EVOTAZ 300 mg/150 mg film-coated tablets

EVOTAZ is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults and adolescents (aged 12 years and older weighing at least 35 kg) without known mutations associated with resistance to atazanavir (see sections 4.4 and 5.1).

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

Posology

The recommended dose of EVOTAZ for adults and adolescents (aged 12 years and older weighing at least 35 kg) 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 medicinal product (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

Children from birth to 3 months of age

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.

Children from 3 months to < 12 years of age or weighing < 35 kg

The safety and efficacy of EVOTAZ in children less than 12 years of age or weighing less than 35 kg 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.

Pregnancy and postpartum

Treatment with EVOTAZ during pregnancy results in low atazanavir exposure. Therefore, therapy with EVOTAZ should not be initiated during pregnancy, and women who become pregnant during therapy with EVOTAZ should be switched to an alternative regimen (see sections 4.4 and 4.6).

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.

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)

▪ dabigatran (anticoagulant)

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

▪ lomitapide (lipid-modifying agent)

▪ grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection) (see section 4.5)

▪ glecaprevir/pibrentasvir fixed dose combination (see section 4.5)

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

Moderate to severe hepatic impairment.

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

Pregnancy

Treatment with atazanavir/cobicistat 300/150 mg during the second and third trimester has been shown to result in low atazanavir exposure. Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in atazanavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with EVOTAZ should not be initiated during pregnancy, and women who become pregnant during therapy with EVOTAZ should be switched to an alternative regimen (see sections 4.2 and 4.6).

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 medicinal product 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 aetiologies. 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.

Chronic kidney disease

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during post-marketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.8).

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 jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) 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 International Normalized Ratio (INR) 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

Plasma concentrations of drospirenone are increased following administration of drospirenone/ethinyloestradiol with atazanavir/cobicistat. If drospirenone/ethinyloestradiol is co-administered with atazanavir/cobicistat, clinical monitoring is recommended due to the potential for hyperkalemia.

Data are not available to make recommendations regarding the use of EVOTAZ with other oral contraceptives. Alternative forms of contraception (non-hormonal) should be considered (see section 4.5).

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, 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), lomitapide, lovastatin, orally administered midazolam, pimozide, quetiapine, quinidine, lurasidone, simvastatin, sildenafil (when used to treat pulmonary arterial hypertension), avanafil, systemic lidocaine, ticagrelor, terfenadine and triazolam.

Co-administration of EVOTAZ with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (used to treat chronic hepatitis C infection) is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with the increase in grazoprevir concentrations (see section 4.3 and Table 1). Co-administration of EVOTAZ with glecaprevir/pibrentasvir fixed dose combination is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecaprevir and pibrentasvir plasma concentrations (see section 4.3).

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). Co-administration with dabigatran, a substrate of P-gp, is contraindicated. 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

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

EVOTAZ is not recommended during pregnancy nor should it be initiated in pregnant patients; an alternative regimen is recommended (see sections 4.2 and 4.4). This is due to substantially lower exposures of cobicistat and consequently, lower exposures of co-administered antiretroviral agents, including atazanavir, during the second and third trimesters, compared to postpartum.

Animal studies with EVOTAZ are insufficient 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 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.

EVOTAZ has a minor influence on the ability to drive or use machines. Dizziness may occur following administration of regimens containing atazanavir and cobicistat (see section 4.8).

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 a Phase III study (GS-US-216-0114), the most frequently reported adverse reactions in the atazanavir boosted with cobicistat group were associated with elevated bilirubin levels (see Table 2).

In two controlled clinical trials, where subjects received atazanavir alone (400 mg once daily) or atazanavir (300 mg daily) boosted with ritonavir (100 mg daily), 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).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance (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

^a These 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).

^b See 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 and autoimmune hepatitis) 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 naï ve 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

Paediatric patients aged 3 months to < 12 years

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.

