Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]
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Black Box Warning
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POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
See full prescribing information for complete Boxed Warning.
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Overview
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a combination of an HIV-1 integrase strand transfer inhibitor, a CYP3A inhibitor, and two HIV-1 nucleoside analog reverse transcriptase inhibitors that is FDA approved 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 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea and decreased bone mineral density.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated as a complete regimen for the treatment of HIV-1 infection in adults 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 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Dosing Information
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF).
- The recommended dosage of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is one tablet taken orally once daily with food in adults with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated as a complete regimen for the treatment of HIV-1 infection in 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 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Dosing Information
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF).
- The recommended dosage of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is one tablet taken orally once daily with food in pediatric patients 12 years of age and older with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in pediatric patients.
Contraindications
- Coadministration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and possible resistance) are listed in Table 1.
Warnings
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POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
See full prescribing information for complete Boxed Warning.
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- Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
- Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not approved for the treatment of chronic HBV infection and the safety and efficacy of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide have not been established in patients coinfected with HIV-1 and HBV.
- Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
- Patients coinfected with HIV-1 and HBV who discontinue elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
- If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
- The concomitant use of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and possible development of resistance.
- Possible clinically significant adverse reactions from greater exposures of concomitant drugs.
- See TABLE 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide therapy; review concomitant medications during elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide therapy; and monitor for the adverse reactions associated with the concomitant drugs.
- The concomitant use of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine, a component of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
- New Onset or Worsening Renal Impairment
- Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials.
- In clinical trials of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT).
- In clinical trials of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naïve subjects and in virologically suppressed subjects switched to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
- In a study of virologically suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for a median duration of 108 weeks, elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was permanently discontinued due to worsening renal function in three of 80 (4%) subjects with a baseline eGFR between 30 and 50 mL per minute and two of 162 (1%) with a baseline eGFR greater than or equal to 50 mL per minute.
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
- Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.
- It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and during therapy in all patients as clinically appropriate. Discontinue elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
- Cobicistat, a component of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration.
- The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
- Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals.
- Treatment with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials in Treatment-Naïve Adults
The primary safety assessment of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was based on Week 96 pooled data from 1,733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide once daily. The most common adverse reaction (all grades) reported in at least 10% of subjects in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group was nausea. The proportion of subjects who discontinued treatment with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide or STRIBILD® due to adverse events, regardless of severity, was 1% and 2%, respectively. Table 2 displays the frequency of adverse reactions (all grades) greater than or equal to 5% in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group.
The majority of events presented in Table 2 occurred at severity Grade 1.
Clinical Trials in Virologically Suppressed Adults
The safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically-suppressed adults was based on Week 96 data from 959 subjects in a randomized, open-label, active-controlled trial (Study 109) in which virologically-suppressed subjects were switched from a TDF-containing combination regimen to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. Overall, the safety profile of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in subjects in this study was similar to that of treatment-naïve subjects. Additional adverse reactions observed with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in Study 109 included suicidal ideation, suicidal behavior, and suicide attempt (<1% combined); all of these events were serious and all occurred in subjects with a preexisting history of depression or psychiatric illness.
Clinical Trials in Adult Subjects with Renal Impairment
In an open-label trial (Study 112), 248 HIV-1 infected subjects with eGFR of 30 to 69 mL per minute (by Cockcroft-Gault method) were treated with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for a median duration of 108 weeks. Of these subjects, 65% had previously been on a stable TDF-containing regimen. A total of 5 subjects permanently discontinued elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide due to the development of renal adverse events. Three of these five were among the 80 subjects with baseline eGFRs of < 50mL/min and two subjects were among the 162 subjects with baseline eGFRs of ≥ 50mL/min. One additional subject with baseline eGFR of ≥ 50mL/min developed acute renal failure. Following a brief interruption, elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was resumed and this subject's renal function returned to baseline. Overall, renally impaired subjects receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in this study had a mean serum creatinine of 1.5 mg/dL at baseline and 1.4 mg/dL at Week 96. Otherwise, the safety profile of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in subjects in this study was similar to that of subjects with normal renal function.
