4.1. Therapeutic indications

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is indicated for the treatment of human immunodeficiency virus‑1 (HIV‑1) infection without any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or tenofovir in adults and paediatric patients aged from 2 years and with body weight at least 14 kg

See sections 4.2 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 paediatric patients weighing at least 25 kg

One 150 mg/150 mg/200 mg/10 mg tablet to be taken once daily with food.

If the patient misses a dose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead within 18 hours of the time it is usually taken, the patient should take Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead by more than 18 hours, 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 Alafenamide Gilead another tablet should be taken.

Special populations

Elderly

No dose adjustment of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is required in elderly patients (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be discontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (see section 5.2).

No dose adjustment of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should generally be avoided but may be used in these patients if the potential benefits are considered to outweigh the potential risks (see sections 4.4 and 5.2). On days of haemodialysis, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be administered after completion of haemodialysis treatment.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be avoided in patients with estimated CrCl ≥ 15 mL/min and < 30 mL/min, or < 15 mL/min who are not on chronic haemodialysis, as the safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead has not been established in these populations.

No data are available to make dose recommendations in children aged less than 12 years with renal impairment or in children less than 18 years with end stage renal disease.

Hepatic impairment

No dose adjustment of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is required in patients with mild (Child‑Pugh Class A) or moderate (Child‑Pugh Class B) hepatic impairment. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C); therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in children younger than 2 years of age, or weighing < 14 kg, have not yet been established. No data are available.

Method of administration

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be taken orally, once daily with food (see section 5.2). Due to the bitter taste, it is recommended that the film‑coated tablet not be chewed or crushed. For patients who are unable to swallow the tablet whole, the tablet may be split in half and both halves taken one after the other, ensuring that the full dose is taken immediately.

4.3. Contraindications

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

Co‑administration with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious or life‑threatening adverse reactions. Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be co‑administered with medicinal products that include, but are not limited to, the following (see sections 4.4 and 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

• lipid-modifying agent: lomitapide

• neuroleptics/antipsychotics: pimozide, lurasidone

• PDE‑5 inhibitors: sildenafil for the treatment of pulmonary arterial hypertension

• sedatives/hypnotics: orally administered midazolam, triazolam

Co‑administration 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 Alafenamide Gilead. Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be co‑administered with medicinal products that include, but are not limited to, the following (see sections 4.4 and 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 (see section 4.5).

4.4. Special warnings and precautions for use

Patients co‑infected with HIV and hepatitis B or C virus

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

The safety and efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in patients co‑infected with HIV‑1 and hepatitis C virus (HCV) have not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide Gilead should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment.

Liver disease

The safety and efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in patients with significant underlying liver disorders have not been established.

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 (hyperlactataemia, hyperlipasaemia). 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 Alafenamide 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.

Nephrotoxicity

Post marketing cases of renal impairment, including acute renal failure and proximal renal tubulopathy have been reported with tenofovir alafenamide containing products.

A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapy with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be considered.

Patients with end stage renal disease on chronic haemodialysis

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh the potential risks (see section 4.2). In a study of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in HIV-1 infected adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Although there were no new safety issues identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co‑administration of other medicinal products

Some medicinal products should not be co‑administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead (see sections 4.3 and 4.5).

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be co‑administered with other antiretroviral medicinal products (see section 4.5).

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection (see section 4.5).

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 Alafenamide 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 Alafenamide Gilead and clinical monitoring is recommended due to the potential for hyperkalaemia (see section 4.5).

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

Paediatric population

Reductions in BMD (≥ 4%) of the spine and total-body-less-head (TBLH) have been reported in patients aged between 3 to < 12 years receiving Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead for 48 weeks in study GS-US-292-0106 (see sections 4.8 and 5.1). The long-term effects of changes in BMD on the growing bone, including the risk of fracture, are uncertain. A multidisciplinary approach is recommended to decide the appropriate monitoring during treatment.

Excipients

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 medicinal product 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

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be co‑administered with other antiretroviral medicinal products. Therefore, information regarding drug‑drug interactions with other antiretroviral products (including protease inhibitors [PIs] and non‑nucleoside reverse transcriptase inhibitors [NNRTIs]) is not provided (see section 4.4). Interaction studies have only been performed in adults.

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection.

