4.1. Therapeutic indications

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead (see sections 4.2, 4.4 and 5.1).

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 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.

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). Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should be administered with caution to elderly patients (see section 4.4).

Adults with renal impairment

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in patients with creatinine clearance below 90 mL/min.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should be discontinued if creatinine clearance declines below 50 mL/min during treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Paediatric patients with renal impairment

Use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 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). Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

If Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in children under the age of 12 years or weighing < 35 kg have not been established (see section 5.2).

Method of administration

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 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. Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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

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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead (see section 4.3).

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.

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 µmol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety.

See also under Co-administration of other medicinal products below.

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 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.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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).

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). Mean percentage decreases in BMD from baseline to Week 144 in the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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.

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 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, 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 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. As in adults, adolescents who experience a confirmed increase in serum creatinine of greater than 26.5 µmol/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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not recommended in paediatric patients with renal impairment (see section 4.2). Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be initiated in paediatric patients with renal impairment and should be discontinued in paediatric patients who develop renal impairment during Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead (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. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C). 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 (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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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).

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 µg 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead concomitantly with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir should be monitored for adverse reactions related to tenofovir disoproxil.

Elderly

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be initiated during pregnancy, and women who become pregnant during therapy with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should be switched to an alternative regimen (see section 4.6).

Excipients

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and development of resistance (see Concomitant use contraindicated and section 4.3).

Concomitant use contraindicated

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and potential co‑administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). The interactions described are based on studies conducted with the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead as individual agents and/or in combination, or are potential drug interactions that may occur with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Table 1: Interactions between the individual components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and other medicinal products

Medicinal product by therapeutic areas

Effects on drug levels

Mean percent change in AUC, Cmax, Cmin1

Recommendation concerning co‑administration with Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Gilead

ANTI-INFECTIVES

Antifungals

Ketoconazole (200 mg twice daily)/Elvitegravir (150 mg once daily)2

Elvitegravir:

AUC: ↑ 48%

Cmin: ↑ 67%

Cmax: ↔

Concentrations of ketoconazole and/or cobicistat may increase with co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

When administering with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, the maximum daily dose of ketoconazole should not exceed 200 mg per day. Caution is warranted and clinical monitoring is recommended during the co‑administration.

Itraconazole3

Voriconazole3

Posaconazole3

Fluconazole

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of itraconazole, fluconazole and posaconazole may be increased when co‑administered with cobicistat.

Concentrations of voriconazole may increase or decrease when co‑administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Clinical monitoring should be made upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. When administering with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, the maximum daily dose of itraconazole should not exceed 200 mg per day.

An assessment of benefit/risk ratio is recommended to justify use of voriconazole with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Antimycobacterials

Rifabutin (150 mg every other day)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)

Co‑administration of rifabutin, potent CYP3A inducer, may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Rifabutin:

AUC: ↔

Cmin: ↔

Cmax: ↔

25‑O-desacetyl‑rifabutin

AUC: ↑ 525%

Cmin: ↑ 394%

Cmax: ↑ 384%

Elvitegravir:

AUC: ↓ 21%

Cmin: ↓ 67%

Cmax: ↔

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and rifabutin is not recommended. If the combination is needed, the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday).

Increased monitoring for rifabutin‑associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to desacetyl‑rifabutin. Further dose reduction of rifabutin has not been studied. It should be kept in mind that a twice weekly dose of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure.

Hepatitis Cvirus (HCV) antiviral agents

Ledipasvir/Sofosbuvir

Interaction not studied with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may lead to increased tenofovir exposure.

Increased plasma concentrations of tenofovir resulting from co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and ledipasvir/sofosbuvir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring, if other alternatives are not available (see section 4.4).

Ledipasvir/Sofosbuvir (90 mg/400 mg once daily) + Elvitegravir/Cobicistat (150 mg/150 mg once daily)

Observed:

Ledipasvir:

AUC: ↑ 78%

Cmin: ↑ 91%

Cmax: ↑ 63%

Sofosbuvir:

AUC: ↑ 36%

Cmin: N/A

Cmax: ↑ 33%

GS‑3310075:

AUC: ↑ 44%

Cmin: ↑ 53%

Cmax: ↑ 33%

Elvitegravir:

AUC: ↔

Cmin: ↑ 36%

Cmax: ↔

Cobicistat:

AUC: ↑ 59%

Cmin: ↑ 325%

Cmax: ↔

Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir Disoproxil (150 mg/150 mg/200 mg/245 mg once daily)

Sofosbuvir:

AUC: ↔

Cmax: ↔

GS‑3310075:

AUC: ↔

Cmax: ↔

Cmin: ↑ 45%

Velpatasvir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 37%

Elvitegravir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Cobicistat:

AUC: ↔

Cmax: ↔

Cmin: ↑ 71%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↔

Cmax: ↑ 36%

Cmin: ↑ 45%

Increased plasma concentrations of tenofovir resulting from co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and sofosbuvir/velpatasvir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring (see section 4.4).

