STRIBILD 150 MG / 150 MG / 200 MG / 245 MG FILM-COATED TABLETS - summary of medicine characteristics

Stribild 150 mg/150 mg/200 mg/245 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).

Excipients with known effect

Each tablet contains 10.4 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Green, capsule-shaped, film-coated tablet of dimensions 20 mm x 10 mm, debossed on one side with “GSI” and the number “1” surrounded by a square box on the other side.

4.1

Therapeutic indications

Stribild is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild (see sections 4.2, 4.4 and 5.1).

Stribild is also indicated for the treatment of HIV-1 infection in adolescents aged 12 to < 18 years weighing > 35 kg who are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

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

Posology

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.

Special populations

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years (see sections 4.4 and 5.1). Stribild should be administered with caution to elderly patients (see section 4.4).

Adults with renal impairment

Stribild should not be initiated in patients with creatinine clearance below

70 mL/min (see sections 4.4 and 5.2). See section 4.4 regarding initiation of Stribild in patients with creatinine clearance below 90 mL/min.

Stribild should be discontinued if creatinine clearance declines below 50 mL/min during treatment with Stribild as dose interval adjustment is required for emtricitabine and tenofovir disoproxil and this cannot be achieved with the fixed-dose combination tablet (see sections 4.4 and 5.2). See section 4.4 regarding patients with creatinine clearance that falls below 70 mL/min while on treatment with Stribild.

Paediatric patients with renal impairment

Use of Stribild is not recommended in paediatric patients under the age of 18 years with renal impairment (see section 4.4).

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). Therefore, Stribild is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

If Stribild is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Paediatric population

The safety and efficacy of Stribild in children under the age of 12 years or weighing < 35 kg have not been established (see section 5.2).

Pregnancy

Treatment with cobicistat and elvitegravir during pregnancy results in lower elvitegravir exposure (see sections 4.4 and 5.2). Therefore, therapy with Stribild should not be initiated during pregnancy, and women who become pregnant during therapy with Stribild should be switched to an alternative regimen (see sections 4.4 and 4.6).

Method of administration

Stribild should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not be chewed or crushed.

4.3 Contraindications

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

Patients who have previously discontinued treatment with tenofovir disoproxil due to renal toxicity, with or without reversal of the effects postdiscontinu­ation.

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. Therefore, Stribild should not be co-administered with medicinal products that include, but are not limited to, the following (see section 4.5):

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 Stribild. Therefore, Stribild should not be co-administered with medicinal products that include, but are not limited to, the following (see section 4.5):

anticonvulsants: carbamazepine, phenobarbital, phenytoin

antimycobacterials: rifampicin

herbal products: St. John’s wort (Hypericum perforatum)

Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate, is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil (see section 4.8).

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.

Patients who have previously discontinued treatment with tenofovir disoproxil due to renal toxicity, with or without reversal of the effects post-discontinuation, should not be treated with Stribild (see section 4.3).

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.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance (see section 4.8). Patients who experience a confirmed increase in serum creatinine of greater than 26.5 ^mol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety.

See also under Co-administration of other medicinal productsbelow.

Renal management

If serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance is decreased to < 70 mL/min, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8). 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.

Stribild should be discontinued in patients with confirmed creatinine clearance that falls to < 50 mL/min (since the required dose interval adjustments are not possible using this fixed dose combination tablet) or with decreases in serum phosphate to < 0.32 mmol/L (1.0 mg/dL) (see sections 4.2 and 5.2).

Bone effects

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8).

Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).

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). Mean percentage decreases in BMD from baseline to Week 144 in the Stribild group were comparable to the ATV/r+FTC/tenofovir disoproxil group at the lumbar spine (-1.43% versus –3.68%, respectively) and at the hip (-2.83% versus –3.77%, respectively). In the Phase 3 studies GS-US-236–0102 and GS-US-236–0103, bone fractures occurred in 27 subjects (3.9%) in the Stribild group, 8 subjects (2.3%) in the EFV/FTC/tenofovir disoproxil group, and 19 subjects (5.4%) in the ATV/r+FTC/tenofovir disoproxil group.

In a 144-week controlled clinical study (GS-99–903) that compared tenofovir disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naive patients, small decreases in BMD of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks in this study.

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 that are at a high risk for 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 is recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1 infected paediatric patients aged 2 to < 12 years in a clinical study of tenofovir disoproxil (GS-US-104–0352) (see sections 4.8 and 5.1).

Renal monitoring

Renal function (creatinine clearance and urine glucose and urine protein) should be evaluated prior to treatment initiation, and creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored during treatment as in HIV-1 infected adults (see above).

