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mechanism of action is Breast Cancer Resistance Protein Inhibitors [MoA], Nucleoside Reverse Transcriptase Inhibitors [MoA], Cytochrome P450 2D6 Inhibitors [MoA], Cytochrome P450 3A Inhibitors [MoA], HIV Integrase Inhibitors [MoA], Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA], Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA], Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA], Cytochrome P450 2C9 Inducers [MoA] or P-Glycoprotein Inhibitors [MoA]

Stribild

(Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate)

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Dosage & Administration

* Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (

2.1 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: One tablet taken once daily with food. (

2.2 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 in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. (

2.3 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.

)

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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

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy

[see Dosage and Administration (2.1)]

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued emtricitabine or TDF, two of the components of STRIBILD. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

]

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

14 CLINICAL STUDIES

14.1 Description of Clinical Trials

The efficacy and safety of STRIBILD were evaluated in the studies summarized in Table 13.

Table 13 Trials Conducted with STRIBILD in Subjects with HIV-1 Infection
Trial	Population	Study Arms (N)Randomized and dosed.	Timepoint (Week)
Study 102Randomized, double blind, active-controlled trial.^,Patients had estimated creatinine clearance greater than or equal to 70 mL/min at screening.	Adults with no antiretroviral treatment history	STRIBILD (348) ATRIPLA (352)	144
Study 103 ^,	Adults with no antiretroviral treatment history	STRIBILD (353) TRUVADA+atazanavir+ritonavir (355)	144
Study 115 ^,Randomized, open label, active-controlled trial.	Virologically suppressed adults without a history of virologic failureHIV-1 RNA less than 50 copies per mL.	STRIBILD (293) TRUVADA+PI+ritonavir (140)	48
Study 121 ^,		STRIBILD (291) TRUVADA+NNRTI (143)	48
Study 112Open label trial.	Treatment-naïve adolescents between the ages of 12 to less than 18 years	STRIBILD (50)	48

14.2 Clinical Trial Results in HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History

In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (N=352) once daily. The mean age was 38 years (range 18–67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm³(range 3–1348), and 13% had CD4+ cell counts less than 200 cells per mm³. Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg + RTV 100 mg + TRUVADA (N=355) once daily. The mean age was 38 years (range 19–72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log₁₀copies per mL (range 1.7–6.6). The mean baseline CD4+ cell count was 370 cells per mm³(range 5–1132), and 13% had CD4+ cell count less than 200 cells per mm³. Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.

In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).

Treatment outcomes of Study 102 and Study 103 through 144 weeks are presented in Table 14.

Table 14 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 144Week-144 window is between Day 967 and 1050 (inclusive).
	Study 102		Study 103
	STRIBILD N=348	ATRIPLA N=352	STRIBILD N=353	ATV+RTV+TRUVADA N=355
Virologic Success HIV-1 RNA <50 copies/mL	80%	75%	78%	75%
Treatment Difference	4.9% (95% CI = −1.3%, 11.1%)		3.1% (95% CI = −3.2%, 9.4%)
Virologic FailureIncludes subjects who had ≥50 copies/mL in the Week-144 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.	7%	10%	8%	7%
No Virologic Data in Week 144 Window
Discontinued Study Drug Due to AE or DeathIncludes patients who discontinued due to an adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.	6%	8%	6%	8%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.	5%	7%	8%	9%
Missing Data During Window but on Study Drug	1%	0%	1%	1%

In Study 102, the mean increase from baseline in CD4+ cell count at Week 144 was 298 cells per mm³in the STRIBILD-treated subjects and 272 cells per mm³in the ATRIPLA -treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 144 was 261 cells per mm³in the STRIBILD-treated subjects and 269 cells per mm³in the ATV+RTV+TRUVADA-treated subjects.