Elvitegravir

Elvitegravir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A may affect the exposure of elvitegravir. Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead with medicinal products that induce CYP3A may result in decreased plasma concentrations of elvitegravir and reduced therapeutic effect of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead (see “Concomitant use contraindicated” and section 4.3). Elvitegravir may have the potential to induce CYP2C9 and/or inducible uridine diphosphate glucuronosyltransferase (UGT) enzymes; as such it may decrease the plasma concentration of substrates of these enzymes.

Cobicistat

Cobicistat is a strong mechanism‑based inhibitor of CYP3A and is also a CYP3A substrate. Cobicistat is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. Medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma concentrations of cobicistat. Medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s).

Medicinal products that are highly dependent on CYP3A metabolism and have high first pass metabolism are the most susceptible to large increases in exposure when co‑administered with cobicistat (see “Concomitant use contraindicated” and section 4.3).

Cobicistat is an inhibitor of the following transporters: P‑gp, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Co‑administration with medicinal products that are substrates of P‑gp, BCRP, OATP1B1 and OATP1B3 may result in increased plasma concentrations of these products.

Emtricitabine

In vitro and clinical pharmacokinetic drug‑drug interaction studies have shown that the potential for CYP‑mediated interactions involving emtricitabine with other medicinal products is low. Co‑administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co‑administered medicinal product. Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P‑gp and BCRP. Medicinal products that strongly affect P‑gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. However, upon co‑administration with cobicistat in Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead, near maximal inhibition of P‑gp by cobicistat is achieved leading to increased availability of tenofovir alafenamide with resulting exposures comparable to tenofovir alafenamide 25 mg administered alone. As such, tenofovir alafenamide exposures following administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead are not expected to be further increased when used in combination with another P‑gp and/or BCRP inhibitor (e.g., ketoconazole). Based on data from an in vitro study, co‑administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo. In vitro and clinical pharmacokinetic drug‑drug interaction studies have shown that the potential for CYP‑mediated interactions involving tenofovir alafenamide with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of OATP in vitro. Inhibitors of OATP and BCRP include ciclosporin.

Concomitant use contraindicated

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 or life‑threatening adverse 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 Alafenamide Gilead and other medicinal products primarily metabolised by CYP3A such as amiodarone, lomitapide, quinidine, cisapride, pimozide, lurasidone, alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3).

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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).

Other interactions

Cobicistat and tenofovir alafenamide are not inhibitors of human UGT1A1 in vitro. It is not known whether cobicistat, emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes.

Interactions between the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead, or the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide), as individual agents and/or in combination, or are potential drug‑drug interactions that may occur with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead.

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

Medicinal product by therapeutic areas

Effects on medicinal product levels.

Mean percent change in AUC, Cmax, Cmin1

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

When administering with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide 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 Alafenamide Gilead.

Clinical monitoring should be made upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead. When administering with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide Gilead.

Antimycobacterials

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

Co‑administration of rifabutin, a 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: ↔

Cobicistat:

AUC: ↔

Cmin: ↓ 66%

Cmax: ↔

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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.

Anti-hepatitis C virus medicinal products

Ledipasvir (90 mg once daily)/ Sofosbuvir (400 mg once daily)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)/ Emtricitabine (200 mg once daily)/ Tenofovir alafenamide (10 mg once daily)5

Ledipasvir:

AUC: ↑ 79%

Cmin: ↑ 93%

Cmax: ↑ 65%

Sofosbuvir:

AUC: ↑ 47%

Cmin: N/A

Cmax: ↑ 28%

Sofosbuvir metabolite GS‑566500:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sofosbuvir metabolite GS‑331007:

AUC: ↑ 48%

Cmin: ↑ 66%

Cmax: ↔

Elvitegravir:

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

Cobicistat:

AUC: ↑ 53%

Cmin: ↑ 225%

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmin: N/A

Cmax: ↔

No dose adjustment of ledipasvir/sofosbuvir and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is warranted upon co‑administration.

Sofosbuvir (400 mg once daily)/ Velpatasvir (100 mg once daily)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)/ Emtricitabine (200 mg once daily)/ Tenofovir alafenamide (10 mg once daily)5

Sofosbuvir:

AUC: ↑ 37%

Cmin: N/A

Cmax: ↔

Sofosbuvir metabolite GS‑331007:

AUC: ↑ 48%

Cmin: ↑ 58%

Cmax: ↔

Velpatasvir:

AUC: ↑ 50%

Cmin: ↑ 60%

Cmax: ↑ 30%

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Cobicistat:

AUC: ↔

Cmin: ↑ 103%

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmin: N/A

Cmax: ↓ 20%

No dose adjustment of sofosbuvir/velpatasvir and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is warranted upon co-administration.