Renal management

If serum phosphate is confirmed to be < 0.96 mmol/L (3.0 mg/dL) in any paediatric patient receiving Stribild, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). If renal abnormalities are suspected or detected then consultation with a nephrologist should be obtained to consider interruption of treatment. Interrupting treatment with Stribild should also be considered in case of progressive decline of renal function when no other cause has been identified. As in adults, adolescents who experience a confirmed increase in serum creatinine of greater than 26.5 |amoi/L (0.3 mg/dL) from baseline should be closely monitored for renal safety (see above).

Co-administration and risk of renal toxicity

The same recommendations apply as in adults (see Co-administration of other medicinal products below).

Renal impairment

The use of Stribild is not recommended in paediatric patients with renal impairment (see section 4.2).

Stribild should not be initiated in paediatric patients with renal impairment and should be discontinued in paediatric patients who develop renal impairment during Stribild therapy.

Bone effects

Tenofovir disoproxil may cause a reduction in BMD. The effects of tenofovir disoproxil-associated changes in BMD on long-term bone health and future fracture risk are uncertain (see section 5.1).

In a clinical study of HIV-1-infected, treatment-naïve patients aged 12 to < 18 years (N=50), small decreases in mean BMD Z-scores were observed following treatment with Stribild (see section 4.8).

If bone abnormalities are detected or suspected in paediatric patients, consultation with an endocrinologist and/or nephrologist should be obtained.

Patients with HIV and hepatitis B or C virus co-infection

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Physicians should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV).

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. Stribild should not be administered concomitantly with other medicinal products containing tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of hepatitis B virus infection.

Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Stribild should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease

The safety and efficacy of Stribild have not been established in patients with significant underlying liver disorders. The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment. The pharmacokinetics of elvitegravir, cobicistat and tenofovir have been studied in patients with moderate hepatic impairment. Stribild has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). No dose adjustment of Stribild is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) 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.

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 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.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of institution of 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 include 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.

Opportunistic infections

Patients receiving Stribild or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

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 CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Co-administration of other medicinal products

Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and must not be administered with other antiretroviral products (see section 4.5).

Stribild should not be administered concomitantly with other medicinal products containing tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of hepatitis B virus infection, or with other medicinal products containing tenofovir alafenamide.

Concomitant use with nephrotoxic medicinal products

Use of Stribild should be avoided with concurrent or recent use of a nephrotoxic medicinal product, e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin 2 (also called aldesleukin) (see section 4.5). If concomitant use of Stribild and nephrotoxic agents is unavoidable, renal function must be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil and with risk factors for renal dysfunction. If Stribild is co-administered with an NSAID, renal function should be monitored adequately.

Contraception requirements

Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 ^g ethinyloestradiol and containing drospirenone or norgestimate as the progestogen or should use an alternative reliable method of contraception (see sections 4.5 and 4.6). The use of Stribild with oral contraceptives containing other progestogens should be avoided (see section 4.5). Plasma concentrations of drospirenone are expected to be increased following co-administration with Stribild and clinical monitoring is recommended due to the potential for hyperkalaemia (see section 4.5).

Use with certain hepatitis C virus antiviral agents

Co-administration of tenofovir disoproxil with ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil in the setting of ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir with Stribild should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Stribild concomitantly with ledipasvir/so­fosbuvir, sofosbuvir/vel­patasvir or sofosbuvir/vel­patasvir/voxi­laprevir should be monitored for adverse reactions related to tenofovir disoproxil.

Elderly

Stribild has limited data in patients over the age of 65 years. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with Stribild.

Pregnancy

Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposures (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, therapy with Stribild should not be initiated during pregnancy, and women who become pregnant during therapy with Stribild should be switched to an alternative regimen (see sections 4.2 and 4.6).

Excipients

Stribild contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

As Stribild contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Stribild. Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and must not be administered with other antiretroviral products. Therefore, information regarding drug-drug interactions with other antiretroviral products (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) is not provided (see section 4.4). Interaction studies have only been performed in adults.

Cobicistat is a strong mechanism-based CYP3A inhibitor and a CYP3A substrate. Cobicistat is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. The transporters that cobicistat inhibits include P-gp, BCRP, OATP1B1 and OATP1B3.

Co-administration of Stribild with medicinal products that are primarily metabolised by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of those products, which could increase or prolong their therapeutic effect and adverse reactions (see Concomitant use contraindicated and section 4.3). Co-administration of Stribild with medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s).

Co-administration of Stribild with medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased cobicistat plasma concentrations.

