Drug Safety-related Labeling Changes (SrLC)

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GENVOYA (NDA-207561)

(COBICISTAT; ELVITEGRAVIR; EMTRICITABINE; TENOFOVIR ALAFENAMIDE FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/07/2022 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Clinical Trials in Pediatric Subjects:

Safety in Pediatric Patients

The safety of GENVOYA in HIV-1 infected pediatric subjects was evaluated in treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), and in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=52) through Week 48 (cohort 2) in an open-label clinical trial (Study 106) [see Clinical Studies (14.5)]. With the exception of a decrease in the mean CD4+ cell count observed in cohort 2 of Study 106, the safety profile in pediatric subjects who received treatment with GENVOYA was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.

Bone Mineral Density Effects

Cohort 1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg)

Among the subjects in cohort 1 receiving GENVOYA, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were -0.07 for lumbar spine and -0.20 for TBLH at Week 48. One GENVOYA subject had significant (at least 4%) lumbar spine BMD loss at Week 48.

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Among the subjects in cohort 2 receiving GENVOYA, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. Six GENVOYA subjects had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 subjects also had at least 4% TBLH BMD loss at Week 48.

Change from Baseline in CD4+ cell counts

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Cohort 2 of Study 106 evaluated pediatric subjects (N=52) who were virologically- suppressed and who switched from their antiretroviral regimen to GENVOYA. Although all subjects had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 4. All subjects maintained their CD4+ cell counts above 400 cells/mm3 [see Pediatric Use (8.4) and Clinical Studies (14.5)].

Table 4           Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to GENVOYA

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8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of GENVOYA for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 25 kg [see Indications and Usage (1) and Dosage and Administration (2.2)].

Use of GENVOYA in pediatric patients less than 18 years of age and weighing at least 25 kg is supported by studies in adults and by an open-label study in antiretroviral treatment-naïve HIV-1 infected pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg (cohort 1 of Study 106, N=50) and in virologically-suppressed pediatric subjects aged 6 to less than 12 years and weighing at least 25 kg (cohort 2 of Study 106, N=52). The safety and efficacy of GENVOYA in adolescent subjects was similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)]. The safety and efficacy of GENVOYA in subjects 6 to 12 years of age weighing at least 25 kg was similar to that in antiretroviral treatment-naïve adults and adolescents with the exception of a decrease from baseline CD4+ cell count [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].

A pharmacokinetic evaluation of a reduced strength GENVOYA formulation containing 90 mg of EVG, 90 mg of COBI, 120 mg of FTC, and 6 mg TAF was performed in 27 virologically-suppressed pediatric patients at least 2 years of age and weighing at least 14 to less than 25 kg (cohort 3 of Study 106). Virologic, immunologic, and safety outcomes were similar to those observed in cohort 2 of Study 106. No clinically meaningful differences in drug exposures except EVG were identified between pediatric patients in cohort 3 receiving the reduced strength formulation and adults receiving the GENVOYA tablet containing 150 mg of EVG,150 mg of COBI, 200 mg of FTC, and 10 mg TAF. The median observed EVG Ctrough values in subjects in cohort 3 were significantly lower than the values correlated with efficacy in adults. Therefore, efficacy cannot be extrapolated from adults to pediatric patients weighing 14 to 25 kg.

Safety and effectiveness of GENVOYA in pediatric patients weighing less than 25 kg have not been established.

09/13/2021 (SUPPL-27)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pregnancy

(Additions and/or revisions underlined)

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for EVG, COBI, FTC or TAF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%.

Data

Human Data

Elvitegravir (EVG):

Based on prospective reports to the APR of over 440 exposures to EVG-containing regimens during pregnancy resulting in live births (including over 350 exposed in the first trimester and 70 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 1.5% to 5.2%) and 1.4% (95% CI: 0.0% to 7.7%) following first and second/third trimester exposure, respectively, to EVG- containing regimens.

Cobicistat (COBI):

Based on prospective reports to the APR of over 560 exposures to COBI-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) following first and second/third trimester, respectively, to COBI- containing regimens.

Emtricitabine (FTC):

Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

Tenofovir Alafenamide (TAF):

Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens.

03/04/2021 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment

 Additions and/or revisions underlined

Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)].

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6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

Renal Laboratory Tests and Renal Safety

…

Across these trials, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA.

…

6.2 Postmarketing Experience

 

Additions underlined

…

Renal and Urinary Disorders

Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions underlined

…

Renal Impairment

Advise patients to avoid taking GENVOYA with concurrent or recent use of nephrotoxic agents. Postmarketing cases of renal impairment, including acute renal failure, have been reported [see Warnings and Precautions (5.4)].