Renal Laboratory Tests and Renal Safety
Treatment-Naïve Adults:
Cobicistat has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. Increases in serum creatinine occurred by Week 2 of treatment and remained stable through 96 weeks. In two 96-week randomized, controlled trials in a total of 1,733 treatment-naïve adults with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by less than 0.1 mg per dL in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and by 0.1 mg per dL in the STRIBILD group from baseline to Week 96.
Virologically Suppressed Adults:
In a study of 1,436 virologically-suppressed TDF-treated adults with a mean baseline eGFR of 112 mL per minute who were randomized to continue their treatment regimen or switch to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, at Week 96 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Bone Mineral Density Effects
Treatment-Naïve Adults:
In a pooled analysis of Studies 104 and 111, the effects of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 96 were assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 96 by −0.96% with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide compared to −2.79% with STRIBILD at the lumbar spine and −0.67% compared to −3.28% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 12% of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide subjects and 26% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 11% of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide subjects and 26% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known.
Virologically Suppressed Adults:
In Study 109, TDF-treated subjects were randomized to continue their TDF-based regimen or switch to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; changes in BMD from baseline to Week 96 were assessed by DXA. Mean BMD increased in subjects who switched to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (2.12% lumbar spine, 2.44% total hip) and decreased slightly in subjects who continued their baseline regimen (−0.09% lumbar spine, −0.46% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2% of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide subjects and 6% of subjects who continued their TDF-based regimen. BMD declines of 7% or greater at the femoral neck were experienced by 2% of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide subjects and 7% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known.
Laboratory Abnormalities:
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in Studies 104 and 111 are presented in Table 3.
Serum Lipids:
Subjects receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide experienced greater increases in serum lipids compared to those receiving STRIBILD.
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 4.
Clinical Trials in Pediatric Subjects:
The safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1 infected, treatment-naïve pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg (77 lbs) was evaluated through Week 48 in an open-label clinical trial (Study 106). The safety profile in 50 adolescent subjects who received treatment with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide that resolved and did not require discontinuation of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Among the 50 pediatric subjects receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head. Mean changes from baseline BMD Z-scores were −0.07 for lumbar spine and −0.20 for total body less head at Week 48. One elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide subject had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 48.
Postmarketing Experience
There is limited information regarding Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide Postmarketing Experience in the drug label.
Drug Interactions
- Not Recommended with Other Antiretroviral Medications
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with other antiretroviral medications for treatment of HIV-1 infection should be avoided. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
- Potential for elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide to Affect Other Drugs
- Cobicistat, a component of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs (see TABLE 5).
- Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.
- Potential for Other Drugs to Affect One or More Components of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir alafenamide
- Elvitegravir and cobicistat, components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.
- Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat, elvitegravir, and TAF, which may lead to loss of therapeutic effect of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and development of resistance (see TABLE 5).
- Coadministration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see TABLE 5).
- TAF, a component of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, is a substrate of P-gp, BCRP, OATP1B1 and OATP1B3. Drugs that inhibit P-gp and/or BCRP, such as cobicistat, may increase the absorption of TAF (see TABLE 10). However, when TAF is administered as a component of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, its availability is increased by cobicistat and a further increase of TAF concentrations is not expected upon coadministration of an additional P-gp and/or BCRP inhibitor.
- Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF.
- Drugs Affecting Renal Function
- Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions.
- Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
- 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, the components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide as individual agents and/or in combination, or are predicted drug interactions that may occur with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
- The table includes potentially significant interactions but is not all inclusive.