Elvitegravir is a modest inducer and may have the potential to induce CYP2C9 and/or inducible UGT enzymes; as such it may decrease the plasma concentration of substrates of these enzymes. Elvitegravir is metabolised by CYP3A and, to a minor extent, by UGT1A1. Medicinal products that induce CYP3A activity are expected to increase the clearance of elvitegravir, resulting in decreased plasma concentration of elvitegravir which may lead to loss of therapeutic effect of Stribild and development of resistance (see Concomitant use contraindicated and section 4.3).

Concomitant use contraindicated

Co-administration of Stribild and some medicinal products that are primarily metabolised by CYP3A may result in increased plasma concentrations of these products, which are associated with the potential for serious and/or life-threatening reactions such as peripheral vasospasm or ischaemia (e.g., dihydroergotamine, ergotamine, ergometrine), or myopathy, including rhabdomyolysis (e.g., simvastatin, lovastatin), or prolonged or increased sedation or respiratory depression (e.g., orally administered midazolam or triazolam). Co-administration of Stribild and other medicinal products primarily metabolised by CYP3A such as amiodarone, quinidine, cisapride, pimozide, lurasidone, alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3).

Co-administration of Stribild and some medicinal products that induce CYP3A such as St. John’s wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital and phenytoin may result in significantly decreased cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance (see section 4.3).

Concomitant use not recommended

Renally eliminated medicinal products

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Stribild with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of Stribild should be avoided with concurrent or recent use of nephrotoxic medicinal products. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).

Other interactions

Interactions between the components of Stribild and potential co-administered medicinal products are listed in Table 1 below (increase is indicated as “f”, decrease as “j”, no change as “<->”). The interactions described are based on studies conducted with the components of Stribild as individual agents and/or in combination, or are potential drug interactions that may occur with Stribild.

Table 1: Interactions between the individual components of Stribild and other medicinal products

N/A = not applicable

NC = not calculated

DOAC = direct oral anticoagulant

1 When data available from drug interaction studies.

2 Studies performed with ritonavir boosted elvitegravir.

3 These are drugs within class where similar interactions could be predicted.

4 Study conducted using Stribild.

5 The predominant circulating metabolite of sofosbuvir.

6 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

7 Study conducted with emtricitabine/te­nofovir disoproxil + darunavir (800 mg) + ritonavir (100 mg).

8 Study conducted with elvitegravir/co­bicistat/emtri­citabine/teno­fovir alafenamide fixed dose combination tablet.

Studies conducted with other medicinal products

Based on drug interaction studies conducted with the components of Stribild, no clinically significant drug interactions have been either observed or are expected between the components of Stribild and the following medicinal products: entecavir, famciclovir, famotidine, omeprazole, ribavirin and sertraline.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / contraception in males and females

The use of Stribild must be accompanied by the use of effective contraception (see section 4.5).

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of Stribild in pregnant women. However, a large amount of data in pregnant women (more than1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with emtricitabine and tenofovir disoproxil.

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

Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposure (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child

transmission of HIV infection. Therefore, therapy with Stribild should not be initiated during pregnancy, and women who become pregnant during therapy with Stribild should be switched to an alternative regimen (see sections 4.2 and 4.4).

Breast-feeding

It is not known whether elvitegravir or cobicistat are excreted in human milk. Emtricitabine and tenofovir have been shown to be excreted in human milk. In animal studies it has been shown that elvitegravir, cobicistat and tenofovir are excreted in milk. There is insufficient information on the effects of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil in newborns/infants. Therefore Stribild should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances.

Fertility

No human data on the effect of Stribild on fertility are available. Animal studies do not indicate harmful effects of elvitegravir, cobicistat, emtricitabine or tenofovir disoproxil on fertility.

4.7 Effects on ability to drive and use machines

Stribild has no or negligible influence on the ability to drive and use machines. However, patients should be informed that dizziness, fatigue and insomnia have been reported during treatment with Stribild.

4.8 Undesirable effects

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 treatmentnaive 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. Monitoring of renal function is recommended for patients receiving Stribild (see section 4.4).

Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see section 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).

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

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.

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.

4 See section 4.8, 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 incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

In the clinical studies of Stribild over 144 weeks, 13 (1.9%) subjects in the Stribild group (n = 701) and 8 (2.3%) subjects in the ATV/r+FTC/tenofovir disoproxil group (n = 355) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 7 in the Stribild group and 1 in the ATV/r+FTC/tenofovir disoproxil group occurred during the first 48 weeks. The types of renal adverse reactions seen with Stribild were consistent with previous experience with tenofovir disoproxil. Four (0.6%) of the subjects who received Stribild developed laboratory findings consistent with proximal tubulopathy leading to discontinuation of Stribild during the first 48 weeks. No additional proximal renal tubular dysfunction cases were reported from Week 48 to Week 144. Two of the four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL/min) at baseline. The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved without clinical consequence upon discontinuation of Stribild, but did not completely resolve in all subjects. Three (0.8%) subjects who received ATV/r+FTC/tenofovir disoproxil developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of ATV/r+FTC/tenofovir disoproxil after Week 96 (see section 4.4).