Paediatric patients aged 12 to < 18 years and weighing more than 35 kg

The safety of atazanavir administered with cobicistat plus two NRTIs (N = 14) was evaluated in HIV-1 infected virologically suppressed paediatric patients between the ages of 12 to < 18 years through 48 weeks in an open-label clinical study (GS-US-216-0128). In this study, the safety profile of atazanavir and cobicistat was similar to that in adults.

Other special populations

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

Co-infected patients with hepatitis B and/or C 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 medicinal products (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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.

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-naï ve 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-naï ve (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 48^a and 144^b

^a Week 48 window is between Day 309 and 378 (inclusive)

^b Week 144 window is between Day 967 and 1,050 (inclusive)

^c Includes 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.

^d Includes 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.

^e Includes 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.

^f Plus 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

Paediatric patients aged 3 months to < 12 years or weighing less than 35 kg

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).

Paediatric patients aged 12 to < 18 years and weighing more than 35 kg

The safety and efficacy of atazanavir with cobicistat were evaluated in an open-label phase 2/3 Study GS-US-216-0128 in HIV-1 infected virologically suppressed paediatric patients between the ages of 12 and < 18 years with baseline estimated creatinine clearance ≥ 90 mL/min. Fourteen patients received atazanavir 300 mg once daily with cobicistat 150 mg once daily administered with a background regimen containing two NRTIs.

The median age of patients was 14 years (range: 12 to 17); median weight of patients was 52.7 kg (range: 46.5 to 63.3); 71% were male; 57% were Asian, 29% were White, and 14% were Black. At baseline, 13/14 subjects had plasma HIV-1 RNA < 50 copies/mL and 1 subject had plasma HIV-1 RNA = 50 copies/mL.

In patients treated with atazanavir + cobicistat, the median baseline CD4+ cell count and CD4+% was 770 cells/mm³ (range: 486 to 1765) and 33% (range: 23% to 45%), respectively. At Week 48, 93% (13/14) of patients retained HIV-1 RNA < 50 copies/mL and the median change from baseline in CD4+ cell count and CD4+% was -60 cells/mm³ and -0.3%, respectively. Three out of 14 patients qualified for resistance analysis: 1 patient showed no resistance in protease or reverse transcriptase and 2 had missing data due to assay failure.

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 C_max, AUC_tau and C_tau (mean ± SD) values were 3.9 ± 1.9 mcg/mL, 46.1 ± 26.2 mcg• hr/mL and 0.80 ± 0.72 mcg/mL, respectively. Steady-state cobicistat C_max, AUC_tau and C_tau (mean ± SD) values were 1.5 ± 0.5 mcg/mL, 11.1 ± 4.5 mcg• hr/mL and 0.05 ± 0.07 mcg/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 C_max, a 28% increase in atazanavir AUC, a 31% increase in cobicistat C_max, 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 C_max with no change in atazanavir AUC or cobicistat exposures (C_max, 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 T_max increased from 2.0 to 3.5 hours. C_max 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 C_max 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

Paediatric Patients aged 3 months to < 12 years

For paediatric patients aged 3 months to ≤ 12 years, no data are available on the pharmacokinetics of atazanavir and cobicistat in combination.

Paediatric Patients aged 12 to < 18 years and weighing more than 35 kg

In paediatric patients aged 12 to < 18 years who received cobicistat-boosted atazanavir (n = 14) in Study GS-US-216-0128, exposures of atazanavir and cobicistat (AUC_tau, C_max, and C_trough) were higher (24% to 180%) than in adults; however, the increases were not considered clinically significant as the safety profiles were similar in adult and 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.

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) C_max. 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 C_max.

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 μ M) of atazanavir corresponding to 30-fold the free drug concentration at C_max 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.

Tablet core

cellulose, microcrystalline (E460(i))

croscarmellose sodium (E468)

sodium starch glycolate

crospovidone (E1202)

stearic acid (E570)

magnesium stearate (E470b)

hydroxypropylcellulose (E463)

silica (E551)

Film-coating

hypromellose (hydroxypropyl methyl cellulose, E464)

titanium dioxide (E171)

talc (E553b)

triacetin (E1518)

red iron oxide (E172)

Not applicable.

2 years

Do not store above 30 ° C.

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.

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