DRUG INTERACTIONS-

 • GENVOYA should not be administered with other antiretroviral medications for treatment of HIV-1 infection.

 • GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of GENVOYA.

Consult the full prescribing information prior to and during treatment for potential drug-drug interactions.

34/15 PRODUCT DETAILS 

Name of the drug-      GENVOYA

Active ingriendents-   A Fixed dose combn of tab contg Elvitgravir

FDA approved use-    To treat perinatal, infitile and juvenile -onset hypophosphatasia                                         ( HPP)                                                                                                                 

 Date of Approval         10/23/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GENVOYA safely and effectively.

See full prescribing information for GENVOYA. GENVOYA® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use

Initial U.S. Approval: 2015

WARNING:

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning.

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs.

) • GENVOYA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B 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 GENVOYA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

-INDICATIONS AND USAGE-

 GENVOYA is a four-drug combination of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir alafenamide (TAF), both HIV 1 nucleoside analog reverse transcriptase inhibitors (NRTIs) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.

ADVERSE REACTIONS-

 Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea.

-CONTRAINDICATIONS-

 Coadministration of GENVOYA is contraindicated with drugs that: • Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events.

 • Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of GENVOYA and possiblle

WARNINGS AND PRECAUTIONS-

 • Avoid coadministration with other antiretroviral products: Do not use with drugs containing elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate, lamivudine, ritonavir, or adefovir dipivoxil.

 • Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of GENVOYA and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of GENVOYA and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs.

 • Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

 • Immune reconstitution syndrome: May necessitate further evaluation and treatment.

 • New onset or worsening renal impairment: Assess creatinine clearance, urine glucose, and urine protein in all patients before initiating GENVOYA therapy and monitor during therapy. Monitor serum phosphorus in patients with chronic kidney disease.

 • Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. 

.

DOSAGE AND ADMINISTRATION--

 • Testing: Prior to initiation of GENVOYA, patients should be tested for hepatitis B infection. (

 • Recommended dosage: One tablet taken orally once daily with food.

 • Renal impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

 • Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment

DOSAGE FORMS AND STRENGTHS-

 Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide.

PATIENT COUNSELING INFORMATION--

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Gilead Sciences Reference ID: 

Drug Interactions GENVOYA 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

Coadministration of GENVOYA with other antiretroviral products is not recommended [see Warnings and Precautions and Drug Interactions 

Lactic Acidosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to GENVOYA.

Advise patients that treatment with GENVOYA should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness

Testing Prior to Initiation of GENVOYA and HBV Co-Infection Instruct patients that hepatitis B testing is recommended prior to initiating antiretroviral therapy.

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 occur with GENVOYA

Advise the patient to not discontinue GENVOYA without first informing his or her healthcare provider.

Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known 

 Immune Reconstitution Syndrome: Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started 

Renal Impairment- Advise patients to avoid taking GENVOYA 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

Decrease in Bone Mineral Density -Advise patients that decreases in bone mineral density have been observed with the use of GENVOYA. Assessment of bone mineral density (BMD) should be Gilead Sciences  considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss

 Missed Dosage- Inform patients that it is important to take GENVOYA on a regular dosing schedule with food and to avoid missing doses.

Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to GENVOYA

Lactation- Inform patients that at least one of the drugs contained in GENVOYA can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 Gilead Sciences

CLINICAL PHARMACOLOGY

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

2. Pharmacodynamics -                                                                                           Cardiac Electrophysiology -Thorough QT studies have been conducted for elvitegravir, cobicistat, and TAF. The effect of emtricitabine or the combination regimen GENVOYA 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 GENVOYA) 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 GENVOYA) 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 ) 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 GENVOYA fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with GENVOYA 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

3. Pharmacokinetics The pharmacokinetic properties of the components of GENVOYA are provided in Table 6.

The multiple dose pharmacokinetic parameters of elvitegravir, cobicistat, emtricitabine, TAF and its metabolite tenofovir are provided in Table 7.

Effect of light meal (relative to fasting)a ?34% Not clinically significant Effect of high fat meal (relative to fasting)a ?87%

Distribution % Bound to human plasma proteins ~99 ~98 <4 ~80 Source of protein binding data Ex vivo In vitro In vitro Ex vivo Blood-to-plasma ratio 0.73 0.5 0.6 1.0

Metabolism- Metabolism CYP3A (major) UGT1A1/3 (minor) CYP3A (major) CYP2D6 (minor) Not significantly metabolized Cathepsin Ab (PBMCs) CES1 (hepatocytes) CYP3A (minimal)

Elimination- Major route of elimination Metabolism Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose) t1/2 (h)c 12.9 3.5 10 0.51 % Of dose excreted in urined 6.7 8.2 70 <1% % Of dose excreted in fecesd 94.8 86.2 13.7 31.7 PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1. a. Values refer to mean systemic exposure.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, GENVOYA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

 2.Pediatric Use -                                                                                                             The pharmacokinetics, safety, and virologic and immunologic responses were evaluated in 23 treatment-naïve, HIV-1 infected subjects aged 12 to less than 18 years receiving GENVOYA through 24 weeks in an open-label trial

3.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.

4. 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 

5.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.

No pharmacokinetic or safety data are available regarding the use of GENVOYA in patients with severe hepatic impairment (Child-Pugh Class C

Therefore, GENVOYA is not recommended for use in patients with severe hepatic impairment .

 OVERDOSAGE -                                                                                                                  No data are available on overdose of GENVOYA in patients. If overdose occurs, the patient must be monitored for evidence of toxicity

Treatment of overdose with GENVOYA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.