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

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

Excipients with known effect: Each tablet contains 10.9 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

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

 

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

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

Posology

One tablet to be taken once daily with food (see section 5.2).

If the patient misses a dose of Stribild within 18 hours of the time it is usually taken, the patient should take Stribild with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Stribild by more than 18 hours and it is almost time for the next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Stribild another tablet should be taken.

Special populations

Elderly

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

Renal impairment

Stribild should not be initiated in patients with creatinine clearance below 70 mL/min (see sections 4.4 and 5.2). See section 4.4 regarding initiation of Stribild in patients with creatinine clearance below 90 mL/min.

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

Hepatic impairment

No dose adjustment of Stribild is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Stribild has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Stribild is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

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

Paediatric population

The safety and efficacy of Stribild in children aged 6 to less than 18 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Stribild should not be used in children aged 0 to less than 6 years because of safety/efficacy concerns.

Method of administration

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

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 fumarate due to renal toxicity, with or without reversal of the effects post-discontinuation.

Co-administration with the following medicinal products due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild (see section 4.5):

• alpha 1-adrenoreceptor antagonists: alfuzosin

• antiarrhythmics: amiodarone, quinidine

• anticonvulsants: carbamazepine, phenobarbital, phenytoin

• antimycobacterials: rifampicin

• ergot derivatives: dihydroergotamine, ergometrine, ergotamine

• gastrointestinal motility agents: cisapride

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

• HMG Co-A reductase inhibitors: lovastatin, simvastatin

• neuroleptics: pimozide

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

• sedatives/hypnotics: orally administered midazolam, triazolam

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

Co-administration of other medicinal products

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

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

Contraception requirements

Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 µg ethinylestradiol and containing norgestimate as the progestagen or should use an alternative reliable method of contraception (see sections 4.5 and 4.6). Co-administration of Stribild with oral contraceptives containing progestagens other than norgestimate has not been studied and, therefore, should be avoided.

Opportunistic infections

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

Effects on renal function

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 fumarate (see section 4.8).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil fumarate and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil fumarate without cobicistat.

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

Before initiating treatment with Stribild

Creatinine clearance should be calculated and urine glucose and urine protein should be determined in all patients. Stribild should not be initiated in patients with creatinine clearance < 70 mL/min. It is recommended that Stribild is not initiated in patients with creatinine clearance < 90 mL/min unless, after review of the available treatment options, it is considered that Stribild is the preferred treatment for the individual patient.

During treatment with Stribild

Creatinine clearance, serum phosphate, urine glucose and urine protein should be monitored every four weeks during the first year and then every three months during Stribild therapy. In patients at risk for renal impairment a more frequent monitoring of renal function is required.

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

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-eva luated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8). It is recommended that Stribild is discontinued in patients with creatinine clearance that falls to < 70 mL/min while on treatment unless it is considered that the potential benefit of this combination of antiretroviral agents for the individual patient outweighs the possible risks of continuing with therapy. Interrupting treatment with Stribild should also be considered in case of progressive decline of renal function when no other cause has been identified.

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

Concomitant use with nephrotoxic medicinal products

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

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

Treatment switching

When switching patients who are CYP2B6 poor metabolisers from an efavirenz-containing regimen to Stribild, there is a potential for lower elvitegravir exposure due to prolonged CYP3A induction by efavirenz. Monitoring of viral load is recommended for these patients during the first month after switching treatment to Stribild.

Bone effects

In the Phase 3 study GS-US-236-0103, bone mineral density (BMD) was assessed in a non-random subset of 120 subjects (Stribild group n = 54; ritonavir-boosted atazanavir (ATV/r) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) group n = 66). Mean percentage decreases in BMD from baseline to Week 144 in the Stribild group were comparable to the ATV/r+FTC/TDF group at the lumbar spine (-1.43% versus -3.68%, respectively) and at the hip (-2.83% versus -3.77%, respectively). In the Phase 3 studies GS-US-236-0102 and GS-US-236-0103, bone fractures occurred in 27 subjects (3.9%) in the Stribild group, 8 subjects (2.3%) in the efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) group, and 19 subjects (5.4%) in the ATV/r+FTC/TDF group.

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

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8). If bone abnormalities are suspected then appropriate consultation should be obtained.

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

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

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

In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products. Stribild should not be administered concomitantly with other medicinal products containing tenofovir disoproxil (as fumarate), lamivudine or adefovir dipivoxil used for the treatment of hepatitis B virus infection.

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

Liver disease

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

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Lipodystrophy

CART has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include eva luation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be excluded. However, 144-week clinical data from antiretroviral-naïve patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. 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 eva luated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) 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.

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.