Sofosbuvir/Velpatasvir/ Voxilaprevir (400 mg/100 mg/ 100 mg+100 mg once daily)6 + Emtricitabine/Tenofovir disoproxil (200 mg/245 mg once daily)7

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may lead to increased tenofovir exposure.

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir:

AUC: ↑ 39%

Cmax: ↑ 48%

Cmin: ↑ 47%

Increased plasma concentrations of tenofovir resulting from co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and sofosbuvir/velpatasvir/voxilaprevir may increase adverse reactions related to tenofovir disoproxil, including renal disorders. The safety of tenofovir disoproxil when used with sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic enhancer (e.g. cobicistat) has not been established.

The combination should be used with caution with frequent renal monitoring (see section 4.4).

Sofosbuvir/Velpatasvir/ Voxilaprevir (400 mg/100 mg/ 100 mg+100 mg once daily)6 + Elvitegravir/Cobicistat (150 mg/150 mg once daily)8

Sofosbuvir:

AUC: ↔

Cmax: ↑ 27%

Cmin: N/A

GS-3310075:

AUC: ↑ 43%

Cmax:↔

Cmin: N/A

Velpatasvir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 46%

Voxilaprevir:

AUC: ↑ 171%

Cmax:↑ 92%

Cmin: ↑ 350%

Elvitegravir:

AUC: ↔

Cmax: ↔

Cmin: ↑ 32%

Cobicistat:

AUC: ↑ 50%

Cmax: ↔

Cmin: ↑ 250%

Nucleoside reverse transcriptase inhibitors (NRTIs)

Didanosine

Co‑administration of tenofovir disoproxil and didanosine results in a 40‑60% increase in systemic exposure to didanosine.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and didanosine is not recommended.

Increased systemic exposure to didanosine may increase didanosine related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co‑administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co‑administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV‑1 infection.

However, in case of initiation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in patients previously taking didanosine or discontinuation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and change to a regimen including didanosine there could be a short period when measurable plasma levels of didanosine and tenofovir occur.

Macrolide antibiotics

Clarithromycin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of clarithromycin and/or cobicistat may be altered with co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

No dose adjustment of clarithromycin is required for patients with normal renal function or mild renal impairment (ClCr 60‑90 mL/min). Clinical monitoring is recommended for patients with ClCr < 90 mL/min. For patients with ClCr < 60 mL/min, alternative antibacterials should be considered.

Telithromycin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of telithromycin and/or cobicistat may be altered with co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Clinical monitoring is recommended upon co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

GLUCOCORTICOIDS

Corticosteroids

Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone).

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Plasma concentrations of these medicinal products may be increased when co-administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, resulting in reduced serum cortisol concentrations.

Concomitant use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Co-administration with CYP3A‑metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects. Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long‑term use.

For coadministration of cutaneously-administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for conditions or uses that augment its systemic absorption.

MEDICINAL PRODUCTS or ORAL SUPPLEMENTS CONTAINING POLYVALENT CATIONS (e.g. Mg, Al, Ca, Fe, Zn)

Magnesium/aluminium-containing antacid suspension (20 mL single dose)/Elvitegravir (50 mg single dose)/Ritonavir (100 mg single dose)

Elvitegravir (antacid suspension after ± 2 hours):

AUC: ↔

Cmin: ↔

Cmax: ↔

Elvitegravir (simultaneous administration):

AUC: ↓ 45%

Cmin: ↓ 41%

Cmax: ↓ 47%

Elvitegravir plasma concentrations are lower with antacids due to local complexation in the gastrointestinal tract and not to changes in gastric pH.

It is recommended to separate Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and administration of antacids, medicinal products or oral supplements containing polyvalent cations by at least 4 hours.

For information on other acid reducing agents (e.g. H2‑receptor antagonists and proton pump inhibitors), see Studies conducted with other medicinal products.

Calcium or iron supplements (including multivitamins)

Other cation‑containing antacids

Cation‑containing laxatives

Sucralfate

Buffered medicinal products

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Elvitegravir plasma concentrations are expected to be lower with antacids, medicinal products or oral supplements containing polyvalent cations, due to local complexation in the gastrointestinal tract and not to changes in gastric pH.