The cobicistat component of Stribild has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies GS-US-236–0102 and GS-US-236–0103, decreases in estimated creatinine clearance occurred early in treatment with Stribild, after which they stabilised. The mean change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –14.0 ± 16.6 mL/min for Stribild,

–1.9 ± 17.9 mL/min for EFV/FTC/tenofovir disoproxil, and

–9.8 ± 19.4 mL/min for ATV/r+FTC/tenofovir disoproxil.

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

Metabolic parameters

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

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of 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).

Paediatric population

Studies with Stribild

The safety of Stribild in 50 HIV-1-infected, treatment-naive paediatric patients aged 12 to < 18 years was evaluated through 48 weeks in an open-label clinical study (GS-US-236–0112, see section 5.1). In this study, the safety profile of Stribild was similar to that in adults (see section 4.8, Tabulated summary of adverse reactions). Among the 50 paediatric patients receiving Stribild, mean BMD increased from baseline to Week 48, +0.68% for lumbar spine and +0.77% for total body less head. Mean changes from baseline BMD Z-scores (height-age adjusted) were –0.09 for lumbar spine and –0.12 for total body less head at Week 48.

Studies with emtricitabine

Assessment of adverse reactions related to emtricitabine is based on experience in three paediatric studies (n = 169) where treatment-naive (n = 123) and treatment-experienced (n = 46) paediatric HIV infected patients aged 4 months to 18 years were treated with emtricitabine in combination with other antiretroviral agents. In addition to the adverse reactions reported in adults, anaemia (9.5%) and skin discolouration (31.8%) occurred more frequently in clinical trials in paediatric patients than in adults (see section 4.8, Tabulated summary of adverse reactions).

Studies with tenofovir disoproxil

Assessment of adverse reactions related to tenofovir disoproxil is based on two randomised trials (studies GS-US-104–0321 and GS-US-104–0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received treatment with tenofovir disoproxil (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral agents for 48 weeks (see section 5.1). The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil were consistent with those observed in clinical studies of tenofovir disoproxil in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1).

Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents (aged 12 to < 18 years), the BMD Z-scores observed in subjects who received tenofovir disoproxil were lower than those observed in subjects who received placebo. In HIV-1 infected children (aged 2 to 15 years), the BMD Z-scores observed in subjects who switched to tenofovir disoproxil were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1).

In study GS-US-104–0352, 89 paediatric patients with a median age of 7 years (range 2 to 15 years) were exposed to tenofovir disoproxil for a median of 331 weeks. Eight of the 89 patients (9.0%) discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2. Among them, 3 patients experienced a clinically meaningful decline in estimated GFR during therapy which improved after discontinuation of tenofovir disoproxil.

Insufficient safety data are available for children below 12 years of age. Stribild is not recommended in this population (see section 4.2).

Other special population(s)

Patients with renal impairment

Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any adult with renal impairment treated with Stribild (see sections 4.2, 4.4 and 5.2). The use of Stribild is not recommended in paediatric patients with renal impairment (see sections 4.2 and 4.4).

Exacerbations of hepatitis after discontinuation of treatment

In HIV infected patients co-infected with HBV, clinical and laboratory evidence of hepatitis have occurred after discontinuation of treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary.

There is no specific antidote for overdose with Stribild. As elvitegravir and cobicistat are highly bound to plasma proteins it is unlikely that elvitegravir and cobicistat will be significantly removed by haemodialysis or peritoneal dialysis. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR09

Mechanism of action and pharmacodynamic effects

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection.

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 elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir have activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in DNA chain termination.

Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Antiviral activity in vitro

The dual-drug combinations and the triple combination of elvitegravir, emtricitabine and tenofovir demonstrated synergistic activity in cell culture. Antiviral synergy was maintained for elvitegravir, emtricitabine, and tenofovir when tested in the presence of cobicistat. No antagonism was observed for any of these combinations.

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM).

Cobicistat has no detectable anti-HIV activity and does not antagonise or enhance the antiviral effects of elvitegravir, emtricitabine, or tenofovir.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013 to 0.64 |iM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 |iM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 |iM).

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 |iM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 to 2.2 |iM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 to 5.5 |1M).

Resistance

In cell culture

Resistance to emtricitabine or tenofovir has been seen in vitro and in the HIV-1 from some patients due to the development of the M184V or M184I emtricitabine resistance substitution in reverse transcriptase or the K65R tenofovir resistance substitution in reverse transcriptase. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected clinically by tenofovir disoproxil and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine.