These images are provided by the National Library of Medicine
- Drugs without Clinically Significant Interactions with Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir alafenamide
- Based on drug interaction studies conducted with the components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, no clinically significant drug interactions have been either observed or are expected when elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, ledipasvir, lorazepam, methadone, proton pump inhibitors, ribavirin, sertraline, sofosbuvir, and velpatasvir.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Prospective pregnancy data from the Antiviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. TAF use in women during pregnancy has not been evaluated; however, elvitegravir, cobicistat, and emtricitabine use during pregnancy has been evaluated in a limited number of women as reported to the APR. Available data from the APR through January 2016 show no birth defects reported for elvitegravir or cobicistat, and no difference in the overall risk of major birth defects for emtricitabine 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). In animal studies, no adverse developmental effects were observed when the components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rat and rabbits, respectively: elvitegravir), 1.6 and 3.8 times (rats and rabbits, respectively: cobicistat), 60 and 108 times (mice and rabbits, respectively; emtricitabine) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dosage of these components in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. 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 human exposure at the recommended therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily dose. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Human Data:
Elvitegravir: Based on prospective reports from the APR through January 2016 of 73 exposures to elvitegravir-containing regimens during pregnancy resulting in live births (including 51 exposed in the first trimester), there have been no birth defects reported.
Cobicistat: Based on prospective reports from the APR through January 2016 of 77 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including 54 exposed in the first trimester), there have been no birth defects reported.
Emtricitabine: Based on prospective reports to the APR through January 2016 of 3,155 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including 2,145 exposed in the first trimester and 1,010 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.2% (95% CI: 1.6% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to emtricitabine-containing regimens.
Animal Data:
Elvitegravir: Elvitegravir was administered orally to pregnant rats (0, 300, 1000, and 2000 mg/kg/day) and rabbits (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/postnatal developmental study, elvitegravir was administered orally to rats 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, 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 1.6 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 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 3.8 times higher than human exposures at the recommended daily dose. In a pre/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 (250, 500, or 1000 mg/kg/day) and rabbits (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 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with emtricitabine, mice were administered 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 Alafenamide (TAF): TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide during labor and delivery.
Nursing Mothers
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 published data, emtricitabine has been shown to be present in human breast milk; it is unknown if elvitegravir, cobicistat, and TAF are present in human breast milk. Elvitegravir and cobicistat are present in rat milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. It is unknown if TAF is present in animal milk.
It is not known if elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide affects milk production or has 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 elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
Data
Animal Data:
Elvitegravir: During the pre/postnatal developmental toxicology study at doses up to 2000 mg/kg/day, a mean elvitegravir milk to plasma ratio of 0.1 was measured 30 minutes after administration to rats on lactation day 14.
Cobicistat: During the pre/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.
Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. During the pre/postnatal developmental toxicology study, tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.
Pediatric Use
The efficacy and safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for the treatment of HIV-1 infection was established in pediatric patents aged 12 years and older with body weight greater than or equal to 35 kg. Use of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in this age group is supported by studies in adults and by an open-label trial of 50 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide through Week 48 (Study 106). The safety and efficacy of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in these subjects was similar to that in antiretroviral treatment-naïve adults.
Safety and effectiveness of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in pediatric patients less than 12 years of age or less than 35 kg have not been established.
Geriatic Use
Clinical trials of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide included 97 subjects (80 receiving elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) aged 65 years and over. No differences in safety or efficacy have been observed between elderly subjects and those between 12 and less than 65 years of age.
Gender
There is no FDA guidance on the use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with respect to specific racial populations.
Renal Impairment
The pharmacokinetics, safety, and virologic and immunologic responses of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1 infected adult subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated in 248 subjects in an open-label trial, Study 112.
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. The safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide has not been established in patients with estimated creatinine clearance that declines below 30 mL per minute.
Hepatic Impairment
No dosage adjustment of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not recommended for use in patients with severe hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in patients who are immunocompromised.
Administration and Monitoring
Administration
Testing Prior to Initiation and During Treatment with Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir alafenamide
Prior to initiation of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, patients should be tested for hepatitis B virus infection. It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and during therapy in all patients as clinically appropriate.
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).
Monitoring
There is limited information regarding Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide and IV administrations.
Overdosage
No data are available on overdose of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.
Elvitegravir: Limited clinical experience is available at doses higher than the recommended dose of elvitegravir in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. In one study, elvitegravir (administered with the CYP3A inhibitor cobicistat) equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Cobicistat: Limited clinical experience is available at doses higher than the recommended dose of cobicistat in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. In two studies, a single dose of cobicistat 400 mg (2.7 times the dose in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Emtricitabine: Limited clinical experience is available at doses higher than the recommended dose of emtricitabine in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dose of TAF in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. A single dose of 125 mg TAF (12.5 times the dose in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.
