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2015年11月5日，美国FDA批准Genvoya（一款固定剂量的复方片剂，由埃替格韦、Cobicistat、恩曲他滨及替诺福韦艾拉酚胺组成）作为一种完整方案在成年与12岁及以上年龄儿科患者中用于HIV-1感染治疗。
美国疾病预防与控制中心估计，有120万13岁及以上年龄的人感染有HIV，这一年龄组中另有逾15万人有HIV，但他们尚未意识到自己的感染。在过去十年，感染HIV患者的人数已经增长，而每年新HIV感染人数仍保持相对稳定。
对含有一种新形式替诺福韦复方药物的批准为HIV-1感染患者提供了另一种有效的日用一次的完整方案，FDA药物评价与研究中心抗微生物产品办公室主任、医学博士 Cox称。
Genvoya被批准用于从未使用过HIV治疗药物的（既往未治疗的）HIV感染成年患者与 12岁及以上年龄，体重至少35kg的儿童，以及 HIV-1病毒目前被抑制的HIV感染成年患者。虽然Genvoya未被推荐用于严重肾损伤患者，但那些有中重肾损伤的患者可以使用Genvoya。
Genvoya用于成年患者的安全性及有效性在3171名受试者参与的四项临床试验中得到评价。根据试验，受试者被随机配给 Genvoya或另一种FDA批准的HIV治疗药物。结果显示，Genvoya能有效降低病毒载量，并与其它治疗方案相差无几。
Genvoya 含有一种新形式的之前未被批准的替诺福韦。这种新形式的替诺福韦在血流中提供了较低水平的药物，但在HIV-1复制的细胞内却有较高的水平。这款药物的开发旨在帮助降低一些药物的副作用。
Genvoya似乎与更少的肾脏毒性相关，与先前批准的基于实验室检测的包含替诺福韦的方案相比，Genvoya能减少骨密度。在研究中，接受Genvoya治疗的患者与接受其它治疗方案的患者相比，其血脂（总胆固醇及低密度脂蛋白）会经历更大程度的降低。
Genvoya带有一项黑框警告，提醒患者与医疗保健提供者这款药物可导致血液中乳酸积聚及严重的肝脏问题，而这两种情况均有可能是致命的。该黑框警告还指出，Genvoya未被批准用于治疗慢性乙肝病毒感染。与Genvoya相关的最常见副作用是恶心。
严重副作用包括新的或日益恶化的肾脏问题、骨密度降低、脂肪重新分配及免疫系统变化（免疫重构综合征）。建议卫生保健提供者监控患者的肾脏及骨副作用。Genvoya 不应与其它抗病毒产品一起使用，它与多种其它常用药物可能有药物相互作用。Genvoya由加州福斯特城的吉利德科学公司上市销售。
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 BSee 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. (5.1)
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. (5.2)
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. (1)
DOSAGE AND ADMINISTRATION
Testing: Prior to initiation of GENVOYA, patients should be tested for hepatitis B infection. (2.1)
Recommended dosage: One tablet taken orally once daily with food. (2.2)
Renal impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute. (2.3)
Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment. (2.4)
DOSAGE FORMS AND STRENGTHS
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide. (3)
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. (4)
Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of GENVOYA and possible resistance. (4)
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. (5.3)
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. (5.4)
Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.5)
Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.6)
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. (5.7)
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. (5.8)
ADVERSE REACTIONS
Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
GENVOYA should not be administered with other antiretroviral medications for treatment of HIV-1 infection. (5.3, 7.1)
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. (4, 7.2, 7.3, 12.3)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1)
Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of GENVOYA
Prior to initiation of GENVOYA, patients should be tested for hepatitis B infection [see Warnings and Precautions (5.2)].
2.2 Recommended Dosage in Adults and Pediatric Patients 12 Years of Age and Older with Body Weight at Least 35 kg (at Least 77 lbs)
Weight at Least 35 kg (at Least 77 lbs)The recommended dosage of GENVOYA is one tablet taken orally once daily with food [see Clinical Pharmacology (12.3)].
2.3 Dosage Adjustment in Patients with Renal Impairment
No dosage adjustment of GENVOYA is required in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.
GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population is insufficient [see Warnings and Precautions (5.7), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
2.4 Use in Patients with Hepatic Impairment
GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Each GENVOYA tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF) (equivalent to 11.2 mg of tenofovir alafenamide fumarate).
The tablets are green, capsule-shaped, film-coated tablets, debossed with "GSI" on one side of the tablet and the number "510" on the other side of the tablet.