Emtricitabine-resistant viruses with the M184V/I substi­tution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R substitution can also be selected by abacavir, stavudine or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil should be avoided in patients with HIV-1 harbouring the K65R substitution.

In patients, HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil.

HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was most commonly associated with the integrase substitutions T66I, E92Q and Q148R.

Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K. HIV-1 with the

raltegravir-selected substitutions T66A/K, Q148H/K, and N155H showed cross-resistance to elvitegravir. Primary mutations for raltegravir/el­vitegravir do not affect the in vitro susceptibility of dolutegravir as single mutations, and the additional presence of secondary mutations (except Q148) also does not result in relevant fold changes in experiments with site directed mutants.

No development of resistance to cobicistat can be demonstrated in HIV-1 in vitro due to its lack of antiviral activity.

Substantial cross-resistance was observed between most elvitegravir-resistant HIV-1 isolates and raltegravir, and between emtricitabine-resistant isolates and lamivudine. Patients who failed treatment with Stribild and who had HIV-1 with emergent Stribild resistance substitutions harboured virus that remained susceptible to all PIs, NNRTIs, and most other NRTIs.

In treatment-naive patients

In a pooled analysis of antiretroviral-naive patients receiving Stribild in Phase 3 studies GS-US-236–0102 and GS-US-236–0103 through Week 144, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed virologic failure or who had HIV-1 RNA > 400 copies/mL at virologic failure, at Week 48, at Week 96, at Week 144 or at the time of early study drug discontinuation. As of Week 144, the development of one or more primary elvitegravir, emtricitabine, or tenofovir resistance-associated substitutions was observed in 18 of the 42 patients with evaluable genotypic data from paired baseline and Stribild treatment-failure isolates (2.6%, 18/701 patients). Of the 18 patients with viral resistance development, 13 occurred through Week 48, 3 occurred between Week 48 to Week 96, and 2 occurred between Week 96 to Week 144 of treatment. The substitutions that emerged were M184V/I (n = 17) and K65R (n = 5) in reverse transcriptase and E92Q (n = 9), N155H (n = 5), Q148R (n = 3), T66I (n = 2), and T97A (n = 1) in integrase. Other substitutions in integrase that occurred in addition to a primary INSTI resistance substitution each in single cases were H51Y, L68V, G140C, S153A, E157Q, and G163R. Most patients who developed resistance substitutions to elvitegravir developed resistance substitutions to both emtricitabine and elvitegravir. In phenotypic analyses of isolates from patients in the resistance analysis population, 13 patients (31%) had HIV-1 isolates with reduced susceptibility to elvitegravir, 17 patients (40%) had reduced susceptibility to emtricitabine, and 2 patients (5%) had reduced susceptibility to tenofovir.

In Study GS-US-236–0103, 27 patients treated with Stribild had HIV-1 with the NNRTI-associated K103N substitution in reverse transcriptase at baseline and had virologic success (82% at Week 144) similar to the overall population (78%), and no emergent resistance to elvitegravir, emtricitabine, or tenofovir in their HIV-1.

In virologically-suppressed patients

No emergent resistance to Stribild was identified in clinical studies of virologically-suppressed patients who switched from a regimen containing a ritonavir-boosted protease inhibitor (PI+RTV) (Study GS-US-236–0115), an

NNRTI (Study GS-US-236–0121) or raltegravir (RAL) (Study GS-US-236–0123).

Twenty patients from these studies who switched to Stribild had the NNRTI-associated K103N substitution in their historical genotype prior to starting initial antiretroviral therapy. Eighteen of these 20 patients maintained virologic suppression through 48 weeks. Due to protocol violation, two patients with historical K103N substitutions discontinued early with HIV-1 RNA < 50 copies/mL.

Clinical experience

The efficacy of Stribild in HIV-1 infected treatment-naive adult patients is based on the analyses of 144-week data from 2 randomised, double-blinded, active-controlled, Phase 3 studies, GS-US-236–0102 and GS-US-236–0103 (n = 1,408). The efficacy of Stribild in HIV-1 infected virologically-suppressed adult patients is based on the analyses of 48-week data from two randomised, open-label studies (Studies GS-US-236–0115 and GS-US-236–0121) and a single group open-label study (Study GS-US-236–0123) (n = 910; 628 receiving Stribild).

