Stribild

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 Stribild within 18 hours of the time it is usually taken, the patient should take Stribild with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Stribild 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 Stribild another tablet should be taken. 1). 4). 2). 4 regarding initiation of Stribild 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 Stribild.

4). Hepatic impairment No dose adjustment of Stribild is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Stribild 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 Stribild in clinical studies through 144 weeks in treatment-naïve adult patients were nausea (16%) and diarrhoea (12%).

The most frequently reported adverse reactions to Stribild 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 Stribild 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).

23 Table 2: Tabulated summary of adverse reactions associated with Stribild 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 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 Stribild but identified from clinical studies or post-marketing experience for emtricitabine or tenofovir disoproxil when used with other antiretrovirals.

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 Stribild Creatinine clearance should be calculated and urine glucose and urine protein should be determined in all patients. Stribild should not be initiated in patients with creatinine clearance < 70 mL/min.

It is recommended that Stribild is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Stribild is the preferred treatment for the individual patient.

During treatment with Stribild 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 Stribild 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 Stribild 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 Stribild 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 (Stribild group n = 54; ritonavir-boosted atazanavir (ATV/r) plus emtricitabine (FTC)/tenofovir disoproxil group n = 66).

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 4 • 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 Stribild.

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