4 CONTRAINDICATIONS(What is this?)
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 and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed in Table 1 [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].
Table 1 Drugs that are Contraindicated with GENVOYA
Indicates that a drug-drug interaction trial was conducted.
See Drug Interactions (7), Table 5 for sildenafil when used for erectile dysfunction.
See Drug Interactions (7), Table 5 for parenterally administered midazolam
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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) [see Boxed Warning].
5.2 Patients Coinfected with HIV-1 and HBV
It is recommended that all patients with HIV-1 be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1)]. GENVOYA is not approved for the treatment of chronic HBV infection and the safety and efficacy of GENVOYA have not been established in patients coinfected with HIV-1 and HBV. 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 TDF, and may occur with GENVOYA. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients coinfected with HIV-1 and HBV who discontinue GENVOYA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure [see Boxed Warning].
5.3 Avoid Use with Other Antiretroviral Products
Coadministration of GENVOYA with other antiretroviral products is not recommended [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
GENVOYA is not recommended for coadministration with drugs that contain any of the following:
elvitegravir,
cobicistat,
emtricitabine,
tenofovir disoproxil fumarate,
lamivudine,
adefovir dipivoxil,
ritonavir.
5.4 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 [see Contraindications (4) and Drug Interactions (7.5)]:
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.
5.5 Fat Redistribution
Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.6 Immune Reconstitution Syndrome
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, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.7 New Onset or Worsening Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of GENVOYA, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of GENVOYA in treatment naïve subjects and in virally suppressed subjects switched to GENVOYA with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 43 weeks, GENVOYA was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions (6.1)]. GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
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.
Estimated creatinine clearance, urine glucose and urine protein should be assessed before initiating GENVOYA therapy and should be monitored during therapy in all patients. Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue GENVOYA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
Cobicistat, a component of GENVOYA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Adverse Reactions (6.1)]. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
5.8 Bone Loss and Mineralization Defects
Bone Mineral Density (BMD):
In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in bone mineral density and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naïve adults, a significant decline in bone mineral density was observed in 15% of subjects treated with GENVOYA [see Adverse Reactions (6.1)]. The long-term clinical significance of these changes has not been established.
Assessment of BMD should be considered for adults and pediatric patients treated with GENVOYA who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
Mineralization Defects:
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.7)]. While not observed in clinical studies of GENVOYA, the risk of osteomalacia with GENVOYA is not known.
6 ADVERSE REACTIONS
The following adverse drug reactions are discussed in other sections of the labeling:
Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning and Warnings and Precautions (5.1)]
Severe Acute Exacerbations of Hepatitis B [see Boxed Warning and Warnings and Precautions (5.2)]
Immune Reconstitution Syndrome [see Warnings and Precautions (5.6)]
New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.7)]
Bone Loss and Mineralization Defects [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials in Treatment Naïve Adults
The primary safety assessment of GENVOYA was based on Week 48 pooled data from 1733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of GENVOYA once daily [see Clinical Studies (14.2)].
The most common adverse reaction (all Grades) reported in at least 10% of subjects in the GENVOYA group was nausea. The proportion of subjects who discontinued treatment with GENVOYA or STRIBILD® due to adverse events, regardless of severity, was 0.9% and 1.5%, respectively. Table 2 displays the frequency of adverse reactions (all Grades) greater than or equal to 5% in the GENVOYA group.
Table 2 Adverse Reactions* (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 48 analysis)
Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator
The majority of events presented in Table 2 occurred at severity Grade 1.
Clinical Trials in Virologically Suppressed Adults
The safety of GENVOYA in virologically-suppressed adults was based on Week 48 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 one tablet taken orally once daily. Overall, the safety profile of GENVOYA in subjects in this study was similar to that of treatment naïve subjects [see Clinical Studies (14.3)].
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 43 weeks. Of these subjects, 64% had previously been on a stable TDF-containing regimen. Among the 80 subjects with baseline eGFR less than 50 mL per minute receiving GENVOYA, two subjects developed worsening renal impairment and discontinued treatment. One subject with an eGFR over 50 mL per minute developed transient acute renal failure. Otherwise, the safety profile of GENVOYA in subjects in this study was similar to that of subjects with normal renal function [see Clinical Studies (14.4)].
Renal Laboratory Tests
Treatment Naïve Adults:
In two 48-week randomized, controlled trials in a total of 1733 treatment naïve adults with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL in the GENVOYA and STRIBILD groups from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48 in the GENVOYA group. Median UPCR was 44 mg per gram at baseline and 55 mg per gram at Week 48 in those receiving STRIBILD.