14.3 Clinical Trial Results in Virologically Suppressed HIV-1 Infected Adult Subjects with No History of Virologic Failure

In Study 115, subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, with no current or past history of resistance to the antiretroviral components of STRIBILD, and must have been suppressed (HIV-1 RNA <50 copies/mL) on a ritonavir-boosted PI in combination with TRUVADA for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to STRIBILD (STRIBILD arm, N=293; randomized and dosed) or stay on their baseline antiretroviral regimen for 48 weeks (PI+RTV+TRUVADA arm, N=140; randomized and dosed). Subjects had a mean age of 41 years (range 21–76), 86% were male, 80% were White, and 15% were Black. The mean baseline CD4+ cell count was 610 cells per mm³(range 74–1919). At screening subjects were receiving atazanavir (40%), darunavir (40%), lopinavir (17%), fosamprenavir (3%), or saquinavir (<1%) as the PI in their regimen.

In Study 121, subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, with no current or past history of resistance to the antiretroviral components of STRIBILD, and must have been suppressed (HIV-1 RNA <50 copies/mL) on a NNRTI in combination with TRUVADA for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to STRIBILD (STRIBILD arm, N=291; randomized and dosed) or stay on their baseline antiretroviral regimen for 48 weeks (NNRTI+TRUVADA arm, N=143; randomized and dosed). Subjects had a mean age of 41 years (range 20–72); 93% were male, 78% were White, and 17% were Black. The mean baseline CD4+ cell count was 588 cells per mm³(range 100–1614). Randomization was stratified by use of efavirenz in the baseline regimen. At screening subjects were receiving efavirenz (78%) (predominantly as ATRIPLA [74%]), nevirapine (17%), rilpivirine (4%) (as COMPLERA^®[4%]), or etravirine (1%) as the NNRTI in their regimen.

Virologic outcomes of Study 115 and Study 121 are presented in Table 15. Five treated subjects were excluded from the efficacy analysis: in Study 115, three STRIBILD subjects had protocol-prohibited documented resistance and one PI+RTV+TRUVADA subject was not on a protease inhibitor-based regimen at screening; in Study 121, one STRIBILD subject had protocol-prohibited documented resistance.

Table 15 Virologic Outcomes of Randomized Treatment in Study 115 and Study 121 at Week 48
	Study GS-US-236-0115Week-48 window is between Day 295 and 378 (inclusive).		Study GS-US-236-0121
	STRIBILD N=290	PI+RTV+TRUVADA N=139	STRIBILD N=290	NNRTI+TRUVADA N=143
Virologic Success HIV-1 RNA <50 copies/mL	94%	87%	93%	88%
Virologic FailureIncludes subjects who had ≥50 copies/mL in the Week-48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.	1%	1%	1%	1%
No Virologic Data in Week 48 Window	6%	12%	6%	11%
Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.	2%	1%	2%	1%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.	4%	10%	4%	9%
Missing Data During Window but on Study Drug	0%	0%	0%	1%

14.4 Clinical Trial Results in HIV-1Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18 Years

In Study 112, the efficacy, safety, and pharmacokinetics of STRIBILD were evaluated in a single group, open-label trial in HIV-1 infected treatment-naïve adolescents aged 12 to less than 18 years of age and weighing at least 35 kg (N=50). Mean age was 15 years (range 12–17); 70% were male, 68% black, and 28% Asian. At baseline, mean plasma HIV-1 RNA was 4.60 log₁₀copies per mL (range 3.18–5.73), mean CD4+ cell count was 399 cells per mm³(range 133–734), and mean CD4+ percentage was 20.9% (range 4.5%–41.1%). Twenty percent had baseline plasma HIV-1 RNA >100,000 copies per mL.

At Week 48, 44 of 50 (88%) adolescent patients treated with STRIBILD achieved HIV-1 RNA <50 copies per mL and 4 had HIV-1 RNA ≥50 copies per mL; 1 patient discontinued study drug; 1 had no virologic data at Week 48. The mean decrease from baseline in HIV-1 RNA was −3.16 log₁₀copies per mL; mean increase from baseline in CD4+ cell count was 229 cells per mm³. No emergent resistance to STRIBILD was detected through Week 48.