Treatment-naive HIV-1 infected adult patients

In Study GS-US-236–0102 HIV-1 infected antiretroviral treatment-naive adult patients received once-daily treatment of Stribild or once-daily treatment of fixed-dose combination of EFV/FTC/tenofovir disoproxil. In Study GS-US-236–0103 HIV-1 infected antiretroviral treatment-naive adult patients received once daily treatment of Stribild or ritonavir-boosted atazanavir (ATV/r) plus fixed-dose combination of emtricitabine (FTC)/tenofovir disoproxil. For both studies at 48 weeks, the virologic response rate was evaluated in both treatment arms. Virologic response was defined as achieving an undetectable viral load (< 50 HIV-1 RNA copies/mL, snapshot analysis).

Baseline characteristics and treatment outcomes for both Studies GS-US-236–0102 and GS-US-236–0103 are presented in Tables 3 and 4, respectively.

Table 3: Demographic and baseline characteristics of antiretroviral treatment-naive

HIV-1 infected adult subjects in studies GS-US-236–0102 and GS-US-236–0103

a Patients were stratified by baseline HIV-1 RNA in both studies.

Table 4: Virologic outcome of randomised treatment of studies GS-US-236–0102 and GS-US-236–0103 at Week 48 (snapshot analysis)a and Week 144b

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 Week 144 window, 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 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, etc.

Stribild met the non-inferiority criteria in achieving HIV-1 RNA

< 50 copies/mL when compared to efavirenz/emtri­citabine/teno­fovir disoproxil and when compared to atazanavir/ri­tonavir + emtricitabine/te­nofovir disoproxil.

In Study GS-US-236–0102, the mean increase from baseline in CD4+ cell count at Week 48 was 239 cells/mm3 in the Stribild-treated patients and

206 cells/mm3 in the EFV/FTC/tenofovir disoproxil-treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 321 cells/mm3 in the Stribild-treated patients and 300 cells/mm3 in the EFV/FTC/tenofovir disoproxil-treated patients. In Study GS-US-236–0103, the mean increase from baseline in CD4+ cell count at Week 48 was 207 cells/mm3 in the Stribild-treated patients and 211 cells/mm3 in the ATV/r+FTC/tenofovir disoproxil-treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 280 cells/mm3 in the Stribild-treated patients and 293 cells/mm3 in the ATV/r+FTC/tenofovir disoproxil-treated patients.

Virologically-suppressed HIV-1 infected patients

In Study GS-US-236–0115 and Study GS-US-236–0121, patients had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to the antiretroviral components of Stribild and must have been suppressed on a PI+RTV or an NNRTI in combination with FTC/tenofovir disoproxil (HIV-1 RNA < 50 copies/mL) for at least six months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Stribild or stay on their baseline antiretroviral regimen (SBR) for 48 weeks. In Study GS-US-236–0115, virologic success rates were: Stribild 93.8% (272 of 290 patients); SBR 87.1% (121 of 139 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 40 cells/mm3 in the Stribild-treated patients and 32 cells/mm3 in the PI+RTV+FTC/te­nofovir disoproxil-treated patients. In Study GS-US-236–0121, virologic success rates were: Stribild 93.4% (271 of 290 patients) and SBR 88.1% (126 of 143 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 56 cells/mm3 in the Stribild-treated patients and 58 cells/mm3 in the NNRTI+FTC/tenofovir disoproxil-treated patients.

In Study GS-US-236–0123, patients had to have previously only received RAL in combination with FTC/tenofovir disoproxil as their first antiretroviral regimen for at least six months. Patients had to be stably suppressed for at least six months prior to study entry, have no current or past history of resistance to the antiretroviral components of Stribild, and have HIV-1 RNA < 50 copies/mL at screening. All 48 patients who received at least one dose of Stribild remained suppressed (HIV-1 RNA < 50 copies/mL) through Week 48. The mean increase from baseline in CD4+ cell count at Week 48 was 23 cells/mm3.

Paediatric population

Studies with Stribild

The efficacy and safety of Stribild in HIV-1-infected, treatment-naïve paediatric patients aged 12 to less than 18 years is based on the analyses of 48-week data from the single-group, open-label study GS-US-236–0112 (N=50). Mean age was 15 years (range, 12–17), 70% were male, 68% black, 28% Asian. At baseline, mean plasma HIV-1 RNA was 4.60 log10 copies/mL, mean CD4+ cell count 399 cells/mm3 (range, 133–734), and mean CD4+% 20.9% (range, 4.5%-41.1%). Twenty percent had baseline plasma HIV-1 RNA >100,000 copies/mL.

At Week 48, 44 of 50 (88%) adolescent patients treated with Stribild achieved HIV-1 RNA <50 copies/mL and 4 achieved HIV-1 RNA >50 copies/mL; 1 patient discontinued study drug, and 1 had no virologic data at Week 48. The mean decrease in HIV-1 RNA was –3.16 log10 copies/mL, and the mean increase in CD4+ cell count was 229 cells/mm3. No emergent resistance to Stribild was detected through Week 48.