Pharmacology
Mechanism of Action
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a fixed-dose combination of antiretroviral drugs elvitegravir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide.
Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
Tenofovir Alafenamide (TAF): TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.
Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in cell culture based on several assays including mitochondrial DNA analyses.
Structure
Elvitegravir: The chemical name of elvitegravir is 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.88. It has the following structural formula:
Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3R,6R,9S)-. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.02. It has the following structural formula:
Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.
Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)-enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:
Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). It has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.5. It has the following structural formula:
Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.
Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for elvitegravir, cobicistat, and TAF. The effect of emtricitabine or the combination regimen elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide on the QT interval is not known.
Elvitegravir: In a thorough QT/QTc study in 126 healthy subjects, elvitegravir (coadministered with 100 mg ritonavir) 125 mg and 250 mg (0.83 and 1.67 times the dose in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) did not affect the QT/QTc interval and did not prolong the PR interval.
Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide will result in clinically relevant PR prolongation.
Tenofovir Alafenamide (TAF): In a thorough QT/QTc study in 48 healthy subjects, TAF at the therapeutic dose or at a supratherapeutic dose approximately 5 times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.
Effects on Serum Creatinine
The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an eGFR of at least 80 mL per minute (N=18) and with an eGFR of 50 to 79 mL per minute (N=12). A statistically significant change of eGFRCG from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an eGFR of at least 80 mL per minute (−9.9 ± 13.1 mL/min) and subjects with an eGFR of 50 to 79 mL per minute (−11.9 ± 7.0 mL per minute). These decreases in eGFRCG were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an eGFR of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion
The pharmacokinetic (PK) properties of the components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide are provided in Table 6. The multiple dose PK parameters of elvitegravir, cobicistat, emtricitabine, TAF and its metabolite tenofovir are provided in Table 7.
Special Populations
Patients with Renal Impairment
The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated in a subset of virologically suppressed subjects in an open-label trial, Study 112 (Table 8).
Patients with Hepatic Impairment
Elvitegravir and Cobicistat: A study of the pharmacokinetics of elvitegravir (administered with the CYP3A inhibitor cobicistat) was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects.
Emtricitabine: The pharmacokinetics of emtricitabine has 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 Alafenamide (TAF): Clinically relevant changes in TAF and tenofovir pharmacokinetics were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment.
Hepatitis B and/or Hepatitis C Virus Co-infection
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 elvitegravir (administered with the CYP3A inhibitor cobicistat).
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 Tenofovir Alafenamide (TAF): Pharmacokinetics of emtricitabine and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Pediatric Patients
Exposures of TAF achieved in 24 pediatric subjects aged 12 to less than 18 years who received elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in Study 106 were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, but were overall deemed acceptable based on exposure-response relationships; the other components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide had similar exposures in adolescents compared to treatment-naïve adults.
Geriatric Patients
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.
Race
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.
Gender
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.
Drug Interaction Studies
The drug-drug interaction studies described in Tables 9–11 were conducted with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, elvitegravir (coadministered with cobicistat or ritonavir), cobicistat administered alone, or TAF (administered alone or coadministered with emtricitabine).
As elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided.
The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 9. The effects of coadministered drugs on the exposure of TAF are shown in Table 10. The effects of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide or its components on the exposure of coadministered drugs are shown in Table 11.
These images are provided by the National Library of Medicine
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14 times, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27 times, respectively in male and female, the human systemic exposure. Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation. Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30 times higher exposures (AUC), respectively, than in humans at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18 times higher than human exposures at the recommended 150 mg daily dose.
In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the recommended daily dose. Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4 times higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2 times higher than human exposures at the recommended 150 mg daily dose.
In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays. Emtricitabine did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice 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 200 mg daily dose.