]

Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (
2.1 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: One tablet taken once daily with food. (
2.2 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 in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. (
2.3 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.
)

Pregnancy: Not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during pregnancy. STRIBILD should not be initiated in pregnant individuals. (
2.5 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)]
.
,
8.1 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: Breastfeeding is not recommended due to the potential for HIV transmission. (
8.2 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.
)
Pediatrics: Not recommended for patients less than 12 years of age or weighing less than 35 kg. (
8.4 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.
)

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

7.5 Established and Other Potentially Significant Interactions

Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD or the components of STRIBILD (elvitegravir, cobicistat, emtricitabine, and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction

see Clinical Pharmacology (12.3)].

The table includes potentially significant interactions but is not all inclusive

[see Contraindications (4)

and

Clinical Pharmacology (12.3)].

In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.

Coadministration of STRIBILD in patients on tadalafil:

Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.

Use of PDE-5 inhibitors for erectile dysfunction:

The below PDE-5 inhibitors can be used along with increased monitoring for PDE-5-inhibitor associated adverse events:

Sildenafil at a single dose not exceeding 25 mg in 48 hours, or
Tadalafil at a single dose not exceeding 10 mg in 72 hours, or
Vardenafil at a single dose not exceeding 2.5 mg in 72 hours

Table 5 Established and Other Potentially SignificantThis table is not all inclusive.Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration↑=Increase, ↓=Decrease	Clinical Comment
Alpha 1-adrenoreceptor antagonist: alfuzosin	↑ alfuzosin	Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.
Antiarrhythmics: e.g., amiodarone bepridil digoxinIndicates that a drug-drug interaction trial was conducted. disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine	↑ antiarrhythmics ↑ digoxin	Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials: clarithromycin	↑ clarithromycin ↑ cobicistat	Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%.
Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban	↑ apixaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration with STRIBILD depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information.
	↑ rivaroxaban	Coadministration of rivaroxaban with STRIBILD is not recommended because it may lead to an increased bleeding risk.
	↑ betrixaban ↑ dabigatran ↑ edoxaban	Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as STRIBILD depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
warfarin	Effect on warfarin unknown	Monitor international normalized ratio (INR) upon coadministration of warfarin with STRIBILD.
Anticonvulsants: carbamazepine phenobarbital phenytoin	↓ elvitegravir ↓ cobicistat	Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance.
oxcarbazepine		Alternative anticonvulsants should be considered when STRIBILD is coadministered with oxcarbazepine.
clonazepam ethosuximide	↑ clonazepam ↑ ethosuximide	Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine	↑ SSRIs (except sertraline) ↑ TCAs ↑ trazodone	Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD.
Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion
trazodone
Antifungals: itraconazole ketoconazole voriconazole	↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole	When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout: colchicine	↑ colchicine	STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifampin	↓ elvitegravir ↓ cobicistat	Coadministration with rifampin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance .
rifabutin rifapentine		Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Antiplatelets:
ticagrelor clopidogrel	↑ ticagrelor ↓ clopidogrel active metabolite	Coadministration with ticagrelor is not recommended. Coadministration with clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.
Antipsychotics:
lurasidone	↑ lurasidone	Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions.
pimozide	↑ pimozide	Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
quetiapine	↑ quetiapine	Initiation of STRIBILD in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking STRIBILD : Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Other antipsychotics e.g., perphenazine risperidone thioridazine	↑ antipsychotic	A decrease in the dose of antipsychotics that are metabolized by CYP3A4 or CYP2D6 may be needed when coadministered with STRIBILD.
Beta-Blockers: e.g., metoprolol timolol	↑ beta-blockers	Clinical monitoring is recommended and a dose decrease of the beta-blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers: e.g., amlodipine diltiazem felodipine nicardipine nifedipine verapamil	↑ calcium channel blockers	Clinical monitoring is recommended upon coadministration of calcium channel blockers with STRIBILD.
Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone	↓ elvitegravir ↓ cobicistat ↑ corticosteroids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to elvitegravir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine	↑ ergot derivatives	Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir	↑ tenofovir	The safety of increased tenofovir concentrations in the setting of HARVONI^®(ledipasvir/sofosbuvir) and STRIBILD has not been established. Coadministration is not recommended. Patients receiving STRIBILD concomitantly with EPCLUSA^®(sofosbuvir/velpatasvir) or VOSEVI^®(sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ elvitegravir ↓ cobicistat	Coadministration is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance.
Hormonal Contraceptives: drospirenone/ethinyl estradiol levonorgestrel norgestimate/ethinyl estradiol	↑ drospirenone ↑ levonorgestrel ↑ norgestimate ↓ ethinyl estradiol	Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with STRIBILD. Plasma concentrations of drospirenone may be increased when coadministered with cobicistat- containing products. Clinical monitoring is recommended due to the potential for hyperkalemia. The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than drospirenone, levonorgestrel, or norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g., cyclosporine sirolimus tacrolimus	↑ immuno-suppressants	Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Lipid-modifying Agents: HMG-CoA Reductase Inhibitors:
lovastatin simvastatin	↑ lovastatin ↑ simvastatin	Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.
atorvastatin	↑ atorvastatin	Initiate atorvastatin with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety (e.g., myopathy). Do not exceed a dosage of atorvastatin 20 mg daily.
Other Lipid-modifying Agents: lomitapide	↑ lomitapide	Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases.
Narcotic Analgesics: buprenorphine/naloxone	↑ buprenorphine ↑ norbuprenorphine ↓ naloxone	Patients should be closely monitored for sedation and cognitive effects.
fentanyl	↑ fentanyl	Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.
tramadol	↑ tramadol	A dose decrease may be needed for tramadol with concomitant use.
Inhaled Beta Agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol and STRIBILD is not recommended because it may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Medications or Oral Supplements Containing Polyvalent Cations (e.g., Mg, Al, Ca, Fe, Zn): calcium or iron supplements, including multivitamins cation-containing antacids or laxatives sucralfate buffered medications	↓ elvitegravir	Separate STRIBILD and administration of medications, antacids, or oral supplements containing polyvalent cations by at least 2 hours.
Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil	↑ PDE-5 inhibitors	Coadministration of sildenafil with STRIBILD is contraindicated when used for treatment of pulmonary arterial hypertension (PAH), due to potential for PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of tadalafil for PAH: Coadministration of tadalafil in patients on STRIBILD:
Sedative/hypnotics:
midazolam (oral), triazolam	↑ midazolam ↑ triazolam	Coadministration with triazolam or orally administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentrations of these benzodiazepines.
Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem	↑ sedatives/hypnotics	Coadministration of parenteral midazolam with STRIBILD should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.