Sofosbuvir/Velpatasvir/ Voxilaprevir (400 mg/100 mg/100 mg+100 mg once daily)7/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)/ Emtricitabine (200 mg once daily)/ Tenofovir alafenamide (10 mg once daily)5

Sofosbuvir:

AUC: ↔

Cmin: N/A

Cmax: ↑ 27%

Sofosbuvir metabolite GS‑331007:

AUC: ↑ 43%

Cmin: N/A

Cmax: ↔

Velpatasvir:

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

Voxilaprevir:

AUC: ↑ 171%

Cmin: ↑ 350%

Cmax: ↑ 92%

Elvitegravir:

AUC: ↔

Cmin: ↑ 32%

Cmax: ↔

Cobicistat:

AUC: ↑ 50%

Cmin: ↑ 250%

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmin: N/A

Cmax: ↓ 21%

No dose adjustment of sofosbuvir/velpatasvir/voxilaprevir and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead is warranted upon co‑administration.

Macrolide antibiotics

Clarithromycin

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

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

Clarithromycin dosing should be based on the patient's CrCl, taking into consideration the effect of cobicistat on CrCl and serum creatinine (see section 4.8).

Patients with CrCl greater than or equal to 60 mL/min:

No dose adjustment of clarithromycin is required.

Patients with CrCl between 30 mL/min and 60 mL/min:

The dose of clarithromycin should be reduced by 50%.

Telithromycin

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

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

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

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 plasma concentrations.

Elvitegravir:

AUC: ↓ 69%

Cmin: ↓ 97%

Cmax: ↓ 45%

Cobicistat:

AUC: ↓ 84%

Cmin: ↓ 90%

Cmax: ↓ 72%

Carbamazepine:

AUC: ↑ 43%

Cmin: ↑ 51%

Cmax: ↑ 40%

Carbamazepine‑10,11‑epoxide:

AUC: ↓ 35%

Cmin: ↓ 41%

Cmax: ↓ 27%

Carbamazepine decreases plasma concentrations of elvitegravir and cobicistat, which may result in loss of therapeutic effect and development of resistance. Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead with carbamazepine is contraindicated (see section 4.3).

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 Alafenamide Gilead.

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

Concomitant use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide 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 Alafenamide 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 Alafenamide Gilead.

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

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

NARCOTIC ANALGESICS

Methadone (80‑120 mg)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)

Methadone:

AUC: ↔

Cmin: ↔

Cmax: ↔

Cobicistat:

AUC: ↔

Cmin: ↔

Cmax: ↔

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment of methadone is required.

Buprenorphine/Naloxone (16/4 to 24/6 mg)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)

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 Alafenamide 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 hyperkalaemia.

Caution should be exercised when co‑administering Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 (0.180/0.215/0.250 mg once daily)/ Ethinyloestradiol (0.025 mg once daily)/ Emtricitabine/Tenofovir alafenamide (200/25 mg once daily)6

Norelgestromin:

AUC: ↔

Cmin: ↔

Cmax: ↔

Norgestrel:

AUC: ↔

Cmin: ↔

Cmax: ↔

Ethinyloestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

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 Alafenamide Gilead.

Disopyramide

Flecainide

Systemic lidocaine

Mexiletine

Propafenone

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

ANTI-HYPERTENSIVES

Metoprolol

Timolol

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

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

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

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

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

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

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

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide Gilead.

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

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

Apixaban

Rivaroxaban

Edoxaban

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

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide Gilead.

Warfarin

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

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

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

ANTIPLATELETS

Clopidogrel

Interaction not studied with any of the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead with clopidogrel is not recommended.

Prasugrel

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

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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.

INHALED BETA AGONIST

Salmeterol

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

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

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

HMG CO‑A REDUCTASE INHIBITORS

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

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 Alafenamide 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: N/A

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 Alafenamide Gilead.

Pitavastatin

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

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

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

Pravastatin

Fluvastatin

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

Lovastatin

Simvastatin

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

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

LIPID-MODIFYING AGENTS

Lomitapide

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

Lomitapide is highly dependent on CYP3A for its metabolism and co-administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead may result in increased concentrations of lomitapide and potential for markedly increased transaminases.

