat.

5.3Preclinical safety data

In a 3-month combination oral toxicity study of atazanavir and cobicistat in rats, there were no toxicologic interactions apparent as no additive or synergistic toxicities were observed. When compared to their single-agent profiles all findings could be attributed to either atazanavir or cobicistat.

In an ex vivo rabbit pharmacology study, isolated hearts were exposed to atazanavir, cobicistat, or atazanavir and cobicistat in combination. Each single agent produced effects on left ventricular contractility and PR prolongation at concentrations at least 35-fold higher than the free atazanavir and cobicistat concentrations at the recommended human dose (RHD) Cmax. When administered in combination, no clear additive or synergistic cardiovascular effects were observed at atazanavir and cobicistat concentrations at least 2-fold higher than the free atazanavir and cobicistat concentrations at the RHD Cmax.

The following statements reflect the preclinical safety results of the individual active substances of EVOTAZ.

Atazanavir

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.

Cobicistat

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects were observed in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinal column and sternebra of foetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and may slightly prolong the PR interval and decrease left ventricular function at mean concentrations at least 10-fold higher than the human exposure at the recommended 150 mg daily dose.

A long-term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for this species that is regarded as of no relevance for humans. A long-term carcinogenicity study in mice did not show any carcinogenic potential.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

microcrystalline cellulose (E460(i)) croscarmellose sodium (E468) sodium starch glycolate crospovidone (E1202)

stearic acid (E570) magnesium stearate (E470b)

hydroxypropyl cellulose (E463) silicon dioxide (E551)

Film-coating

hypromellose (hydroxypropyl methyl cellulose, E464) titanium dioxide (E171)

talc (E553b) triacetin (E1518)

red iron oxide (E172)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

Do not store above 30°C.

6.5Nature and contents of container

High density polyethylene (HDPE) bottle with a child-resistant polypropylene closure. Each bottle contains 30 film-coated tablets and a silica gel dessicant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.

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/1/15/1025/001-002

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 July 2015

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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