ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR DISOPROXIL GILEAD

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

Posology Adults and adolescents aged 12 years and older weighing at least 35 kg:

One tablet, once daily with food. If the patient misses a dose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead within 18 hours of the time it is usually taken, the patient should take Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead with food as soon as possible and resume the normal dosing schedule.

If a patient misses a dose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead by more than 18 hours and it is almost time for the next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead another tablet should be taken. 1). 4). 2). 4 regarding initiation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in patients with creatinine clearance below 90 mL/min.

2). 4 regarding patients with creatinine clearance that falls below 70 mL/min while on treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. 4). Hepatic impairment No dose adjustment of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). 2). 4). 2). 2). The film-coated tablet should not be chewed or crushed.

Summary of the safety profile The most frequently reported adverse reactions considered possibly or probably related to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in clinical studies through 144 weeks in treatment-naïve adult patients were nausea (16%) and diarrhoea (12%).

The most frequently reported adverse reactions to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in clinical studies through 48 weeks in virologically-suppressed adult patients were nausea (3% to 5%) and fatigue (6%).

In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported.

4). 4). Tabulated summary of adverse reactions Adverse reactions to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead from Phase 3 clinical studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals, are listed in Table 2, below, by body system organ class and highest frequency observed.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2:

Tabulated summary of adverse reactions associated with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead based on experience from Phase 3 studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil from clinical studies and post-marketing experience, when used with other antiretrovirals Frequency Adverse reaction Blood and lymphatic system disorders: Common: neutropenia1 Uncommon: anaemia1,2 Immune system disorders: Common: allergic reaction1 Metabolism and nutrition disorders: Very common: hypophosphataemia1,3 Common: hyperglycaemia1, hypertriglyceridaemia1, decreased appetite Uncommon: hypokalaemia1,3 Rare: lactic acidosis1 Psychiatric disorders: Common: insomnia, abnormal dreams Uncommon: suicidal ideation and suicide attempt (in patients with a pre- existing history of depression or psychiatric illness), depression Frequency Adverse reaction Nervous system disorders: Very common: headache, dizziness Gastrointestinal disorders: Very common: diarrhoea, vomiting, nausea Common: elevated amylase including elevated pancreatic amylase1, elevated serum lipase1, abdominal pain, dyspepsia, constipation, abdominal distension1, flatulence Uncommon: pancreatitis1 Hepatobiliary disorders: Common: increased transaminases1, hyperbilirubinaemia1 Rare: hepatic steatosis1, hepatitis1 Skin and subcutaneous tissue disorders: Very common: rash Common: vesiculobullous rash1, pustular rash1, maculopapular rash1, pruritus1, urticaria1, skin discolouration (increased pigmentation)1,2 Uncommon: angioedema1 Musculoskeletal and connective tissue disorders: Very common: elevated creatine kinase1 Common: bone mineral density decreased Uncommon: rhabdomyolysis1,3, muscular weakness1,3 Rare: osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3,5, myopathy1,3 Renal and urinary disorders: Common: increased blood creatinine4 Uncommon: renal failure4, proximal renal tubulopathy including Fanconi syndrome acquired4, proteinuria Rare: acute tubular necrosis1, nephritis (including acute interstitial nephritis)1,5, nephrogenic diabetes insipidus1 General disorders and administration site conditions: Very common: asthenia1 Common: pain1, fatigue 1 This adverse reaction was not observed in the Phase 3 clinical studies for Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead but identified from clinical studies or post-marketing experience for emtricitabine or tenofovir disoproxil when used with other antiretrovirals.

2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients. 3 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.

8, Description of selected adverse reactions for more details. 5 This adverse reaction was identified through post-marketing surveillance for emtricitabine or tenofovir disoproxil but not observed in randomised, controlled clinical studies in adults or paediatric HIV clinical studies for emtricitabine or in randomised controlled clinical studies or the tenofovir disoproxil expanded access program for tenofovir disoproxil.

The frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in randomised controlled clinical studies (n = 1,563) or tenofovir disoproxil in randomised controlled clinical studies and the expanded access program (n = 7,319).

Description of selected adverse reactions Renal impairment Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation.

Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing […]

Renal and bone effects in adults Renal effects Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. 8). 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.

3). Renal monitoring Before initiating treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead Creatinine clearance should be calculated and urine glucose and urine protein should be determined in all patients.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be initiated in patients with creatinine clearance < 70 mL/min. It is recommended that Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is the preferred treatment for the individual patient.

During treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead Creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored every four weeks during the first year and then every three months during Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead therapy.

In patients at risk for renal impairment a more frequent monitoring of renal function is required. 8). 3 mg/dL) from baseline should be closely monitored for renal safety. See also under Co-administration of other medicinal products below.

8). It is recommended that Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is discontinued in patients with creatinine clearance that falls to < 70 mL/min while on treatment unless it is considered that the potential benefit of this combination of antiretroviral agents for the individual patient outweighs the possible risks of continuing with therapy.

Interrupting treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should also be considered in case of progressive decline of renal function when no other cause has been identified. 2). 8). In the Phase 3 Study GS-US-236-0103, BMD was assessed in a non-random subset of 120 subjects (Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead group n = 54; ritonavir-boosted atazanavir (ATV/r) plus emtricitabine (FTC)/tenofovir disoproxil group n = 66).

77%, respectively). 4%) in the ATV/r+FTC/tenofovir disoproxil group. Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil in randomised controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients.

These BMD decreases generally improved after treatment discontinuation. In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.

Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or with a history of bone fractures.

If bone abnormalities are suspected or detected then appropriate consultation should be obtained. Renal and bone effects in the paediatric population There are uncertainties associated with the long-term effects of tenofovir disoproxil bone and renal toxicity.

Moreover, the reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach […]

1. Patients who have previously discontinued treatment with tenofovir disoproxil due to renal toxicity, with or without reversal of the effects post-discontinuation. Co-administration is contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

5): • alpha 1-adrenoreceptor antagonists: alfuzosin • antiarrhythmics: amiodarone, quinidine • ergot derivatives: dihydroergotamine, ergometrine, ergotamine • gastrointestinal motility agents: cisapride • HMG Co-A reductase inhibitors: lovastatin, simvastatin • neuroleptics/antipsychotics: pimozide, lurasidone • PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension • sedatives/hypnotics: orally administered midazolam, triazolam Co-administration is contraindicated with medicinal products that are strong inducers of CYP3A due to the potential for loss of virologic response and possible resistance to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

5): • anticonvulsants: carbamazepine, phenobarbital, phenytoin • antimycobacterials: rifampicin • herbal products: St. 5).