Coadministration with lomitapide 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 Alafenamide Gilead.

PDE‑5 inhibitors are primarily metabolised by CYP3A. Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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 Alafenamide 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 Alafenamide 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 Alafenamide Gilead.

ANTIDEPRESSANTS

Sertraline (50 mg single dose)/ Elvitegravir (150 mg once daily)/ Cobicistat (150 mg once daily)/ Emtricitabine (200 mg once daily)/ Tenofovir alafenamide (10 mg once daily)5

Elvitegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sertraline:

AUC: ↔

Cmin: ↔

Cmax: ↔

Concentrations of sertraline are not affected upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead. No dose adjustment is required upon co‑administration.

Tricyclic antidepressants (TCAs)

Trazodone

Selective serotonin reuptake inhibitors (SSRIs)

Escitalopram

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

Concentrations of antidepressant agents may be increased when co‑administered 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 Alafenamide 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 Alafenamide Gilead.

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Lorazepam

Triazolam

Zolpidem

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

Triazolam is primarily metabolised by CYP3A. Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead may result in increased plasma concentrations of this medicinal product, which is associated with the potential for serious or life‑threatening adverse reactions.

Concentrations of other benzodiazepines, including diazepam, may be increased when administered with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead.

Based on non‑CYP‑mediated elimination pathways for lorazepam, no effect on plasma concentrations is expected upon co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead.

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

Orally administered midazolam (2.5 mg single dose)/ Tenofovir alafenamide (25 mg once daily)

Intravenously administered midazolam (1 mg single dose)/ Tenofovir alafenamide (25 mg once daily)

Midazolam:

AUC: ↔

Cmax: ↔

Midazolam is primarily metabolised by CYP3A. Due to the presence of cobicistat, co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead may result in increased plasma concentrations of this medicinal product, which is associated with the potential for serious or life‑threatening adverse reactions.

Co‑administration of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead and orally administered midazolam is contraindicated (see section 4.3).

ANTI-GOUT

Colchicine

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

Co‑administration with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead may result in increased plasma concentrations of this medicinal product.

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

N/A = not applicable

DOAC = direct oral anticoagulant

1 When data available from drug‑drug interaction studies.

2 These studies were performed with ritonavir boosted elvitegravir.

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

4 This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.

5 This study was conducted using Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead.

6 This study was conducted using emtricitabine/tenofovir alafenamide.

7 This study was conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV infected patients.

Studies conducted with other medicinal products

Based on drug‑drug interaction studies conducted with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead or the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead, no clinically significant drug‑drug interactions have been either observed or are expected between the components of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead and the following medicinal products: entecavir, famciclovir, ribavirin, famotidine, and omeprazole.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / contraception in males and females

The use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be accompanied by the use of effective contraception (see sections 4.4 and 4.5).

Pregnancy

There are no adequate and well‑controlled studies of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead or its components in pregnant women. There are no or limited data (less than 300 pregnancy outcomes) from the use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in pregnant women. However, a large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of elvitegravir, cobicistat, or emtricitabine, administered separately, with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development. Studies of tenofovir alafenamide in animals have shown no evidence of harmful effects of tenofovir alafenamide on fertility parameters, pregnancy, or foetal development (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 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 Alafenamide Gilead should not be initiated during pregnancy, and women who become pregnant during therapy with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead should be switched to an alternative regimen (see section 4.4).

Breast‑feeding

It is not known whether elvitegravir, cobicistat, or tenofovir alafenamide are excreted in human milk. Emtricitabine is 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 in newborns/infants. Therefore, Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 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

There are no data on fertility from the use of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in humans. In animal studies there were no effects of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide on mating or fertility parameters (see section 5.3).

4.7. Effects on ability to drive and use machines

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead.

4.8. Undesirable effects

Summary of the safety profile

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead and from post-marketing experience. The most frequently reported adverse reactions in clinical studies through 144 weeks were nausea (11%), diarrhoea (7%), and headache (6%).

