Dosage & Administration
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Stribild Prescribing Information
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD. Hepatic function should be monitored closely, with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].
STRIBILD® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD [see Clinical Studies (14)].
Testing Prior to Initiation and During Treatment with STRIBILD
Prior to initiation of STRIBILD, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].
Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2)].
Recommended Dosage
STRIBILD is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF. The recommended dosage of STRIBILD is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with a body weight at least 35 kg and creatinine clearance greater than or equal to 70 mL per minute [see Clinical Pharmacology (12.3)].
Dosage Adjustment in Patients with Renal Impairment
Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Clinical Studies (14)].
No data are available to make dose recommendations for pediatric patients with renal impairment.
Not Recommended in Patients with Severe Hepatic Impairment
STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Not Recommended During Pregnancy
STRIBILD is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters [see Use in Specific Populations (8.1)].
STRIBILD should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with STRIBILD [see Use in Specific Populations (8.1)].
Each STRIBILD tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil).
The tablets are green, capsule shaped, film coated, and debossed with "GSI" on one side and the number "1" surrounded by a square box ( 
) on the other side.
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to STRIBILD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
STRIBILD is not recommended during pregnancy [see Dosage and Administration (2.5)]. A literature report evaluating the pharmacokinetics (PK) of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters (see Data).
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, elvitegravir, cobicistat, emtricitabine, and TDF use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no significant difference in the overall risk of major birth defects for elvitegravir, cobicistat, emtricitabine, or TDF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%.
In animal studies, no adverse developmental effects were observed when the components of STRIBILD were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rats and rabbits, respectively, elvitegravir), 1.8 and 4.3 times (rats and rabbits, respectively, cobicistat), and 60 and 120 times (mice and rabbits, respectively, emtricitabine) the exposure at the recommended daily dose of these components in STRIBILD, and at 14 and 19 times (rats and rabbits, respectively, TDF) the human dose based on body surface area comparisons [see Data]. Likewise, no adverse developmental effects were seen when elvitegravir or cobicistat was administered to rats through lactation at exposures up to 18 times or 1.2 times, respectively, the exposure at the recommended daily therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily therapeutic dose. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 2.7 times the exposure at the recommended daily dosage of STRIBILD.
Data
Human Data
A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.
Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of STRIBILD are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.
Elvitegravir: Based on prospective reports to the APR of exposures to elvitegravir-containing regimens during pregnancy resulting in live births (including over 300 exposed in the first trimester and over 60 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.4% (95% CI: 1.7% to 6.0%) and 1.5% (95% CI: 0% to 7.9%) following first and second/third trimester exposure, respectively, to elvitegravir-containing regimens.
Cobicistat: Based on prospective reports to the APR of exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 400 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.2% to 6.3%) and 1.2% (95% CI: 0.0% to 6.5%) following first and second/third trimester exposure, respectively, to cobicistat-containing regimens.
Emtricitabine: Based on prospective reports to the APR of exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3,600 exposed in the first trimester and over 1,400 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.1% to 3.2%) and 2.4% (95% CI: 1.6% to 3.3%) following first and second/third trimester exposure, respectively, to emtricitabine-containing regimens.
Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 1,800 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 2.9%) and 2.4% (95% CI: 1.8% to 3.2%) following first and second/third trimester exposure, respectively, to TDF-containing regimens.
Animal Data
Elvitegravir: Elvitegravir was administered orally to pregnant rats (at 0, 300, 1000, and 2000 mg/kg/day), and rabbits (at 0, 50, 150, and 450 mg/kg/day) through organogenesis (on gestation days 7 through 17 and days 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with elvitegravir in rats at exposures (AUC) approximately 23 times higher and in rabbits at approximately 0.2 times higher than human exposures at the recommended daily dose. In a pre- and postnatal developmental study in rats, elvitegravir was administered orally at doses of 0, 300, 1000, and 2000 mg/kg from gestation day 7 to day 20 of lactation. At doses of 2000 mg/kg/day of elvitegravir, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 18 times the human exposures at the recommended daily dose.
Cobicistat: Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.8 times higher than human exposures at the recommended daily dose.
In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.3 times higher than human exposures at the recommended daily dose. In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose.
Emtricitabine: Emtricitabine was administered orally to pregnant mice (at 0, 250, 500, or 1000 mg/kg/day), and rabbits (at 0, 100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, emtricitabine was administered orally at doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.
Tenofovir DF: Tenofovir DF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of STRIBILD.
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Based on limited published data, emtricitabine and tenofovir have been shown to be present in human breast milk. It is not known whether elvitegravir or cobicistat are present in human breast milk, while elvitegravir and cobicistat have been shown to be present in rat milk (see Data).
It is not known if the components of STRIBILD affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving STRIBILD (see Data).
Animal Data
Elvitegravir: During the prenatal and postnatal developmental toxicology study at doses up to 2000 mg/kg/day mean elvitegravir milk to plasma ratio of 0.1 was measured 30 minutes after administration to rats on lactation day 14.
Cobicistat: During the prenatal and postnatal developmental toxicology study at doses up to 75 mg/kg/day mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.
Pediatric Use
The pharmacokinetics, safety, and virologic and immunologic responses were evaluated in 50 treatment-naïve, HIV-1 infected subjects aged 12 to less than 18 years weighing at least 35 kg receiving STRIBILD through 48 weeks in an open-label trial (Study 112). The safety and efficacy of STRIBILD in these subjects was similar to that in antiretroviral treatment-naïve adults [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)].
Safety and effectiveness of STRIBILD in pediatric patients less than 12 years of age or weighing less than 35 kg have not been established.
Geriatric Use
Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of STRIBILD in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
Renal Impairment
Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per min is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD as dose interval adjustment required for emtricitabine and TDF cannot be achieved [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
No data are available to make dose recommendations for pediatric patients with renal impairment.
Clinical Trials in Adult Subjects with Mild to Moderate Renal Impairment
In Study 118, 33 HIV-1 infected treatment-naïve subjects with mild to moderate renal impairment (eGFR by Cockcroft-Gault method between 50 and 89 mL/minute) were studied in an open-label clinical trial evaluating the safety of 48 weeks of treatment with STRIBILD. After 48 weeks of treatment, the mean change in serum creatinine was 0.17 ± 0.14 mg/dL and the mean change in eGFR by Cockcroft-Gault method was −6.9 ± 9.0 mL/minute for subjects treated with STRIBILD.
Twelve of the 33 subjects studied had baseline eGFR between 50 and 70 mL/minute. Three subjects, all with baseline eGFR between 50–60 mL/minute, discontinued STRIBILD due to a renal adverse event. The safety of STRIBILD among 21 of the 33 subjects with baseline eGFR greater than or equal to 70 mL/minute was consistent with the safety profile in studies 102 and 103.
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. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed below [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].
- Alpha 1-adrenoreceptor antagonist: alfuzosin
- Anticonvulsants: carbamazepine, phenobarbital, phenytoin
- Antimycobacterial: rifampin
- Antipsychotics: lurasidone, pimozide
- Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
- Herbal Products: St. John's wort (Hypericum perforatum)
- Lipid-modifying Agents: lomitapide, lovastatin, simvastatin
- Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio® for the treatment of pulmonary arterial hypertension
- Sedative/hypnotics: triazolam, orally administered midazolam