Studies with emtricitabine

In infants and children older than 4 months, the majority of patients taking emtricitabine achieved or maintained complete suppression of plasma HIV-1 RNA through 48 weeks (89% achieved < 400 copies/ml and 77% achieved < 50 copies/ml).

Studies with tenofovir disoproxil

In study GS-US-104–0321, 87 HIV-1-infected treatment experienced patients 12 to < 18 years of age were treated with tenofovir disoproxil (n = 45) or placebo (n = 42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at week 24.

In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Z-score was –1.004 and –0.809, and mean total body BMD Z-score was –0.866 and –0.584, respectively, at baseline. Mean changes at week 48 (end of double blind phase) were –0.215 and –0.165 in lumbar spine BMD Z-score, and –0.254 and –0.179 in total body BMD Z-score for the tenofovir disoproxil and placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4% loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z-scores declined by –0.341 for lumbar spine and –0.458 for total body.

In study GS-US-104–0352, 97 treatment experienced patients 2 to < 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine or zidovudine with tenofovir disoproxil (n = 48) or continue on their original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/mL. The difference in the proportion of patients who maintained < 400 copies/mL at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/mL at week 48.

Reductions in BMD have been reported in paediatric patients. In patients who received treatment with tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was –1.034 and –0.498, and mean total body BMD Z-score was –0.471 and –0.386, respectively, at baseline. Mean changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, and –0.184 and –0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or zidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil treated subject and no stavudine or zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48. BMD Z-scores declined by –0.012 for lumbar spine and by –0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil for 96 weeks. BMD Z-scores were not adjusted for height and weight.

In study GS-US-104–0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy (median tenofovir disoproxil exposure 331 weeks).

The safety and efficacy of Stribild in children under the age of 12 years have not been established (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following oral administration of Stribild with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the rapid conversion of tenofovir disoproxil. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) following multiple doses of Stribild in HIV-1 infected subjects, respectively, were 1.7 ± 0.39 Lg/mL, 23 ± 7.5 Lig^li/ml., and 0.45 ± 0.26 Lg/mL for elvitegravir, which provides inhibitory quotient of ~ 10 (ratio of Ctrough: protein binding-adjusted IC95 for wild-type HIV-1 virus). Corresponding steady-state mean Cmax, AUCtau, and Ctrougi (mean ± SD) were 1.1 ± 0.40 L g/mL, 8.3 ± 3.8 Lg^h/mL, and 0.05 ± 0.13 Lg/mL for cobicistat, 1.9 ± 0.5 Lg/mL, 13 ± 4.5 Lg^h/mL, and 0.14 ± 0.25 Lg/mL for emtricitabine, and 0.45 ± 0.16 Lg/mL, 4.4 ± 2.2 Lg^h/mL, and 0.1 ± 0.08 Lg/mL for tenofovir.

Relative to fasting conditions, the administration of Stribild with a light meal (~373 kcal, 20% fat) or high-fat meal (~800 kcal, 50% fat) resulted in increased exposures of elvitegravir and tenofovir. For elvitegravir, Cmax and AUC increased 22% and 36% with a light meal, while increasing 56% and 91% with a high-fat meal, respectively. The Cmax and AUC of tenofovir increased 20% and 25% respectively with a light meal, while the Cmax was unaffected and AUC increased 25% with a high fat meal. Cobicistat exposures were unaffected by a light meal and although there was a modest decrease of 24% and 18% in Cmax and AUC respectively with a high-fat meal, no difference was observed in its pharmacoenhancing effect on elvitegravir. Emtricitabine exposures were unaffected with light or high-fat meal.

Distribution

Elvitegravir is 98–99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng/mL to 1,600 ng/mL. The mean plasma to blood drug concentration ratio was 1.37. Cobicistat is 97–98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.

Following intravenous administration the volume of distribution of emtricitabine and tenofovir was approximately 1,400 mL/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 |ig/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0. In vitro protein binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 |ig/mL.

Biotransformation

Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation by UGT1A1/3 enzymes (minor route). Following oral administration of boosted [14C]elvitegravir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity.

Aromatic and aliphatic hydroxylation or glucuronidation metabolites are present in very low levels, display considerably lower anti-HIV activity and do not contribute to the overall antiviral activity of elvitegravir.

Cobicistat is metabolised via CYP3A and/or CYP2D6-mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat.

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of [14C]emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~ 86%) and faeces

(~ 14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (~ 4% of dose). No other metabolites were identifiable.

In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of a CYP1A1/2 substrate was observed.