Tenofovir Alafenamide (TAF):
Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice is observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose of TDF for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide treatment. At the high dose in female mice, liver adenomas were increased at tenofovir exposures 10 times (300 mg TDF) and 167 times (10 mg TAF in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) that in humans. In rats, the study was negative for carcinogenic findings. TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 155 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.
Animal Toxicology and/or Pharmacology
Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. At the NOAEL for eye toxicity, the systemic exposure in dogs was 5 (TAF) and 15 (tenofovir) times the exposure seen in humans at the recommended daily elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide dosage.
Clinical Studies
The efficacy and safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were evaluated in the studies summarized in Table 12.
Clinical Trial Results in HIV-1 Treatment-Naïve Subjects
In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18–76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3 (range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm3.
Pooled treatment outcomes of Studies 104 and 111 through Week 96 are presented in Table 13.
Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 96 was 280 cells per mm3 in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide-treated subjects and 266 cells per mm3 in STRIBILD-treated subjects.
Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir alafenamide
In Study 109, the efficacy and safety of switching from ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (N=1436). Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide prior to study entry. Subjects were randomized in a 2:1 ratio to either switch to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide at baseline (N=959), or stay on their baseline antiretroviral regimen (N=477). Subjects had a mean age of 41 years (range 21–77), 89% were male, 67% were White, and 19% were Black. The mean baseline CD4+ cell count was 697 cells per mm3 (range 79–1951).
Subjects were stratified by prior treatment regimen. At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.
Treatment outcomes of Study 109 through 96 weeks are presented in Table 14.
Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization. In Study 109, the mean increase from baseline in CD4+ cell count at Week 96 was 60 cells per mm3 in elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide-treated subjects and 42 cells per mm3 in subjects who stayed on their baseline regimen.
Clinical Trial Results in HIV-1 Infected Subjects with Renal Impairment
In Study 112, the efficacy and safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method). Of the 248 enrolled, 6 were treatment-naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
The mean age was 58 years (range 24–82), with 63 subjects (26%) who were 65 years of age or older. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 664 cells per mm3 (range 126–1813). At Week 96, 88% (214/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. All six treatment-naïve subjects were virologically suppressed at Week 96. Five subjects among the entire study population had virologic failure at Week 96.
Clinical Trial Results in HIV-1 Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18
In Study 106, the efficacy, safety, and pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were evaluated in an open-label trial in HIV-1 infected treatment-naïve adolescents aged 12 to less than 18 years weighing at least 35 kg (77 lbs) (N=50). Subjects treated with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide once daily had a mean age of 15 years (range 12-17); 44% were male, 12% were Asian, and 88% were Black. At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies per mL (22% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm3 (range: 95 to 1110), and median CD4+ percentage was 23% (range: 7% to 45%).
In subjects treated with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, 92% (46/50) achieved HIV-1 RNA less than 50 copies per mL at Week 48. The mean increase from baseline in CD4+ cell count at Week 48 was 224 cells per mm3. Three of 50 subjects had virologic failure at Week 48; no emergent resistance to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was detected through Week 48.
How Supplied
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide tablets are green, capsule-shaped, film-coated tablets, debossed with "GSI" on one side of the tablet and the number "510" on the other side. Each bottle contains 30 tablets (NDC 61958-1901-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
Storage
Store below 30 °C (86 °F).
- Keep container tightly closed.
- Dispense only in original container.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Drug Interactions
- Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St John's wort.
- Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection
- Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or TDF, and may likewise occur with discontinuation of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
- Advise the patient to not discontinue elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide without first informing their healthcare provider.
- Immune Reconstitution Syndrome
- Renal Impairment
- Advise patients to avoid taking elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with concurrent or recent use of nephrotoxic agents.
- Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs.
- Lactic Acidosis and Severe Hepatomegaly
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. Advise patients that they should stop elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
- Missed Dosage
- Inform patients that it is important to take elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide on a regular dosing schedule with food and to avoid missing doses as it can result in development of resistance.
- Pregnancy Registry
- Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.
- Lactation
Precautions with Alcohol
Alcohol-Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
GENVOYA
Look-Alike Drug Names
Do not confuse with Genvoya - Stribild.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.