…

PATIENT INFORMATION

Additions underlined

…

What is the most important information I should know about GENVOYA? GENVOYA can cause serious side effects, including:

• Worsening of hepatitis B virus (HBV) infection. Your healthcare provider will test you for HBV infection before or when you start treatment with GENVOYA. If you have HBV infection and take GENVOYA, your HBV may get worse (flare-up) if you stop taking GENVOYA. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

  …

  • If you stop taking GENVOYA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver, and may give you a medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking GENVOYA.

     

    …

12/02/2020 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

(Additions and/or revisions underlined)

The concomitant use of GENVOYA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7.5)]:

• Loss of therapeutic effect of GENVOYA and possible development of resistance.

• Clinically significant adverse reactions, potentially leading to severe, life- threatening, or fatal events, from greater exposures of concomitant drugs metabolized by CYP3A.

• Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites.

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during GENVOYA therapy; review concomitant medications

5.3 Immune Reconstitution Syndrome

(Additions and/or revisions underlined)

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including emtricitabine, a component of GENVOYA. 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, Guillain-Barré syndrome, and autoimmune hepatitis) 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.

7 Drug Interactions

7.2 Potential for GENVOYA to Affect Other Drugs

(Additions and/or revisions underlined)

Cobicistat, a component of GENVOYA, 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 GENVOYA 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.

Coadministration of GENVOYA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (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.

 7.6 Drugs without Clinically Significant Interactions with GENVOYA

(Additions and/or revisions underlined)

Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been observed or are expected when GENVOYA is combined with the following drugs: famciclovir, famotidine, ledipasvir, methadone, omeprazole, prasugrel (active metabolite), sertraline, sofosbuvir, velpatasvir, and voxilaprevir.

Other

(Table 5 is updated with the addition of a new drug class “Antiplatelets” and the information about drugs ticagrelor, clopidogrel and prasugrel. Table 5 is additionally updated with the category “Medications or Oral Supplements Containing Polyvalent Cations” with clinical recommendations that allows for two-hour dose staggering when elvitegravir-containing products are taken with polyvalent cations.)

03/18/2019 (SUPPL-23)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

Table 5 has been revised; please refer to the label.

12/10/2018 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment

‘eGFRs’ are replaced by ‘estimated creatinine clearance’ throughout entire W&P section.

Additions and/or revisions underlined:

GENVOYA is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or in patients with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.

6 Adverse Reactions

6.1 Clinical Trials Experience

Clinical Trials in Adult Subjects with Renal Impairment

Addition of the following:

Virologically-Suppressed Adults with End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis

The safety of GENVOYA in subjects with end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis was assessed in 55 subjects (Study 1825). The most commonly reported adverse reaction (adverse event assessed as causally related by investigator and all grades) was nausea (7%). Serious adverse events were reported in 53% of subjects and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%). Overall 5% of subjects permanently discontinued treatment due to an adverse event.

Newly added subsection:

6.2 Postmarketing Experience

The following events have been identified during post approval use of products containing TAF, including GENVOYA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders

Angioedema, urticaria, and rash

8 Use in Specific Populations

8.6 Renal Impairment

Extensive changes; please refer to label for complete information.

11/02/2018 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

4 CONTRAINDICATIONS

(Additions and/or revisions are underlined)

•  …

• Herbal Products: St. John’s wort (Hypericum perforatum)

• Lipid-modifying Agents: lomitapide, lovastatin, simvastatin

• Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as REVATIO® for the treatment of pulmonary arterial hypertension

• …

7 Drug Interactions

7.6 Drugs without Clinically Significant Interactions with GENVOYA

(Table 5 has been revised; please refer to label)

 

7.6         Drugs without Clinically Significant Interactions with GENVOYA

 (Additions and/or revisions are underlined)

Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been observed when GENVOYA is combined with the following drugs: famciclovir, famotidine, ledipasvir, methadone, omeprazole, sertraline, sofosbuvir, velpatasvir, and voxilaprevir.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

 Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals 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

GENVOYA is not recommended during pregnancy. A literature report evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters.

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects of miscarriage. However, elvitegravir, cobicistat, emtricitabine, and TAF use during pregnancy have been evaluated in a limited number of women as reported to the APR. Available data from the APR show no increase in the overall risk of major birth defects for emtricitabine or cobicistat 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). The number of exposures to TAF and elvitegravir are insufficient to make a risk assessment compared to a reference population. The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%.In animal studies, no adverse developmental effects were observed when the components of 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.