ORAL ANTI-DIABETICS

Metformin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Cobicistat reversibly inhibits MATE1, and concentrations of metformin may be increased when co‑administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

NARCOTIC ANALGESICS

Methadone/Elvitegravir/Cobicistat

Methadone:

AUC: ↔

Cmin: ↔

Cmax: ↔

Cobicistat:

AUC: ↔

Cmin: ↔

Cmax: ↔

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment of methadone is required.

Methadone/Tenofovir disoproxil

Methadone:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Buprenorphine/Naloxone/ Elvitegravir/Cobicistat

Buprenorphine:

AUC: ↑ 35%

Cmin: ↑ 66%

Cmax: ↔

Naloxone:

AUC: ↓ 28%

Cmax: ↓ 28%

Cobicistat:

AUC: ↔

Cmin: ↔

Cmax: ↔

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment of buprenorphine/naloxone is required.

ORAL CONTRACEPTIVES

Drospirenone/Ethinyloestradiol (3 mg/0.02 mg single dose)/Cobicistat (150 mg once daily)

Interaction not studied with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Expected

Drospirenone:

AUC: ↑

Plasma concentrations of drospirenone may be increased when co‑administered with cobicistat‑containing products. Clinical monitoring is recommended due to the potential for hyperkalemia.

Caution should be exercised when co‑administering Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and a hormonal contraceptive. The hormonal contraceptive should contain at least 30 µg ethinyloestradiol and contain drospirenone or norgestimate as the progestogen or patients should use an alternative reliable method of contraception (see sections 4.4 and 4.6).

The long-term effects of substantial increases in progestogen exposure are unknown.

Norgestimate (0.180/0.215 mg once daily)/Ethinyloestradiol (0.025 mg once daily)/ Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)4

Norgestimate:

AUC: ↑ 126%

Cmin: ↑ 167%

Cmax: ↑ 108%

Ethinyloestradiol:

AUC: ↓ 25%

Cmin: ↓ 44%

Cmax: ↔

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

ANTIARRHYTHMICS

Digoxin (0.5 mg single dose)/Cobicistat (150 mg multiple doses)

Digoxin:

AUC: ↔

Cmax: ↑ 41%

It is recommended that digoxin levels be monitored when digoxin is combined with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Disopyramide

Flecainide

Systemic lidocaine

Mexiletine

Propafenone

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of these antiarrhythmic drugs may be increased when co‑administered with cobicistat.

Caution is warranted and clinical monitoring is recommended upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

ANTI-HYPERTENSIVES

Metoprolol

Timolol

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of beta-blockers may be increased when co‑administered with cobicistat.

Clinical monitoring is recommended and a dose decrease may be necessary when these agents are co‑administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of calcium channel blockers may be increased when co‑administered with cobicistat.

Clinical monitoring of therapeutic and adverse effects is recommended when these medicinal products are concomitantly administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may lead to decreased elvitegravir and/or cobicistat exposures and loss of therapeutic effect and development of resistance.

Alternative endothelin receptor antagonists may be considered.

ANTICOAGULANTS

Dabigatran

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may increase dabigatran plasma concentrations with similar effects as seen with other strong P‑gp inhibitors.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead with dabigatran is contraindicated.

Apixaban

Rivaroxaban

Edoxaban

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may result in increased plasma concentrations of the DOAC, which may lead to an increased bleeding risk.

Co‑administration of apixaban, rivaroxaban or edoxaban is not recommended with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Warfarin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of warfarin may be affected upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

It is recommended that the international normalised ratio (INR) be monitored upon co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. INR should continue to be monitored during the first weeks following ceasing treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

ANTIPLATELETS

Clopidogrel

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co-administration of clopidogrel with cobicistat is expected to decrease clopidogrel active metabolite plasma concentrations, which may reduce the antiplatelet activity of clopidogrel.

Co-administration of clopidogrel with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not recommended.

Prasugrel

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not expected to have a clinically relevant effect on plasma concentrations of the active metabolite of prasugrel.

No dose adjustment of prasugrel is required.

ANTICONVULSANTS

Carbamazepine (200 mg twice daily)/Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)

Co‑administration of carbamazepine, a potent CYP3A inducer, may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Carbamazepine:

AUC: ↑ 43%

Cmin: ↑ 51%

Cmax: ↑ 40%

Elvitegravir:

AUC: ↓ 69%

Cmin: ↓ 97%

Cmax: ↓ 45%

Cobicistat:

AUC: ↓ 84%

Cmin: ↓ 90%

Cmax: ↓ 72%

Carbamazepine-10,11-epoxide:

AUC: ↓ 35%

Cmin: ↓ 41%

Cmax: ↓ 27%

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead with carbamazepine, phenobarbital, or phenytoin is contraindicated (see section 4.3).

