Genvoya

Genvoya is part of the drug class:

• Antivirals for treatment of HIV infections, combinations

Tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while taking Genvoya.

• Due to the risk of passing HIV to your baby in your breastmilk, you should not breastfeed if you have HIV.
• One of the medicines contained in this tablet can pass to your baby in your breast milk. It is not known if the other 3 medicines can pass into your breast milk.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose of Genvoya is one tablet (equal to 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide) taken once daily with food.

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Appropriate studies have not been performed on the relationship of age to the effects of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide combination in children younger than 12 years of age with body weight less than 35 kilograms. Safety and efficacy have not been established.

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin
• Carbamazepine
• Cisapride
• Colchicine
• Conivaptan
• Crizotinib
• Dihydroergotamine
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Eletriptan
• Eliglustat
• Eplerenone
• Ergonovine
• Ergotamine
• Fosphenytoin
• Isavuconazonium Sulfate
• Ivabradine
• Lomitapide
• Lovastatin
• Lurasidone
• Maraviroc
• Methylergonovine
• Midazolam
• Naloxegol
• Pazopanib
• Phenobarbital
• Phenytoin
• Pimozide
• Primidone
• Ranolazine
• Rifampin
• Riociguat
• Romidepsin
• Sildenafil
• Silodosin
• Simvastatin
• St John's Wort
• Tolvaptan
• Triazolam
• Venetoclax

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ado-Trastuzumab Emtansine
• Afatinib
• Alprazolam
• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Amiodarone
• Amprenavir
• Apixaban
• Aprepitant
• Aripiprazole
• Avanafil
• Bedaquiline
• Boceprevir
• Bosentan
• Bosutinib
• Bromocriptine
• Budesonide
• Cabazitaxel
• Cabozantinib
• Calcifediol
• Calcium Carbonate
• Carbamazepine
• Cariprazine
• Ceritinib
• Cilostazol
• Clarithromycin
• Clozapine
• Cobimetinib
• Cyclophosphamide
• Cyclosporine
• Dabrafenib
• Daclatasvir
• Darunavir
• Dasatinib
• Delamanid
• Delavirdine
• Dexamethasone
• Diazepam
• Digoxin
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Disopyramide
• Docetaxel
• Domperidone
• Donepezil
• Elbasvir
• Erlotinib
• Erythromycin
• Eslicarbazepine Acetate
• Eszopiclone
• Etravirine
• Everolimus
• Fentanyl
• Flecainide
• Fluoxetine
• Fluticasone
• Fosamprenavir
• Fosaprepitant
• Grazoprevir
• Haloperidol
• Ibrutinib
• Idelalisib
• Ifosfamide
• Iloperidone
• Irinotecan
• Irinotecan Liposome
• Itraconazole
• Ivacaftor
• Ketoconazole
• Lapatinib
• Levomilnacipran
• Lidocaine
• Lopinavir
• Macitentan
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Manidipine
• Mexiletine
• Mifepristone
• Morphine
• Morphine Sulfate Liposome
• Nevirapine
• Nifedipine
• Nilotinib
• Nimodipine
• Nisoldipine
• Olaparib
• Orlistat
• Oxcarbazepine
• Oxycodone
• Palbociclib
• Panobinostat
• Phenobarbital
• Phenytoin
• Pimavanserin
• Piperaquine
• Pixantrone
• Ponatinib
• Propafenone
• Quetiapine
• Quinidine
• Reboxetine
• Regorafenib
• Retapamulin
• Rifabutin
• Rifampin
• Rifapentine
• Ritonavir
• Rivaroxaban
• Rosuvastatin
• Ruxolitinib
• Salmeterol
• Saquinavir
• Saxagliptin
• Simeprevir
• Sirolimus
• Sodium Bicarbonate
• St John's Wort
• Sunitinib
• Suvorexant
• Tacrolimus
• Tadalafil
• Tamoxifen
• Tamsulosin
• Telithromycin
• Temsirolimus
• Ticagrelor
• Tipranavir
• Topotecan
• Toremifene
• Trabectedin
• Tramadol
• Trazodone
• Vardenafil
• Vemurafenib
• Vilanterol
• Vilazodone
• Vinblastine
• Vincristine
• Vincristine Sulfate Liposome
• Vinflunine
• Vorapaxar
• Voriconazole
• Warfarin
• Zolpidem

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir
• Darunavir
• Indinavir
• Nelfinavir

You should not take this medicine if you are allergic to cobicistat, elvitegravir, emtricitabine, or tenofovir.