Data

Human Data

A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of GENVOYA are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

Elvitegravir:

The APR has received prospective reports of 5 birth defects among 180 first trimester exposures to elvitegravir-containing regimens during pregnancy resulting in live births. No birth defects were reported among 52 exposures during the second/third trimester. The number of exposures is insufficient to make a risk assessment compared to a reference population.

Cobicistat:

Based on prospective reports to the APR of 204 first trimester exposures to cobicistat- containing regimens during pregnancy, there was no increase in overall major birth defects with cobicistat 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 2.5% (95% CI: 0.8% to 5.6%) with first trimester exposure to cobicistat-containing regimens; The 58 second/third trimester cobicistat exposures reported to the APR are insufficient to make a risk assessment.

Emtricitabine (FTC):

Based on prospective reports to the APR of exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 2,700 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC 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 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with second/third trimester exposure to emtricitabine-containing regimens.

Tenofovir Alafenamide (TAF):

The APR has received prospective reports of 3 birth defects among 56 first trimester exposures to TAF-containing regimens during pregnancy resulting in live births. No birth defects were reported among 29 exposures during the second/third trimester. The number of exposures is insufficient to make a risk assessment compared to a reference population.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

…

Pregnancy

Advise patients that GENVOYA is not recommended during pregnancy and to alert their healthcare provider if they become pregnant while taking GENVOYA. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to GENVOYA.

…

Other

Patient Information

(Additions and/or revisions are underlined)

…

What should I tell my healthcare provider before taking GENVOYA?

Before taking GENVOYA, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems, including hepatitis B infection

• have kidney problems

• are pregnant or plan to become pregnant.

  • It is not known if GENVOYA can harm your unborn baby.

  • GENVOYA should not be used during pregnancy because you may not have enough GENVOYA in your body during pregnancy.

Tell your healthcare provider if you become pregnant during treatment with GENVOYA. Your healthcare provider may prescribe different medicines if you become pregnant while taking GENVOYA.

Pregnancy Registry: There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

…

 

08/01/2018 (SUPPL-17)

Approved Drug Label (PDF)

4 Contraindications

Section has been reformatted by removing the table and moving the associated clinical comments to Sectionm 7 in Table 5; please refer to label.

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment

Additions and/or revisions underlined:

Prior to or when initiating GENVOYA, and during treatment with GENVOYA on a clinically appropriate schedule, assess serum creatinine … In patients with chronic kidney disease, also assess serum phosphorus …

7 Drug Interactions

Table 5 now includes information regarding drug interactions with Direct Oral Anticoagulants

Other

Table numbers have changed throughout the sections; please refer to label for accuracy.

11/22/2017 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment

(Additions and/or revisions are underlined)

…In a study of virologically suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 144 weeks…

It Prior to and during treatment, as clinically appropriate, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients, and also assess serum phosphorus in patients with chronic kidney disease. Discontinue GENVOYA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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 GENVOYA for a median duration of 144 weeks. Of these subjects, 65% had previously been on a stable TDF- containing regimen. A total of 5 subjects permanently discontinued GENVOYA due to the development of renal adverse events through Week 96. 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 greater than or equal to 50mL/min. There were no further renal discontinuations between Weeks 96 and 144. Overall, renally impaired subjects receiving GENVOYA in this study had a mean serum creatinine of 1.5 mg/dL at baseline and 1.4 mg/dL at Week 144...

7 Drug Interactions

7.6 Drugs without Clinically Significant Interactions with GENVOYA

(Additions and/or revisions are underlined)

Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been either observed or are expected when GENVOYA is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, ledipasvir, lorazepam, methadone, proton pump inhibitors, ribavirin, sertraline, sofosbuvir, velpatasvir, and voxilaprevir.

09/26/2017 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Clinical Trials in Pediatric Subjects:

Safety in Pediatric Patients

The safety of GENVOYA in HIV-1 infected pediatric subjects was evaluated in treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), and in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=23) through Week 24 (cohort 2) in an open-label clinical trial (Study 106). With the exception of a decrease in the mean CD4+ cell count observed in cohort 2 of Study 106, the safety profile in pediatric subjects who received treatment with GENVOYA was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.

Bone Mineral Density Effects

Cohort 1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg)

Among the subjects in cohort 1 receiving GENVOYA, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were ?0.07 for lumbar spine and ?0.20 for TBLH at Week 48. One GENVOYA subject had significant (at least 4%) lumbar spine BMD loss at Week 48.