Elimination

Following oral administration of [14C]elvitegra­vir/ritonavir, 94.8% of the dose was recovered in faeces, consistent with the hepatobiliary elimination of elvitegravir; 6.7% of the administered dose was recovered in urine. The median terminal plasma half-life of elvitegravir following administration of Stribild is approximately 12.9 hours.

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 Stribild is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir Ctrough approximately 10-fold above the protein-binding adjusted IC95 for wild-type HIV-1 virus.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system (human organic anion transporter [hOAT1]) with approximately 70–80% of the dose excreted unchanged in urine following intravenous administration. The apparent clearance of tenofovir averaged approximately 307 mL/min. Renal clearance has been estimated to be approximately 210 mL/min, which is in excess of the glomerular filtration rate. This indicates that active tubular secretion is an important part of the elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.

Elderly

Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been evaluated in the elderly (over 65 years).

Gender

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil.

Ethnicity

No clinically relevant pharmacokinetic differences due to ethnicity have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil.

Paediatric population

Exposures of elvitegravir and tenofovir in paediatric patients aged 12 to <18 years who received Stribild in GS-US-236–0112 were increased by 30% and 37% respectively, when compared with historical adult controls. Tenofovir exposures were in the range of those observed in tenofovir disoproxil-containing boosted-protease inhibitor regimens. Exposures of cobicistat and emtricitabine in paediatric patients aged 12 to <18 years were similar to exposures achieved in adults.

The pharmacokinetics of elvitegravir or cobicistat in paediatric subjects <12 years of age have not been fully established.

Renal impairment

A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with severe renal impairment (creatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with renal impairment. The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end stage renal disease requiring dialysis, Cmax, and AUC of emtricitabine and tenofovir were increased (see section 4.4).

Hepatic impairment

Both elvitegravir and cobicistat are primarily metabolised and eliminated by the liver. A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of elvitegravir or cobicistat has not been studied. The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. Clinically relevant changes in tenofovir pharmacokinetics in patients with hepatic impairment were not observed.

Therefore, no tenofovir disoproxil dose adjustment is required in patients with hepatic impairment.

Hepatitis B and/or hepatitis C virus co-infection

Pharmacokinetics of emtricitabine and tenofovir disoproxil have not been fully evaluated in hepatitis B and/or C virus co-infected patients. Limited data from population pharmacokinetic analysis (n = 24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of boosted elvitegravir.

Pregnancy and postpartum

The results reported from a prospective study (IMPAACT P1026s) showed that treatment with cobicistat and elvitegravir-containing regimens during pregnancy results in lower elvitegravir and cobicistat exposures (Table 5).

Table 5: Changes in pharmacokinetic parameters from the IMPAACT P1026s study for elvitegravir and cobicistat in women receiving cobicistat and elvitegravir-containing regimens during the second and third trimesters of pregnancy compared to paired postpartum data

2T = second trimester; 3T = third trimester; PP =postpartum a paired comparisons

b P<0.10 compared with postpartum

5.3 Preclinical safety data

Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in an in vivo rat micronucleus assay at doses up to 2,000 mg/kg. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.

Cobicistat was not mutagenic or clastogenic in conventional genotoxicity assays. 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 concentrations at least 11-fold higher than the human exposure at the recommended 150 mg daily dose. In a human clinical study of 35 healthy subjects, echocardiograms performed at baseline and after receiving 150 mg cobicistat once daily for at least 15 days indicated no clinically significant change in left ventricular function.

Reproductive toxicity studies in rats and rabbits with cobicistat showed no effects on mating, fertility, pregnancy or foetal parameters. However increased postimplantation loss and decreased foetal weights were observed in rats associated with significant decreases in maternal body weights at 125 mg/kg/day.

Long term oral carcinogenicity studies with elvitegravir and cobicistat did not show any carcinogenic potential in mice and rats.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Non-clinical data on tenofovir disoproxil reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Findings in repeat-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use included kidney and bone changes and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (rats and dogs). Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.

The active substances elvitegravir, cobicistat and tenofovir disoproxil are persistent in the environment.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Croscarmellose sodium

Hydroxypropyl cellulose (E463)

Lactose (as monohydrate)

Magnesium stearate

Microcrystalline cellulose (E460)

Silicon dioxide (E551)

Sodium lauryl sulfate

Film-coating

Indigo carmine aluminium lake (E132)

Macrogol 3350 (E1521)

Polyvinyl alcohol (partially hydrolysed) (E1203)

Talc (E553b)

Titanium dioxide (E171)

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5 Nature and contents of container

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

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.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Gilead Sciences Ltd

280 High Holborn

London

WC1V 7EE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 11972/0021