Some medicines can interact with this medicine and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

• alfuzosin;

• lovastatin, simvastatin;

• oral midazolam, triazolam;

• rifampin;

• sildenafil (Revatio, for treating pulmonary arterial hypertension);

• St. John's wort;

• antipsychotic medicine--lurasidone, pimozide;

• ergot medicine--dihydroergotamine, ergotamine, ergonovine, methylergonovine; or

• seizure medicine--carbamazepine, phenobarbital, phenytoin.

Cobicistat, elvitegravir, emtricitabine, and tenofovir is a complete combination treatment and should not be used with other antiviral medications, especially those that contain adefovir, cobicistat, elvitegravir, emtricitabine, lamivudine, ritonavir, or tenofovir: Atripla, Combivir, Complera, Emtriva, Epivir, Epzicom, Hepsera, Kaletra, Norvir, Triumeq, Trizivir, Truvada, Tybost, Viread, or Viekira.

To make sure cobicistat, elvitegravir, emtricitabine, and tenofovir is safe for you, tell your doctor if you have:

• liver or kidney disease;

• osteopenia (low bone mineral density); or

• a history of hepatitis B or C infection.

Some people taking this medicine develop a serious condition called lactic acidosis. This may be more likely in women, in people who are overweight or have liver disease, and in people who have taken HIV/AIDS medication for a long time. Talk with your doctor about your risk.

This medicine is not expected to be harmful to an unborn baby. However, HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of this medicine on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Cobicistat, elvitegravir, emtricitabine, and tenofovir is not approved for use by a child younger than 12 years old or weighing less than 77 pounds.

This medicine can harm your kidneys. This effect is increased when you also use certain other medicines, including: antivirals, chemotherapy, injected antibiotics, medicine for bowel disorders, medicine to prevent organ transplant rejection, and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).

Many drugs can interact with cobicistat, elvitegravir, emtricitabine, and tenofovir. Some drugs should not be used together. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with this medicine. Give a list of all your medicines to any healthcare provider who treats you.

In the U.S.

• Genvoya

Available Dosage Forms:

• Tablet

Therapeutic Class: Anti-Infective Agent

Pharmacologic Class: Integrase Inhibitor

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Genvoya 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 of 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) [see Data]. In animal studies, no adverse developmental effects were observed when the components of Genvoya 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 Genvoya [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 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 Genvoya.

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 and in rabbits at approximately 0.2 times the 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 Genvoya. 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 Genvoya.

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 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 [see Data]. It is unknown if TAF is present in animal milk.

It is not known if Genvoya 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 Genvoya.

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 Genvoya for the treatment of HIV-1 infection was established in pediatric patients aged 12 years and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of Genvoya 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 Genvoya through Week 48 (Study 106). The safety and efficacy of Genvoya in these subjects was similar to that in antiretroviral treatment-naïve adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].

Safety and effectiveness of Genvoya in pediatric patients less than 12 years of age or less than 35 kg have not been established.

Geriatric Use

Clinical trials of Genvoya included 97 subjects (80 receiving Genvoya) 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.

Renal Impairment

The pharmacokinetics, safety, and virologic and immunologic responses of Genvoya 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 [see Adverse Reactions (6.1) and Clinical Studies (14.4)].

Genvoya is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of Genvoya is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. The safety of Genvoya has not been established in patients with estimated creatinine clearance that declines below 30 mL per minute [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Hepatic Impairment

No dosage adjustment of Genvoya is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Genvoya has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Genvoya is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Elvitegravir

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.

Cobicistat

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.

Emtricitabine

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 Genvoya 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 Genvoya) 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 Genvoya dosage.

Contraindications

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).1 (See Specific Drugs under Interactions.)