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Among the subjects in cohort 2 receiving GENVOYA, mean BMD increased from baseline to Week 24, +2.9% at the lumbar spine and +1.7% for TBLH. Mean changes from baseline BMD Z-scores were -0.06 for lumbar spine and -0.18 for TBLH at Week 24. Two GENVOYA subjects had significant (at least 4%) lumbar spine BMD loss at Week 24.

Change from Baseline in CD4+ cell counts

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Cohort 2 of Study 106 evaluated pediatric subjects (N=23) who were virologically- suppressed and who switched from their antiretroviral regimen to GENVOYA. Although all subjects had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Week 24. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 24 are presented in Table 5. All subjects maintained their CD4+ cell counts above 400 cells/mm3.

Table 5              Mean Change in CD4+ Count and Percentage from Baseline to Week 24 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to GENVOYA

(please refer to label to view Table 5)

8 Use in Specific Populations

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and effectiveness of GENVOYA for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 25 kg.

Use of GENVOYA in pediatric patients between the ages of 12 to less than 18 years and weighing at least 35 kg is supported by studies in adults and by a study in treatment-naïve HIV-1 infected pediatric subjects ages 12 to less than 18 years GENVOYAand weighing at least 35 kg (cohort 1 of Study 106, N=50). The safety and efficacy of GENVOYA in these pediatric subjects was similar to that in adults.

Use of GENVOYA in pediatric patients weighing at least 25 kg is supported by studies in adults and by an open-label trial in virologically-suppressed pediatric subjects ages 6 to less than 12 years and weighing at least 25 kg, in which subjects were switched from their antiretroviral regimen to GENVOYA (cohort 2 of Study 106, N=23). The safety in these subjects through 24 weeks was similar to that in antiretroviral treatment-naïve adults with the exception of a decrease in mean change from baseline in CD4+ cell count.

Safety and effectiveness of GENVOYA in pediatric patients less than 25 kg have not been established.

8.5 Geriatric Use

(additions underlined)

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 adults between 18 and less than 65 years of age.

08/15/2017 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Clinical Trials in Treatment-Naïve Adults

Week 144 replaces Week 96 throughout this section, including in Table 2 title

Renal Laboratory Tests and Renal Safety

Treatment-Naïve Adults:

144 replaces 96 throughout this section.

Bone Mineral Density Effects

Treatment-Naïve Adults:

Additions and/or revisions underlined:

In a pooled analysis of Studies 104 and 111, the effects of GENVOYA compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 144 were assessed by dual-energy X-ray absorptiometry (DXA).  The mean percentage change in BMD from baseline to Week 144 was ?0.92% with GENVOYA compared to ?2.95% with STRIBILD at the lumbar spine and ?0.75% compared to ?3.36% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects.

Laboratory Abnormalities:

144 replaces 96 throughout section including in Table 3 title and Table 4 data

04/07/2017 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Lactic Acidosis/Severe Hepatomegaly with Steatosis

(Additions and/or revisions are underlined)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of GENVOYA, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported…

Patient Information

(Additions and/or revisions are underlined)

What are the possible side effects of GENVOYA?

GENVOYA may cause serious side effects, including:

• Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

 

02/15/2017 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Clinical Trials in Virologically Suppressed Adults

The safety of GENVOYA 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 GENVOYA. Overall, the safety profile of GENVOYA in subjects in this study was similar to that of treatment-naïve subjects. Additional adverse reactions observed with GENVOYA 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.

 

Renal Laboratory Tests and Renal Safety

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 GENVOYA, at Week 96 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to GENVOYA.

 

Bone Mineral Density Effects

Virologically Suppressed Adults:

In Study 109, TDF-treated subjects were randomized to continue their TDF-based regimen or switch to GENVOYA; changes in BMD from baseline to Week 96 were assessed by DXA. Mean BMD increased in subjects who switched to GENVOYA (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 GENVOYA 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 GENVOYA subjects and 7% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Prospective pregnancy data from the Antiviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects of miscarriage…

 

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.

8.2 Lactation

(Additions and/or revisions are underlined)

Based on published data, emtricitabine has been shown to be present in human breast milk…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Additions and/or revisions are underlined)

What is the most important information I should know about GENVOYA? GENVOYA can cause serious side effects, including:

3. Worsening of Hepatitis B infection. GENVOYA is not for use to treat chronic hepatitis B virus (HBV) infection. If you have hepatitis B virus (HBV) infection and take GENVOYA, your HBV may get worse (flare-up) if you stop taking GENVOYA. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

• It is not known if GENVOYA is safe and effective in people who have both HIV-1 and HBV infection.