and

12.3 Pharmacokinetics

The pharmacokinetic properties of the components of STRIBILD are provided in Table 6. The multiple dose pharmacokinetic parameters of elvitegravir, cobicistat, emtricitabine, and tenofovir are provided in Table 7.

Table 6 Pharmacokinetic Properties of the Components of STRIBILD
	Elvitegravir	Cobicistat	Emtricitabine	Tenofovir
NC=Not Calculated
Absorption
T_max(h)	4	3	3	2
Effect of light meal (relative to fasting)Values refer to mean systemic exposure (90% confidence interval). STRIBILD light meal=~373 kcal, 20% fat; STRIBILD high fat meal=~800 kcal, 50% fat. Increase = ↑; Decrease = ↓	↑34% (↑19, ↑51)	↑3% (↓10, ↑17)	↓5% (↓9, 0)	↑24% (↑18, ↑30)
Effect of high fat meal (relative to fasting)	↑87% (↑66, ↑110)	↓17% (↓27, ↓5)	↓4% (↓8, 0)	↑23% (↑17, ↑29)
Distribution
% Bound to human plasma proteins	~99	~98	<4	<0.7
Source of protein binding data	Ex vivo	In vitro	In vitro	In vitro
Blood-to-plasma ratio	0.73	0.5	0.6	NC
Metabolism
Metabolism	CYP3A (major) UGT1A1/3 (minor)	CYP3A (major) CYP2D6 (minor)	Not significantly metabolized
Elimination
Major route of elimination	Metabolism		Glomerular filtration and active tubular secretion
T_1/2(h)t_1/2values refer to median terminal plasma half-life.	12.9	3.5	10	12–18
% Of dose excreted in urineDosing in mass balance studies: elvitegravir (single dose administration of [¹⁴C] elvitegravir, coadministered with 100 mg RTV); cobicistat (single-dose administration of [¹⁴C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [¹⁴C] emtricitabine after multiple dosing of emtricitabine for ten days); mass balance study not conducted for tenofovir.	6.7	8.2	70	70–80
% Of dose excreted in feces	94.8	86.2	13.7	NC