INHALED BETA AGONIST

Salmeterol

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may result in increased plasma concentrations of salmeterol, which is associated with the potential for serious and/or life-threatening reactions.

Concurrent administration of salmeterol and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead is not recommended.

HMG CO‑A REDUCTASE INHIBITORS

Rosuvastatin (10 mg single dose)/Elvitegravir (150 mg single dose)/Cobicistat (150 mg single dose)

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Rosuvastatin:

AUC: ↑ 38%

Cmin: N/A

Cmax: ↑ 89%

Concentrations of rosuvastatin are transiently increased when administered with elvitegravir and cobicistat. Dose modifications are not necessary when rosuvastatin is administered in combination with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Atorvastatin (10 mg single dose)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)/ Emtricitabine (200 mg once daily)/ Tenofovir alafenamide (10 mg once daily)

Atorvastatin:

AUC: ↑160%

Cmin: NC

Cmax: ↑132%

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Concentrations of atorvastatin are increased when co‑administered with elvitegravir and cobicistat. Start with the lowest possible dose of atorvastatin with careful monitoring upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Pitavastatin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of pitavastatin may be increased when administered with elvitegravir and cobicistat.

Caution should be exercised when co‑administering Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead with pitavastatin.

Pravastatin

Fluvastatin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of these HMG Co‑A reductase inhibitors are expected to transiently increase when administered with elvitegravir and cobicistat.

Dose modifications are not necessary when administered in combination with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Lovastatin

Simvastatin

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and lovastatin and simvastatin is contraindicated (see section 4.3).

PHOSPHODIESTERASE TYPE 5 (PDE‑5) INHIBITORS

Sildenafil

Tadalafil

Vardenafil

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

PDE‑5 inhibitors are primarily metabolised by CYP3A. Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may result in increased plasma concentrations of sildenafil and tadalafil, which may result in PDE‑5 inhibitor-associated adverse reactions.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and sildenafil for the treatment of pulmonary arterial hypertension is contraindicated.

Caution should be exercised, including consideration of dose reduction, when co‑administering Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead with tadalafil for the treatment of pulmonary arterial hypertension.

For the treatment of erectile dysfunction, it is recommended that a single dose of sildenafil no more than 25 mg in 48 hours, vardenafil no more than 2.5 mg in 72 hours, or tadalafil no more than 10 mg in 72 hours be co‑administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

ANTIDEPRESSANTS

Escitalopram

Trazodone

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of trazodone may increase upon co‑administration with cobicistat.

Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended.

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Concentrations of these immunosuppressant agents may be increased when administered with cobicistat.

Therapeutic monitoring is recommended upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Orally administered midazolam

Triazolam

Zolpidem

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Midazolam and triazolam are primarily metabolised by CYP3A. Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may result in increased plasma concentrations of these drugs, which is associated with the potential for serious and/or life-threatening reactions.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead and orally administered midazolam and triazolam is contraindicated (see section 4.3). With other sedatives/hypnotics, dose reduction may be necessary and concentration monitoring is recommended.

ANTI-GOUT

Colchicine

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead may result in increased plasma concentrations of this drug.

Dose reductions of colchicine may be required. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be co‑administered with colchicine to patients with renal or hepatic impairment.

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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, no clinically significant drug interactions have been either observed or are expected between the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be initiated during pregnancy, and women who become pregnant during therapy with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should be switched to an alternative regimen (see section 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants.

Fertility

No human data on the effect of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead.

4.8. Undesirable effects

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. Monitoring of renal function is recommended for patients receiving Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead (see section 4.4).

Discontinuation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 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

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.

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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead over 144 weeks, 13 (1.9%) subjects in the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead were consistent with previous experience with tenofovir disoproxil. Four (0.6%) of the subjects who received Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead developed laboratory findings consistent with proximal tubulopathy leading to discontinuation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, ‑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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead

The safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead in 50 HIV-1-infected, treatment-naïve 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead was similar to that in adults (see section 4.8, Tabulated summary of adverse reactions). Among the 50 paediatric patients receiving Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead, 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-naïve (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. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead (see sections 4.2, 4.4 and 5.2). The use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Gilead. 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.