Elderly

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

Excipients

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

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

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

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

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

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

Concomitant use contraindicated

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

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

Concomitant use not recommended

Renally eliminated medicinal products

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

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

Other interactions

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

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

Medicinal product by therapeutic areas	Effects on drug levels Mean percent change in AUC, Cmax, Cmin1	Recommendation concerning co-administration with Stribild
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 Stribild.	When administering with Stribild, 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 Stribild. 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 Stribild.	Clinical monitoring should be made upon co-administration with Stribild. When administering with Stribild, 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 Stribild.
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 Stribild 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.
HCV protease inhibitors
Telaprevir (750 mg three times daily)/ Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)4	Telaprevir: AUC: ↔ Cmin: ↔ Cmax: ↔ Elvitegravir: AUC: ↔ Cmin: ↑ 29% Cmax: ↔ Cobicistat: AUC: ↔ Cmin: ↑ 232% Cmax: ↔	No dose adjustment is required when Stribild is co-administered with telaprevir.
Boceprevir	Interaction not studied with any of the components of Stribild.	Co-administration with Stribild is not recommended.
Macrolide antibiotics
Clarithromycin	Interaction not studied with any of the components of Stribild. Concentrations of clarithromycin and/or cobicistat may be altered with co-administration of Stribild.	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 Stribild. Concentrations of telithromycin and/or cobicistat may be altered with co-administration of Stribild.	Clinical monitoring is recommended upon co-administration of Stribild.
GLUCOCORTICOIDS
Inhaled/Nasal corticosteroids
Fluticasone	Interaction not studied with any of the components of Stribild. Concomitant use of inhaled or nasal fluticasone propionate and Stribild may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations.	Caution is warranted and clinical monitoring is recommended upon co-administration of Stribild.
ANTACIDS
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 Stribild and antacid administration 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.
FOOD SUPPLEMENTS
Multivitamin supplements	Interaction not studied with any of the components of Stribild.	As the effect of cationic complexation of elvitegravir cannot be excluded when Stribild is co-administered with multivitamin supplements, it is recommended to separate Stribild and multivitamin supplements dosing by at least 4 hours.
ORAL ANTI-DIABETICS
Metformin	Interaction not studied with any of the components of Stribild. Cobicistat reversibly inhibits MATE1, and concentrations of metformin may be increased when co-administered with Stribild.	Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking Stribild.
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 fumarate	Methadone: AUC: ↔ Cmin: ↔ Cmax: ↔ Tenofovir: AUC: ↔ Cmin: ↔ Cmax: ↔
Buprenorphine/Naloxone/ Elvitegravir/Cobicistat	Buprenorphine: AUC: ↑ 35% Cmin: ↑ 66% Cmax: ↑ 12% Naloxone: AUC: ↓ 28% Cmax: ↓ 28% Cobicistat: AUC: ↔ Cmin: ↔ Cmax: ↔ Elvitegravir: AUC: ↔ Cmin: ↔ Cmax: ↔	No dose adjustment of buprenorphine/naloxone is required.
ORAL CONTRACEPTIVES
Norgestimate (0.180/0.215 mg once daily)/Ethinylestradiol (0.025 mg once daily)/ Elvitegravir (150 mg once daily)/Cobicistat (150 mg once daily)4	Norgestimate: AUC: ↑ 126% Cmin: ↑ 167% Cmax: ↑ 108% Ethinylestradiol: AUC: ↓ 25% Cmin: ↓ 44% Cmax: ↔ Elvitegravir: AUC: ↔ Cmin: ↔ Cmax: ↔	Caution should be exercised when co-administering Stribild and a hormonal contraceptive. The hormonal contraceptive should contain at least 30 µg ethinylestradiol and contain norgestimate as the progestagen 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 progesterone exposure are unknown. Co-administration of Stribild with oral contraceptives containing progestagens other than norgestimate has not been studied and therefore should be avoided.
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 Stribild.
Disopyramide Flecainide Systemic lidocaine Mexiletine Propafenone	Interaction not studied with any of the components of Stribild. 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 Stribild.
ANTI-HYPERTENSIVES
Metoprolol Timolol	Interaction not studied with any of the components of Stribild. 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 Stribild.
Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Verapamil	Interaction not studied with any of the components of Stribild. 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 Stribild.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan	Interaction not studied with any of the components of Stribild. Co-administration with Stribild 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
Warfarin	Interaction not studied with any of the components of Stribild. Concentrations of warfarin may be affected upon co-administration with Stribild.	It is recommended that the international normalised ratio (INR) be monitored upon co-administration of Stribild. INR should continue to be monitored during the first weeks following ceasing treatment with Stribild.
Dabigatran	Interaction not studied with any of the components of Stribild. Concentrations of dabigatran may be increased upon co-administration with Stribild.	Clinical monitoring is recommended when dabigatran is co-administered with P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
INHALED BETA AGONIST
Salmeterol	Interaction not studied with any of the components of Stribild. Co-administration with Stribild 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 Stribild 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 Stribild.
Atorvastatin Pitavastatin	Interaction not studied with any of the components of Stribild. Concentrations of atorvastatin and pitavastatin may be increased when administered with elvitegravir and cobicistat.	Co-administration of atorvastatin with Stribild is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring. Caution should be exercised when co-administering Stribild with pitavastatin.
Pravastatin Fluvastatin	Interaction not studied with any of the components of Stribild. 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 Stribild.
Lovastatin Simvastatin	Interaction not studied with any of the components of Stribild.	Co-administration of Stribild 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 Stribild. PDE-5 inhibitors are primarily metabolised by CYP3A. Co-administration with Stribild may result in increased plasma concentrations of sildenafil and tadalafil, which may result in PDE-5 inhibitor-associated adverse reactions.	Co-administration of Stribild and sildenafil for the treatment of pulmonary arterial hypertension is contraindicated. Caution should be exercised, including consideration of dose reduction, when co-administering Stribild 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 Stribild.
ANTIDEPRESSANTS
Escitalopram Trazodone	Interaction not studied with any of the components of Stribild. 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 Stribild. Concentrations of these immunosuppressant agents may be increased when administered with cobicistat.	Therapeutic monitoring is recommended upon co-administration with Stribild.
SEDATIVES/HYPNOTICS
Buspirone Clorazepate Diazepam Estazolam Flurazepam Orally administered midazolam Triazolam Zolpidem	Interaction not studied with any of the components of Stribild. Midazolam and triazolam are primarily metabolised by CYP3A. Co-administration with Stribild 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 Stribild 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 Stribild. Co-administration with Stribild may result in increased plasma concentrations of this drug.	Dose reductions of colchicine may be required. Stribild should not be co-administered with colchicine to patients with renal or hepatic impairment.

¹ When data available from drug interaction studies.

² These studies were performed with ritonavir boosted elvitegravir.

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

⁴ This study was conducted using Stribild.

Studies conducted with other medicinal products

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