Table 7 Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects
Parameter Mean ± SD [range, min:max]	ElvitegravirFrom Population Pharmacokinetic analysis, N=419.	CobicistatFrom Intensive Pharmacokinetic analysis, N=61–62, except cobicistat C_troughN=53.	Emtricitabine	Tenofovir
SD=Standard Deviation
C_max (microgram per mL)	1.7 ± 0.4 [0.4:3.7]	1.1 ± 0.4 [0.1:2.1]	1.9 ± 0.5 [0.6:3.6]	0.45 ± 0.2 [0.2:1.2]
AUC_tau (microgram∙hour per mL)	23.0 ± 7.5 [4.4:69.8]	8.3 ± 3.8 [0.5:18.3]	12.7 ± 4.5 [5.2:34.1]	4.4 ± 2.2 [2.1:18.2]
C_trough (microgram per mL)	0.45 ± 0.26 [0.05:2.34]	0.05 ± 0.13 [0.01:0.92]	0.14 ± 0.25 [0.04:1.94]	0.10 ± 0.08 [0.04:0.58]

Specific Populations

Geriatric Patients

The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients

[see Use in Specific Populations (8.5)].

Pediatric Patients

Exposures (AUC) of elvitegravir and tenofovir in 14 pediatric subjects aged 12 to less than 18 years who received STRIBILD in Study 112 were increased by 30% and 37%, respectively, compared with exposures achieved in adults following administration of STRIBILD, but were deemed acceptable based on the overall safety profile of these agents and exposure-safety assessments. The other components of STRIBILD had similar exposures in adolescents compared with adults

[see Use in Specific Populations (8.4)].

Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. TDF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects less than 12 years of age have not been established

[see Use in Specific Populations (8.4)].

Race, Gender

No clinically significant differences in pharmacokinetics of STRIBILD have been identified based on race or gender.

Patients with Renal Impairment

Elvitegravir and Cobicistat:

A study of the pharmacokinetics of cobicistat+elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per minute). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

Emtricitabine and TDF:

The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per minute or with end-stage renal disease requiring dialysis (ESRD) (Table 8)

[see Warnings and Precautions (5.2)and Use in Specific Populations (8.6)].

Table 8 Pharmacokinetic Parameters of Emtricitabine200 mg, single dose of emtricitabineand Tenofovir300 mg, single dose of TDFin Adults with Varying Degrees of Renal Function
Parameter Mean ± SD	Creatinine Clearance (mL/min)
Parameter Mean ± SD	>80	50–80	30–49	<30	ESRDESRD subjects requiring dialysis
SD=Standard Deviation
Emtricitabine	N=6	N=6	N=6	N=5	N=5
AUC_inf (microgram∙hr per mL)	11.8 ± 2.9	19.9 ± 1.2	25.1 ± 5.7	33.7± 2.1	53.2 ± 9.9
C_max (microgram per mL)	2.2 ± 0.6	3.8 ± 0.9	3.2 ± 0.6	2.8 ± 0.7	2.8 ± 0.5
Tenofovir	N=3	N=10	N=8	N=11	N=9
AUC_inf (microgram∙hr per mL)	2.18 ± 0.26	3.06 ± 0.93	6.01 ± 2.50	15.98 ± 7.22	44.90 ± 12.96
C_max (microgram per mL)	0.34 ± 0.03	0.33 ± 0.06	0.37 ± 0.16	0.60 ± 0.19	1.06 ± 0.25

Patients with Hepatic Impairment

Elvitegravir and Cobicistat:

A study of the pharmacokinetics of cobicistat+elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied

[see Use in Specific Populations (8.7)].

