Combination Products

Adults and pediatric patients 12 years of age and older with body weight at least 40 kg
(at least 88 lbs): The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Renal Impairment: Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

Rifampin Coadministration: When ATRIPLA is administered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended

DOSAGE FORMS AND STRENGTHS
ATRIPLA is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil). The tablets are pink, capsule-shaped, film-coated, debossed with "123" on one side and plain-faced on the other side.

Adults and Adolescents Weighing ≥30 kg
The recommended oral dose of COMBIVIR in HIV-1-infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) twice daily.

Pediatric Patients
The recommended oral dosage of scored COMBIVIR Tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered twice daily.

Before prescribing COMBIVIR Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a COMBIVIR Tablet, the liquid oral formulations should be prescribed: EPIVIR® (lamivudine) Oral Solution and RETROVIR® (zidovudine) Syrup.

Patients Requiring Dosage Adjustment
Because COMBIVIR is a fixed-dose combination tablet, it should not be prescribed for pediatric patients weighing less than 30 kg or patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 50 mL/min), patients with hepatic impairment, or patients experiencing dose-limiting adverse reactions. Liquid and solid oral formulations of the individual components of COMBIVIR are available for these populations.

DOSAGE FORMS AND STRENGTHS
COMBIVIR Tablets contain 150 mg of lamivudine and 300 mg of zidovudine. The tablets are white, scored, film-coated, modified capsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GX FC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet).

This indication is based on safety and efficacy analyses through 96 weeks from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects.

The following points should be considered when initiating therapy with COMPLERA:
   -More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL.
   -Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to subjects with CD4+ cell count greater than or equal to 200 cells/mm3.
   -The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
   -More subjects treated with rilpivirine developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz.
   -COMPLERA is not recommended for patients less than 18 years of age.

DOSAGE AND ADMINISTRATION
Recommended dose: One tablet (containing 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate) taken once daily with a meal.
Dose in renal impairment: Should not be administered in patients with creatinine clearance below 50 mL per minute.

DOSAGE FORMS AND STRENGTHS
Tablets: 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate.

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 DESCOVY. If appropriate, initiation of anti-hepatitis B therapy may be warranted

Initial U.S. Approval:  2016

Mechanism of Action:
DESCOVY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC) and tenofovir alafenamide (TAF)

INDICATIONS AND USAGE:
DESCOVY is a two-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)

Limitations of Use:
DESCOVY is not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.

DOSAGE AND ADMINISTRATION

Testing: Prior to initiation of DESCOVY, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose and urine protein should be obtained. (2.1)
Recommended dosage: One tablet taken once daily with or without food in patients 12 years old and older with body weight at least 35 kg and a creatinine clearance greater than or equal to 30 mL per minute. (2.2)
Renal impairment: DESCOVY is not recommended in patients with estimated creatinine clearance below 30 mL per minute. (2.3)

HOW SUPPLIED:
DOSAGE FORMS AND STRENGTHS
Tablets: 200 mg of FTC and 25 mg of TAF

Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases α, β, and γ.

Dosing (Adults):  One tablet (abacavir 600 mg and lamivudine 300 mg) once daily.

Renal Dosing: crcl <50 ml/min: Use not recommended.
Hepatic Impairment: Use not recommended.

Supplied: Tablet: Abacavir 600 mg & lamivudine 300 mg

Initial U.S. Approval:  2015

Mechanism of Action: GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide

INDICATIONS AND USAGE: GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older 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 per 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 GENVOYA.

HOW SUPPLIED:
Each GENVOYA tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF) (equivalent to 11.2 mg of tenofovir alafenamide fumarate).

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 ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].

Initial U.S. Approval:  2016

Mechanism of Action:
ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and tenofovir alafenamide

INDICATIONS AND USAGE:
ODEFSEY is a three-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY.

DOSAGE AND ADMINISTRATION:
-Testing: prior to initiation of ODEFSEY, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. (2.1)
-Recommended dosage: one tablet taken orally once daily with a meal. (2.2)
-After initiation of ODEFSEY, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. (2.3)
-Renal impairment: ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute. (2.4)

HOW SUPPLIED:
DOSAGE FORMS AND STRENGTHS
Tablets: 200 mg of FTC, 25 mg of RPV and 25 mg of TAF.

Mechanism of Action: STRIBILD is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF

INDICATIONS AND USAGE:  STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir DF, both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA <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.

DOSAGE AND ADMINISTRATION
ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.
Recommended dosage: One tablet taken once daily with food. (2.1)

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. (2.2)

DOSAGE FORMS AND STRENGTHS
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate.

CONTRAINDICATIONS
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 adverse events.

Strongly induce CYP3A which may lead to lower exposure of one or more components and loss of efficacy of STRIBILD and possible resistance.

WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. (5.3)
Avoid coadministration with other anti-retroviral products: Do not use with products containing any of the components of STRIBILD (cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate), including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, TYBOST, VIREAD, or VITEKTA; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. (5.4)
Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of STRIBILD and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs. (5.5)
Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.6)
Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.7)
Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.8)

TRIZIVIR can be taken with or without food.

Adults and Adolescent Patients
The recommended oral dose of TRIZIVIR is one tablet twice daily.

TRIZIVIR is not recommended in adolescents who weigh less than 40 kg because it is a fixed-dose tablet and cannot be dose adjusted.

Dosage Adjustment
Because it is a fixed-dose combination, TRIZIVIR should not be prescribed for:

•patients requiring dosage adjustment such as those with creatinine clearance <50 mL/min.
•patients with hepatic impairment.

Supplied:
Tablet [film coated]: Abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg

Recommended Dose for Treatment of HIV-1 Infection
The recommended dose of TRUVADA in adults and in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Recommended Dose for Pre-exposure Prophylaxis
The dose of TRUVADA in HIV-1 uninfected adults is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Dose Adjustment for Renal Impairment
Treatment of HIV-1 Infection

Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment [See EMTRIVA or VIREAD Package Insert]. Therefore, adjust the dosing interval of TRUVADA in HIV-1 infected adult patients with baseline creatinine clearance 30-49 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].

No dose adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). No data are available to make dose recommendations in pediatric patients with renal impairment.

 Table 1 Dosage Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance

*Calculated using ideal (lean) body weight

 Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment [See Warnings and Precautions (5.3)].

Pre-exposure Prophylaxis
Do not use TRUVADA for a PrEP indication in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min.

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use.

DOSAGE FORMS AND STRENGTHS
TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side and with "701" on the other side.

Initial U.S. Approval:  2014

Mechanism of Action:  Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

INDICATIONS AND USAGE:  TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

Limitations of Use:
TRIUMEQ alone is not recommended for use in patients with current or past history of resistance to any components of TRIUMEQ [see Microbiology (12.4)].
TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See full prescribing information for dolutegravir.

HOW SUPPLIED: Tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.