Stribild

/ Gilead

One tablet to be taken once daily with food.
If the patient misses a dose within 18 hours of the time it is usually taken, the patient should take the drug with food as soon as possible and resume the normal dosing schedule.
If a patient misses a dose 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 the drug another tablet should be taken.
Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years. The drug should be administered with caution to elderly patients.
Renal impairment: This formulation should not be initiated in patients with creatinine clearance below 70 mL/min and should be discontinued if creatinine clearance declines below 50 mL/min during treatment as dose interval adjustment is required for emtricitabine and tenofovir disoproxil fumarate and this cannot be achieved with the fixed-dose combination tablet.
Hepatic impairment: No dose adjustment required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, the drug  is not recommended for use in patients with severe hepatic impairment. If the drug 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.
Paediatric population: The safety and efficacy of in children aged 6 to less than 18 years have not yet been established. No recommendation on a posology can be made. Should not be used in children aged 0 to less than 6 years because of safety/efficacy concerns.
Method of administration: Should be taken orally, once daily with food. There is no information available regarding the crushing/splitting of the product. The film-coated tablet should not be chewed, crushed, or split.

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 this formulation.

Hypersensitivity to the active substances or to any of the excipients.
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 this drug:
-alpha 1-adrenoreceptor antagonists: alfuzosin
-antiarrhythmics: amiodarone, quinidine
-ergot derivatives: dihydroergotamine, ergometrine, ergotamine
-gastrointestinal motility agents: cisapride
-HMG Co-A reductase inhibitors: lovastatin, simvastatin
-neuroleptics/antipsychotics: pimozide, lurasidone
-PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension
-sedatives/hypnotics: orally administered midazolam, triazolam
– anticonvulsants: carbamazepine, phenobarbital, phenytoin
– antimycobacterials: rifampicin
-herbal products: St. John’s wort (Hypericum perforatum)
Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate, is contraindicated.
See prescribing information for full details.

Co-administration of other medicinal products: The drug  is indicated for use as a complete regimen for the treatment of HIV-1 infection and must not be administered with other antiretroviral products. 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, or with other medicinal products containing tenofovir alafenamide.
Concomitant use with nephrotoxic medicinal products: The drug 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). If concomitant use of the drug 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 this formulation is co-administered with an NSAID, renal function should be monitored adequately.
Contraception requirements: Female patients of childbearing potential should use either a hormonal contraceptive containing at least 30 μg ethinylestradiol and containing norgestimate as the progestagen or should use an alternative reliable method of contraception. Co-administration of this drug with oral contraceptives containing progestagens other than norgestimate has not been studied and, therefore, should be avoided.
Use with certain hepatitis C virus antiviral agents: Co-administration of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of ledipasvir/sofosbuvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co administration of ledipasvir/sofosbuvir with Stribild should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving this drug concomitantly with ledipasvir/sofosbuvir should be monitored for adverse reactions related to tenofovir disoproxil fumarate.
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. 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.
Renal monitoring: Before initiating treatment: Creatinine clearance should be calculated and urine glucose and urine protein should be determined in all patients. The drug 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 this formulation: 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 the  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. 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.
Renal management: If serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance is decreased to < 70 mL/min, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations. It is recommended that the drug 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 This drugshould also be considered in case of progressive decline of renal function when no other cause has been identified. The drug 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).
Bone effects:
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy.
Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD).In the Phase 3 study GS-US-236-0103, bone mineral density (BMD) was assessed in a non-random subset of 120 subjects (This druggroup 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. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. 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 have not been established in patients with significant underlying liver disorders.
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 This drugor 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.
Elderly: 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 this drug.

Pregnancy
Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposures. Cobicistat levels decrease and
may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, therapy with Stribild should not be initiated during pregnancy, and women who become pregnant
during therapy with Stribild should be switched to an alternative regimen.
Excipients: The drug 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.
See prescribing information for full details.

The most frequently reported adverse reactions considered possibly or probably related to Stribild in clinical studies through 144 weeks in treatment-naïve adult patients were nausea (16%) and diarrhoea (12%).
The most frequently reported adverse reactions to Stribild in clinical studies through 48 weeks in virologically-suppressed adult patients were nausea (3% to 5%) and fatigue (6%).
In patients receiving tenofovir disoproxil, rare events of renal impairment, renal failure and uncommon events of proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Stribild.
Discontinuation of Stribild therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis.

Lactic acidosis
See prescribing information for full details.

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

Co-administration of Stribild with medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s)
Concomitant use not recommended: Renally eliminated medicinal products:
Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Stribild with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.
Use of Stribild should be avoided with concurrent or recent use of nephrotoxic medicinal products.
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).
Other interactions: Interactions between the components of Stribild and potential co-administered medicinal products are listed in Table 1 at the attached doctor’s leaflet (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.
See prescribing information for full details.

Pregnancy: Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has been shown to result in lower elvitegravir exposure. Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result in virological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore, therapy with Stribild should not be initiated during pregnancy, and women who become pregnant during therapy with Stribild should be switched to an alternative regimen.
Lactation: It is not known whether elvitegravir or cobicistat are excreted in human milk. Therefore Stribild should not be used during breast-feeding.
In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not breast-feed their infants under any circumstances.
See prescribing information for full details.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. There is no specific antidote for overdose with Stribild. As elvitegravir and cobicistat are highly bound to plasma proteins it is unlikely that elvitegravir and cobicistat will be significantly removed by haemodialysis or peritoneal dialysis. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by haemodialysis. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Storage: Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Store at a temperature below 30°C