Emtricitabine:

The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir DF:

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in healthy subjects with moderate to severe hepatic impairment (Child-Pugh Class C). No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.

Hepatitis B and/or Hepatitis C Virus Coinfection

Elvitegravir:

Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.

Cobicistat:

There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and TDF:

The pharmacokinetics of emtricitabine and TDF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Assessment of Drug Interactions

[see Contraindications (4)and Drug Interactions (7)]

The drug-drug interaction studies described were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or RTV), or cobicistat administered alone.

As STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretroviral agents is not provided

The effects of coadministered drugs on the exposure of elvitegravir, emtricitabine, and tenofovir are shown in Table 9, Table 10, and Table 11 respectively. The effects of elvitegravir plus cobicistat, or cobicistat, or emtricitabine on the exposure of coadministered drugs are shown in Table 12. For information regarding clinical recommendations,

[see Drug Interactions (7)]

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers.
Coadministered Drug	Dose of Coadministered Drug	Elvitegravir Dose (mg)	Cobicistat or RTV Booster Dose (mg)	N	Mean Ratio of Elvitegravir Pharmacokinetic Parameters (90% CI); No Effect=1.00
Coadministered Drug	Dose of Coadministered Drug	Elvitegravir Dose (mg)	Cobicistat or RTV Booster Dose (mg)	N	C_max	AUC	C_min
Maximum strength antacidMaximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL.	20 mL single dose given 4 hours before elvitegravir	50 single dose	RTV 100 single dose	8	0.95 (0.84, 1.07)	0.96 (0.88, 1.04)	1.04 (0.93, 1.17)
	20 mL single dose given 4 hours after elvitegravir			10	0.98 (0.88, 1.10)	0.98 (0.91, 1.06)	1.00 (0.90, 1.11)
	20 mL single dose given 2 hours before elvitegravir			11	0.82 (0.74, 0.91)	0.85 (0.79, 0.91)	0.90 (0.82, 0.99)
	20 mL single dose given 2 hours after elvitegravir			10	0.79 (0.71, 0.88)	0.80 (0.75, 0.86)	0.80 (0.73, 0.89)
Atorvastatin	10 mg single dose	150 once dailyStudy conducted with GENVOYA^®(elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide).	Cobicistat 150 once daily	16	0.91 (0.85, 0.98)	0.92 (0.87, 0.98)	0.88 (0.81, 0.96)
Carbamazepine	200 mg twice daily	150 once daily	Cobicistat 150 once daily	12	0.55 (0.49, 0.61)	0.31 (0.28, 0.33)	0.03 (0.02, 0.04)
Famotidine	40 mg once daily given 12 hours after elvitegravir	150 once daily	Cobicistat 150 once daily	10	1.02 (0.89, 1.17)	1.03 (0.95, 1.13)	1.18 (1.05, 1.32)
Famotidine	40 mg once daily given simultaneously with elvitegravir	150 once daily	Cobicistat 150 once daily	16	1.00 (0.92, 1.10)	1.03 (0.98, 1.08)	1.07 (0.98, 1.17)
Ketoconazole	200 mg twice daily	150 once daily	RTV 100 once daily	18	1.17 (1.04, 1.33)	1.48 (1.36, 1.62)	1.67 (1.48, 1.88)
Ledipasvir/Sofosbuvir	90/400 mg once daily	150 once daily	Cobicistat 150 once dailyPercent change of cobicistat PK parameters (90% CI) was 1.25 (1.18 to 1.32) for C_max, 1.59 (1.49 to 1.70) for AUC, and 4.25 (3.47 to 5.22) for C_min.	29	0.88 (0.82, 0.95)	1.02 (0.95, 1.09)	1.36 (1.23, 1.49)
Omeprazole	40 mg once daily given 2 hours before elvitegravir	50 once daily	RTV 100 once daily	9	0.93 (0.83, 1.04)	0.99 (0.91, 1.07)	0.94 (0.85, 1.04)
	20 mg once daily given 2 hours before elvitegravir	150 once daily	Cobicistat 150 once daily	11	1.16 (1.04, 1.30)	1.10 (1.02, 1.19)	1.13 (0.96, 1.34)
	20 mg once daily given 12 hours after elvitegravir	150 once daily	Cobicistat 150 once daily	11	1.03 (0.92, 1.15)	1.05 (0.93, 1.18)	1.10 (0.92, 1.32)
Rifabutin	150 mg once every other day	150 once daily	Cobicistat 150 once daily	12	0.91 (0.84, 0.99)	0.79 (0.74, 0.85)	0.33 (0.27, 0.40)
Rosuvastatin	10 mg single dose	150 once daily	Cobicistat 150 once daily	10	0.94 (0.83, 1.07)	1.02 (0.91, 1.14)	0.98 (0.83, 1.16)
Sertraline	50 mg single dose	150 once daily	Cobicistat 150 once daily	19	0.88 (0.82, 0.93)	0.94 (0.89, 0.98)	0.99 (0.93, 1.05)
Sofosbuvir/Velpatasvir	400/100 mg once daily	150 once dailyStudy conducted with STRIBILD.	Cobicistat 150 once daily ^,Percent change of cobicistat PK parameters (90% CI) was1.11 (1.06, 1.17) for C_max, 1.23 (1.17, 1.29) for AUC, and 1.71 (1.54, 1.90) for C_min.	24	0.93 (0.86, 1.00)	0.93 (0.87, 0.99)	0.97 (0.91, 1.04)
Sofosbuvir/Velpatasvir Voxilaprevir	400/100/100 + 100 Voxilaprevir once dailyStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.	150 once daily	Cobicistat 150 once daily	29	0.79 (0.75, 0.85)	0.94 (0.88, 1.00)	1.32 (1.17, 1.49)