• Concomitant use with drugs that are potent inducers of CYP3A; these drugs may result in decreased elvitegravir and/or cobicistat concentrations resulting in possible decreased antiretroviral efficacy and development of resistance.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Test all HIV-infected patients for presence of HBV before initiating antiretroviral therapy.1 200

EVG/c/FTC/TAF not indicated for treatment of chronic HBV infection.1 Safety and efficacy of EVG/c/FTC/TAF not established in patients coinfected with HIV and HBV.1

Severe acute exacerbations of HBV reported following discontinuance of preparations containing emtricitabine and/or tenofovir DF in HIV-infected patients with HBV infection.1 218 221 HBV exacerbations have been associated with hepatic decompensation and hepatic failure.1 218 Such reactions could occur with EVG/c/FTC/TAF.1

Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after EVG/c/FTC/TAF is discontinued in patients coinfected with HIV and HBV.1 If appropriate, initiation of HBV treatment may be warranted.1

Other Warnings/Precautions

Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with hypophosphatemia), reported with tenofovir prodrugs (e.g., tenofovir DF).1 221

Cobicistat (a component of EVG/c/FTC/TAF) may cause modest increase in Scr and modest decrease in estimated Clcr due to inhibition of tubular secretion of creatinine;1 15 glomerular function not affected.1 15

Determine Scr, estimated Clcr, serum phosphorus, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TAF and routinely monitor during treatment in all patients.1 (See Renal Impairment under Cautions.)

Do not use EVG/c/FTC/TAF in patients with estimated Clcr <30 mL/minute.1

If a confirmed increase in Scr of >0.4 mg/dL from baseline occurs during EVG/c/FTC/TAF treatment, closely monitor for renal toxicity.1 Discontinue EVG/c/FTC/TAF if clinically important decreases in renal function occur or there is evidence of Fanconi syndrome.1

Patients receiving a tenofovir prodrug who have impaired renal function or are receiving a nephrotoxic agent (e.g., high-dose or multiple NSAIAs) are at increased risk of developing adverse renal effects.1 (See Interactions.)

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving HIV NRTIs, including emtricitabine and tenofovir DF, in conjunction with other antiretrovirals.1 218 221

Interrupt EVG/c/FTC/TAF treatment if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1

Tenofovir prodrugs (tenofovir alafenamide, tenofovir DF) have been associated with decreases in bone mineral density (BMD).1 200 221 BMD declines reported in adults receiving tenofovir alafenamide have been smaller than those reported in adults receiving tenofovir DF.1 25 200 In addition, BMD increases reported when some adults were switched from a regimen containing tenofovir DF to a regimen containing tenofovir alafenamide.1 200

Long-term clinical importance of BMD changes reported with tenofovir prodrugs unknown.1 25 200

Consider cautions, precautions, and contraindications associated with each component of EVG/c/FTC/TAF.1 218 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.1 218

EVG/c/FTC/TAF is used alone as a complete regimen for treatment of HIV-1 infection;1 200 do not use in conjunction with other antiretrovirals.1 200 (See Specific Drugs under Interactions.)

Do not use EVG/c/FTC/TAF concomitantly with any preparation that contains any of its components (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide).1 In addition, do not use EVG/c/FTC/TAF concomitantly with any preparation containing tenofovir DF, lamivudine, adefovir dipivoxil, or ritonavir.1

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]);1 this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution;1 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].1 202

Prospective pregnancy data from the Antiretroviral Pregnancy Registry insufficient to date to adequately assess risk of birth defects or miscarriage if EVG/c/FTC/TAF used in pregnant women.1 Registry data available through January 2016 show no birth defects reported for elvitegravir or cobicistat and no difference in overall risk of major birth defects for emtricitabine compared with the background rate of major birth defects in the US.1

In animal studies, no evidence of adverse developmental effects when components of EVG/c/FTC/TAF administered separately during organogenesis at elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide exposures up to 23, 3.8, 108, and 53 times higher, respectively, than human exposures at the recommended daily dosage.1

Experts state data insufficient to recommend routine use of EVG/c/FTC/TAF for initial treatment in pregnant women.202