What is GENVOYA?

GENVOYA is a prescription medicine that is used without other antiviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older:

02/15/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Clinical Trials in Pediatric Subjects:

The safety of GENVOYA 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 GENVOYA was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.

Among the 50 pediatric subjects receiving GENVOYA, 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 GENVOYA subject had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 48.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Prospective pregnancy data from the Antiviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects of miscarriage…

 

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.

8.2 Lactation

(Additions and/or revisions are underlined)

Based on published data, emtricitabine has been shown to be present in human breast milk…

8.4 Pediatric Use

(Additions and/or revisions are underlined)

… 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)…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(Additions and/or revisions are underlined)

What is the most important information I should know about GENVOYA? GENVOYA can cause serious side effects, including:

3. Worsening of Hepatitis B infection. GENVOYA is not for use to treat chronic hepatitis B virus (HBV) infection. If you have hepatitis B virus (HBV) infection and take GENVOYA, your HBV may get worse (flare-up) if you stop taking GENVOYA. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.

• It is not known if GENVOYA is safe and effective in people who have both HIV-1 and HBV infection.

What is GENVOYA?

GENVOYA is a prescription medicine that is used without other antiviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older:

12/07/2016 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 New Onset or Worsening Renal Impairment

(Additions and/or revisions underlined)

… In a study of virologically suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 108 weeks, GENVOYA 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  GENVOYA 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.  is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating GENVOYA and during therapy in all patients as clinically appropriate. Discontinue GENVOYA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

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 GENVOYA 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 GENVOYA 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, GENVOYA was resumed and this subject’s renal function returned to baseline. Overall, renally impaired subjects receiving GENVOYA 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 GENVOYA in subjects in this study was similar to that of subjects with normal renal function.

Renal Laboratory Tests and Renal Safety

Bone Mineral Density Effects

Virologically Suppressed Adults:

… BMD declines of 7% or greater at the femoral neck were experienced by 1% of GENVOYA subjects and 4% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known.

Clinical Trials in Pediatric Patients

The safety of GENVOYA 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 24 weeks …

7 Drug Interactions

7.1 Not Recommended with Other Antiretroviral Medications

(Additions and/or revisions underlined in subheading title)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Summary

… Available data from the APR through January 2016 show no birth defects reported for elvitegravir or cobicistat, and no difference in the risk of overall major birth defects for emtricitabine (2.42%) compared with the background rate for major birth defects …

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

3155 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including 2145 exposed in the first trimester and 1010 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 2.42% (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%) …

 

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PATIENT INFORMATION

(Additions and/or revisions underlined)

What are the possible side effects of GENVOYA? GENVOYA may cause serious side effects, including:

•           See “What is the most important information I should know about GENVOYA?”

New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and taking during treatment with GENVOYA…

09/15/2016 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

Table 1- Drugs that are Contraindicated with GENVOYA

Drug Class : Antipsychotics (added)

  Drugs within Class that are Contraindicated with GENVOYA :

 

      Lurasidone

Clinical Comment :Potential for serious and/or life-threatening reactions.

 

 

      Pimozide

Clinical Comment : Potential for serious and/or life-threatening reactions such as arrhythmias.

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

 

Table 5

Established and Other Potentially Significant Drug Interactions: Alterationin Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class:  Antipsychotics: e.g.,( following drugs added)

Drug name:

perphenazine

risperidone

thioridazine

 

Effect on Concentration: Antipsychotic concentration will increase

Clinical Comment : A decrease in the dose of antipsychotics that are metabolized by CYP3A4 or CYP2D6 may be needed when coadministered with GENVOYA.

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Who should not take GENVOYA?

Do not take GENVOYA if you also take a medicine that contains:

·       lurasidone (LATUDA®)

09/07/2016 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

Lactic Acidosis/Severe Hepatomegaly with Steatosis

…however, cases have also been reported in patients with no known risk factors… Since TAF and emtricitabine are nucleos(t)ide analogs, treatment with GENVOYA 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).

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions replaces Avoid Use with Other Antiretroviral Products

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.

• 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 GENVOYA therapy; review concomitant medications during GENVOYA therapy; and monitor for the adverse reactions associated with the concomitant drugs.