Tabulated summary of adverse reactions

The adverse reactions in Table 2 are listed by system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

Table 2: Tabulated list of adverse reactions

Frequency

Adverse reaction

Blood and lymphatic system disorders

Uncommon:

anaemia1

Psychiatric disorders

Common:

abnormal dreams

Uncommon:

suicidal ideation and suicide attempt (in patients with a pre-existing history of depression or psychiatric illness), depression2

Nervous system disorders

Common:

headache, dizziness

Gastrointestinal disorders

Very common:

nausea

Common:

diarrhoea, vomiting, abdominal pain, flatulence

Uncommon:

dyspepsia

Skin and subcutaneous tissue disorders

Common:

rash

Uncommon:

angioedema3,4, pruritus, urticaria4

General disorders and administration site conditions

Common:

fatigue

1 This adverse reaction was not observed in the Phase 3 clinical studies for Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead but identified from clinical studies or post‑marketing experience for emtricitabine when used with other antiretrovirals.

2 This adverse reaction was not observed in the Phase 3 clinical studies for Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead but identified from clinical studies for elvitegravir when used with other antiretrovirals.

3 This adverse reaction was identified through post‑marketing surveillance for emtricitabine-containing products.

4 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products.

Description of selected adverse reactions

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).

Changes in serum creatinine

Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In clinical studies of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead, increases in serum creatinine occurred by Week 2 of treatment and remained stable through 144 weeks. In treatment‑naïve patients, a mean change from baseline of 0.04 ± 0.12 mg/dL (3.5 ± 10.6 µmol/L) was observed after 144 weeks of treatment. Mean increases from baseline in the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead group were smaller than in the elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) group at Week 144 (difference ‑0.04, p < 0.001).

Changes in lipid laboratory tests

In studies in treatment‑naïve patients, increases from baseline were observed in both treatment groups for the fasting lipid parameters total cholesterol, direct low‑density lipoprotein (LDL)‑ and high‑density lipoprotein (HDL)‑cholesterol, and triglycerides at Week 144. The median increase from baseline for those parameters was greater in the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead group compared with the E/C/F/TDF group at Week 144 (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct LDL‑ and HDL‑cholesterol, and triglycerides). The median (Q1, Q3) change from baseline in total cholesterol to HDL‑cholesterol ratio at Week 144 was 0.2 (‑0.3, 0.7) in the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead group and 0.1 (‑0.4, 0.6) in the E/C/F/TDF group (p = 0.006 for the difference between treatment groups).

Paediatric population

The safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead was evaluated through 48 weeks in HIV‑1 infected adolescent patients aged 12 to < 18 years weighing ≥ 35 kg (n = 100), in children aged 7 to < 12 years weighing > 25 kg (n = 52), and in children aged 3 to 9 years and weighing ≥ 14 to < 25 kg (n = 27). The safety profile in paediatric patients who received treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead was similar to that in adults. After 48 weeks of treatment with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead, reductions in BMD of the spine and of the TBLH ≥ 4% have been reported in 2.1% (1/47) and 0.0% of adolescents, in 12.2% (6/49) and 3.9% (2/51) of children aged 7 to < 12 years weighing at least 25 kg, and in 3.7% (1/27) and 0.0% of children aged at least 3 years and weighing at least 14 kg to < 25 kg respectively.

Other special populations

Patients with renal impairment

The safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in 248 HIV‑1 infected patients who were either treatment‑naïve (n = 6) or virologically suppressed (n = 242) with mild to moderate renal impairment (estimated glomerular filtration rate by Cockcroft‑Gault method [eGFRCG]: 30‑69 mL/min) was evaluated through 144 weeks in an open‑label clinical study (GS‑US‑292‑0112). The safety profile of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in patients with mild to moderate renal impairment was similar to that in patients with normal renal function (see section 5.1).

The safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in 55 virologically suppressed HIV‑1 infected patients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis was evaluated through 48 weeks in a single arm, open‑label clinical study (GS‑US‑292‑1825). There were no new safety issues identified in patients with end stage renal disease on chronic haemodialysis receiving Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead (see section 5.2).

Patients co‑infected with HIV and HBV

The safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead was evaluated in 72 HIV/HBV co‑infected patients receiving treatment for HIV in an open‑label clinical study (GS‑US‑292‑1249), through Week 48, in which patients were switched from another antiretroviral regimen (which included tenofovir disoproxil in 69 of 72 patients) to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead. Based on these limited data, the safety profile of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead in patients with HIV/HBV co‑infection was similar to that in patients with HIV‑1 monoinfection.

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). Treatment of overdose with Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Gilead consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

As elvitegravir and cobicistat are highly bound to plasma proteins, it is unlikely that they would be significantly removed by haemodialysis or peritoneal dialysis. Emtricitabine can be removed by haemodialysis, which removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.