Elvitegravir and cobicistat distributed into milk in rats.1 Tenofovir distributed into milk in animals following administration of tenofovir DF.1 Not known whether elvitegravir, cobicistat, or tenofovir alafenamide distributed into human milk.1 Emtricitabine is distributed into human milk.1

Not known whether EVG/c/FTC/TAF affects human milk production or affects the breast-fed infant.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Safety and efficacy of EVG/c/FTC/TAF not established in pediatric patients <12 years of age or in those weighing <35 kg.1

Experts state that EVG/c/FTC/TAF is a preferred antiretroviral regimen in children and adolescents ≥12 years of age weighing ≥35 kg, including those in early puberty (SMR 1–3).201

Clinical trial data indicate safety and efficacy of EVG/c/FTC/TAF in HIV-1-infected, treatment-naive pediatric patients 12 to <18 years of age is similar to that reported in adults.1

No differences in safety or efficacy of EVG/c/FTC/TAF observed between individuals ≥65 years of age and individuals 12 to <65 years of age.1

Mild hepatic impairment (Child-Pugh class A): No clinically important effects on pharmacokinetics of tenofovir alafenamide.1

Moderate hepatic impairment (Child-Pugh class B): No clinically important effects on pharmacokinetics of elvitegravir, cobicistat, or tenofovir alafenamide;1 not expected to affect pharmacokinetics of emtricitabine.1

Severe hepatic impairment (Child-Pugh class C): EVG/c/FTC/TAF not recommended;1 data not available to date regarding pharmacokinetics or safety in such patients.1

Determine Scr, estimated Clcr, serum phosphorus, urine glucose, and urine protein prior to and routinely monitor during EVG/c/FTC/TAF treatment in all patients.1

Estimated Clcr <30 mL/minute: Do not use EVG/c/FTC/TAF;1 safety not established.1

Common Adverse Effects

Nausea, diarrhea, fatigue, headache.1

• EVG/c/FTC/TAF is a fixed-combination antiretroviral containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.1

• Elvitegravir (EVG) is an HIV integrase strand transfer inhibitor antiretroviral.1 Inhibits activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.1 Active against HIV-1 and also has some in vitro activity against HIV type 2 (HIV-2);1 inactive against HBV and HCV.1

• Cobicistat is a mechanism-based CYP3A inhibitor and is included in EVG/c/FTC/TAF as a pharmacokinetic enhancer to decrease elvitegravir metabolism and increase plasma concentrations of the drug (cobicistat-boosted elvitegravir).1 Has no antiretroviral or antiviral activity and is not active against HIV-1, HBV, or HCV.1 Does not antagonize the antiretroviral activity of elvitegravir, emtricitabine, or tenofovir.1

• Emtricitabine (FTC) is an HIV NRTI.1 218 Inactive until converted intracellularly to an active 5′-triphosphate metabolite.1 26 218 After conversion, active against HIV-1 and also has some in vitro activity against HIV-2.1 218

• Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor antiretroviral classified as an HIV NRTI.1 Tenofovir alafenamide is a tenofovir prodrug that is inactive until hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized by cellular kinases to the active metabolite (tenofovir diphosphate).1 6 7 9 Compared with the tenofovir prodrug tenofovir DF (TDF), tenofovir alafenamide is more stable in blood and plasma and more efficiently converted intracellularly to tenofovir diphosphate, resulting in higher concentrations of active metabolite within HIV target cells and lower circulating concentrations of tenofovir than those reported with tenofovir DF.6 7 9 Active against HIV-1 and also has some in vitro activity against HIV-2;1 221 also active against HBV.221

• HIV-1 resistant to elvitegravir, emtricitabine, or tenofovir have been produced in vitro and have emerged during EVG/c/FTC/TAF therapy.1 In clinical trials in antiretroviral-naive patients, genotypic resistance to elvitegravir, emtricitabine, and/or tenofovir was identified in HIV-1 isolates from patients who received EVG/c/FTC/TAF and were considered to be virologic treatment failures.1

• Cross-resistance between elvitegravir and other HIV integrase inhibitors (e.g., dolutegravir, raltegravir) has been reported.1 16 18 22 23 Cross-resistance also occurs among the HIV NRTIs.1