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers.
Coadministered Drug	Dose of Coadministered Drug (mg)	Emtricitabine Dose (mg)	N	Mean Ratio of Emtricitabine Pharmacokinetic Parameters (90%CI); No Effect=1.00
Coadministered Drug	Dose of Coadministered Drug (mg)	Emtricitabine Dose (mg)	N	C_max	AUC	C_min
NC=Not calculated
Famciclovir	500 single dose	200 single dose	12	0.90 (0.80, 1.01)	0.93 (0.87, 0.99)	NC

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers.
Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)	N	Mean Ratio of Tenofovir Pharmacokinetic Parameters (90%CI); No Effect=1.00
Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)	N	C_max	AUC	C_min
Sofosbuvir/Velpatasvir	400/100 once daily	300 once dailyStudy conducted with STRIBILD.	24	1.36 (1.25, 1.47)	1.35 (1.29, 1.42)	1.45 (1.39, 1.51)

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir plus Cobicistat, Cobicistat, Emtricitabine, or STRIBILDAll interaction studies conducted in healthy volunteers.
Coadministered Drug	Dose of Coadministered Drug (mg)	Elvitegravir DoseNA=Not Applicable (mg)	Cobicistat Booster Dose (mg)	FTC Dose (mg)	N	Mean Ratio of Coadministered Drug Pharmacokinetic ParametersNC=Not Calculated(90% CI); No Effect=1.00
Coadministered Drug	Dose of Coadministered Drug (mg)	Elvitegravir DoseNA=Not Applicable (mg)	Cobicistat Booster Dose (mg)	FTC Dose (mg)	N	C_max	AUC	C_min
FTC=emtricitabine
Atorvastatin	10 single dose	150 once dailyStudy conducted with GENVOYA.	150 once daily	200 once daily	16	2.32 (1.91, 2.82)	2.60 (2.31, 2.93)	NC
Buprenorphine	16–24 once daily	150 once daily	150 once daily	NA	17	1.12 (0.98, 1.27)	1.35 (1.18, 1.55)	1.66 (1.43, 1.93)
Norbuprenorphine	16–24 once daily	150 once daily	150 once daily	NA	17	1.24 (1.03, 1.49)	1.42 (1.22, 1.67)	1.57 (1.31, 1.88)
Carbamazepine	200 twice daily	150 once daily	150 once daily	NA	12	1.40 (1.32, 1.49)	1.43 (1.36, 1.52)	1.51 (1.41, 1.62)
Carbamazepine-10,11-epoxide	200 twice daily	150 once daily	150 once daily	NA	12	0.73 (0.70, 0.78)	0.65 (0.63, 0.66)	0.59 (0.57, 0.61)
Desipramine	50 single dose	NA	150 once daily	NA	8	1.24 (1.08, 1.44)	1.65 (1.36, 2.02)	NC
Digoxin	0.5 single dose	NA	150 once daily	NA	22	1.41 (1.29, 1.55)	1.08 (1.00, 1.17)	NC
Famciclovir	500 single dose	NA	NA	200 single dose	12	0.93 (0.78, 1.11)	0.91 (0.84, 0.99)	NC
Ledipasvir	90/400 once daily	150 once daily	150 once daily	NA	29	1.63 (1.51, 1.75)	1.78 (1.64, 1.94)	1.91 (1.76, 2.08)
Sofosbuvir						1.33 (1.14, 1.56)	1.36 (1.21, 1.52)	NA
GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.						1.33 (1.22, 1.44)	1.44 (1.41, 1.48)	1.53 (1.47, 1.59)
Naloxone	4–6 once daily	150 once daily	150 once daily	NA	17	0.72 (0.61, 0.85)	0.72 (0.59, 0.87)	NA
Norgestimate/ ethinyl estradiol	0.180/0.215/ 0.250 norgestimate once daily	150 once dailyStudy conducted with STRIBILD.	150 once daily	200 once daily	13	2.08 (2.00, 2.17)	2.26 (2.15, 2.37)	2.67 (2.43, 2.92)
Norgestimate/ ethinyl estradiol	0.025 ethinyl estradiol once daily	150 once dailyStudy conducted with STRIBILD.	150 once daily	200 once daily	13	0.94 (0.86, 1.04)	0.75 (0.69, 0.81)	0.56 (0.52, 0.61)
R-Methadone	80–120 daily	150 once daily	150 once daily	NA	11	1.01 (0.91, 1.13)	1.07 (0.96, 1.19)	1.10 (0.95, 1.28)
S-Methadone	80–120 daily	150 once daily	150 once daily	NA	11	0.96 (0.87, 1.06)	1.00 (0.89, 1.12)	1.02 (0.89, 1.17)
Sofosbuvir	400/100 once daily	150 once daily	150 once daily	200 once daily	24	1.01 (0.85, 1.19)	1.24 (1.13, 1.37)	NA
GS-331007						1.13 (1.07, 1.18)	1.35 (1.30, 1.40)	1.45 (1.38, 1.52)
Velpatasvir						1.05 (0.93, 1.19)	1.19 (1.07, 1.34)	1.37 (1.22, 1.54)
Sofosbuvir	400/100/100 + 100 VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patientsonce daily	150 once daily	150 once daily	200 once daily	29	1.27 (1.09, 1.48)	1.22 (1.12, 1.32)	NC
GS-331007						1.28 (1.25, 1.32)	1.43 (1.39, 1.47)	NC
Velpatasvir						0.96 (0.89, 1.04)	1.16 (1.06, 1.27)	1.46 (1.30, 1.64)
Voxilaprevir						1.92 (1.63, 2.26)	2.71 (2.30, 3.19)	4.50 (3.68, 5.50)
Rifabutin	150 once every other day	150 once daily	150 once daily	NA	12	1.09 (0.98, 1.20)Comparison based on rifabutin 300 mg once daily.	0.92 (0.83, 1.03)	0.94 (0.85, 1.04)
25-O-desacetyl-rifabutin	150 once every other day	150 once daily	150 once daily	NA	12	4.84 (4.09, 5.74)	6.25 (5.08, 7.69)	4.94 (4.04, 6.04)
Rosuvastatin	10 single dose	150 once daily	150 single dose	NA	10	1.89 (1.48, 2.42)	1.38 (1.14, 1.67)	NC
Sertraline	50 single dose	150 once daily	150 once daily	200 once daily	19	1.14 (0.94, 1.38)	0.93 (0.77, 1.13)	NA

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

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