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

 

6 Adverse Reactions

Clinical Trials Experience

Clinical Trials in Treatment Naïve Adults (revisions are underlined below)

• The primary safety assessment of GENVOYA was based on Week 96

• The proportion of subjects who discontinued treatment with GENVOYA or STRIBILD® due to adverse events, regardless of severity, was 1% and 2%, respectively.

• Table 2: Adverse Reactions (All Grades) Reported in greater than or equal to 5% of HIV-1 Infected Treatment Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 96 analysis)

Renal Laboratory Tests (revisions are underlined below)

Treatment Naïve Adults: (revisions are underlined below)

• Cobicistat (a component of GENVOYA) 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. (addition)

• In two 96-week randomized, controlled trials.

• mean serum creatinine increased by less than 0.1 mg per dL in the GENVOYA group and by 0.1 mg per dL in the STRIBILD group from baseline to Week 96. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and 42 mg per gram at Week 96 in the GENVOYA group. Median UPCR was 44 mg per gram at baseline and 54 mg per gram at Week 96 in those receiving STRIBILD.

Bone Mineral Density Effects

Treatment Naïve Adults (revisions are underlined below)

• In the pooled analysis of Studies 104 and 111, bone mineral density (BMD) from baseline to Week 96 was assessed by dual-energy X-ray absorptiometry (DXA) to compare the bone safety of TAF to that of TDF when administered as GENVOYA or STRIBILD, respectively. Mean BMD decreased from baseline to Week 96 by minus 0.96% with GENVOYA compared to minus  2.79% with STRIBILD at the lumbar spine and minus 0.67% compared to minus 3.28% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 12% of GENVOYA subjects and 26% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 11% of GENVOYA subjects and 26% of STRIBILD subjects.

Laboratory Abnormalities:

• Table 3: Laboratory Abnormalities (Grades 3–4) Reported in greater than or equal to 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 96 analysis)

  • Table extensively changed; please refer to label.

7 Drug Interactions

Drugs without Clinically Significant Interactions with GENVOYA

• and velpatasvir (added)

Potential for GENVOYA to Affect Other Drugs

• TAF is not an inhibitor or inducer of CYP3A in vivo. (sentence added)

8 Use in Specific Populations

Hepatic Impairment

• GENVOYA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). (revised)

Lactation (PLLR Conversion)

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.

• 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 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 a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving GENVOYA.

Data

Human Data

• Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral

resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.

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 patents aged 12 years and older with body weight greater than or equal to 35 kg. Use of GENVOYA in this age group is supported by studies in adults and by a 24-week open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old treated with GENVOYA (Study 106). The safety and efficacy of GENVOYA in these subjects was similar to that in antiretroviral treatment-naïve adults.

• Safety and effectiveness of GENVOYA in pediatric patients less than 12 years of age or less than 35 kg have not been established. (Addition underlined).

Pregnancy (PLLR Conversion)

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

• There are insufficient human data on the use of GENVOYA during pregnancy to inform a drug-associated risk of birth defects and 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 show no birth defects reported for elvitegravir or cobicistat, and no difference in the risk of overall major birth defects for emtricitabine (2.4%) 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). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. In animal studies, no adverse developmental effects were observed when thecomponents 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. 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.

Data

Human Data

• Elvitegravir: Based on prospective reports from the APR through July 2015 of 49 exposures to elvitegravir-containing regimens during pregnancy resulting in live births (including 31 exposed in the first trimester), there have been no birth defects reported.

• Cobicistat: Based on prospective reports from the APR through July 2015 of 50 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including 32 exposed in the first trimester), there have been no birth defects reported.

• Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including 1984 exposed in the first trimester and 949 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 2.4% (95% CI: 1.7% to 3.1%) 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 postimplantation 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 was 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 a lower tenofovir exposure in rats and mice was 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.

Renal Impairment

• GENVOYA is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). (sentence added)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Co-Infection replaces Testing Prior to Initiation of GENVOYA and HBV Co-Infection

Missed Dosage

• To avoid missing doses as it can result in development of resistance. (added phrase)

Patient Information

Severe Liver Problems

Call your healthcare provider right away if you get any of the following symptoms of liver problems:

• Pain, aching, or tenderness in the right side of your stomach area replaces stomach pain

What is GENVOYA?

• It is not known if GENVOYA is safe and effective in children under 12 years of age or who weigh less than 77 lbs. (addition is underlined)

 

03/08/2016 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

• Table: Established and Other Potentially Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
• Antipsychotics: quetiapine
  • Initiation of Genvoya in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
  • Initiation of quetiapine in patients taking Genvoya: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.