Virologically Suppressed Adults:
In a study of 1436 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 48 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to GENVOYA. Median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48 in subjects switching to GENVOYA. In subjects remaining on their initial regimen, UPCR was 60 mg per gram at baseline and 63 mg per gram at Week 48.
Adult Subjects with Renal Impairment:
In a 24-week trial in 248 subjects with renal impairment (baseline eGFR 30 to 69 mL per minute) who received GENVOYA, mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.
Bone Mineral Density Effects
Treatment Naïve Adults:
In the pooled analysis of Studies 104 and 111, bone mineral density (BMD) from baseline to Week 48 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 48 -1.30% with GENVOYA compared to -2.86% with STRIBILD at the lumbar spine and -0.66% compared to -2.95% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of GENVOYA subjects and 22% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of GENVOYA subjects and 19% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known.
Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the GENVOYA group and 12 (1.4%) subjects in the STRIBILD group through 48 weeks.
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 48 were assessed by DXA. Mean BMD increased in subjects who switched to GENVOYA (1.86% lumbar spine, 1.95% total hip) and decreased slightly in subjects who continued their baseline regimen (-0.11% lumbar spine, -0.14% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% 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 1% of GENVOYA subjects and 4% of subjects who continued their TDF-based regimen.
Fractures (excluding fingers and toes) were reported in 10 (1%) subjects who switched to GENVOYA and 2 (0.4%) subjects who continued their TDF-based regimen through 48 weeks.
Laboratory Abnormalities:
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving GENVOYA in Studies 104 and 111 are presented in Table 3.
Table 3 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 48 analysis)
Frequencies are based on treatment-emergent laboratory abnormalities.
Serum Lipids:
Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD.
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 4.
Table 4 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Studies 104 and 111*
Excludes subjects who received lipid lowering agents during the treatment period.
The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values
Clinical Trials in Pediatric Subjects:
The safety of GENVOYA in HIV-1 infected, treatment naïve pediatric subjects aged 12 to less than 18 years was evaluated through 24 weeks in an open-label clinical trial (Study 106) [see Clinical Studies (14.5)]. The safety profile in 23 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 23 pediatric subjects receiving GENVOYA for 24 weeks, mean BMD increased from baseline to Week 24, + 1.7% at the lumbar spine and + 0.8% for the total body less head. Mean changes from baseline BMD Z-scores were -0.10 for lumbar spine and -0.11 for total body less head at Week 24. Two GENVOYA subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.
7 DRUG INTERACTIONS
7.1 Other Antiretroviral Medications
GENVOYA is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of GENVOYA with other antiretroviral medications for treatment of HIV-1 infection should be avoided. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications, Warnings and Precautions (5.3, 5.4) and Clinical Pharmacology (12.3)].
7.2 Potential for GENVOYA to Affect Other Drugs
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 (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.
7.3 Potential for Other Drugs to Affect One or More Components of GENVOYA
Elvitegravir and cobicistat, components of GENVOYA, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.
Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat, elvitegravir, and TAF, which may lead to loss of therapeutic effect of GENVOYA and development of resistance (see Table 5).
Coadministration of GENVOYA with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 5).
TAF, a component of GENVOYA, is a substrate of P-gp, BCRP, OATP1B1 and OATP1B3. Drugs that inhibit P-gp and/or BCRP, such as cobicistat, may increase the absorption of TAF (see Table 10). However, when TAF is administered as a component of GENVOYA, its availability is increased by cobicistat and a further increase of TAF concentrations is not expected upon coadministration of an additional P-gp and/or BCRP inhibitor. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF.
7.4 Drugs Affecting Renal Function
Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of GENVOYA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.7)].
7.5 Established and Other Potentially Significant Interactions
Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either GENVOYA, the components of GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as individual agents and/or in combination, or are predicted drug interactions that may occur with GENVOYA [for magnitude of interaction, see Clinical Pharmacology (12.3)]. The table includes potentially significant interactions but is not all inclusive.
Table 5 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
This table is not all inclusive.
↑ = Increase, ↓ = Decrease, ↔ = No Effect
Indicates that a drug-drug interaction trial was conducted
7.6 Drugs without Clinically Significant Interactions with GENVOYA
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, and sofosbuvir.
8 USE IN SPECIFIC POPULATIONS
8.1 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.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to GENVOYA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Animal Data
Elvitegravir: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were, respectively, 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Cobicistat: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal NOAELs in rats and rabbits were, respectively, 1.6 and 3.8 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Emtricitabine: The incidence of fetal variations and malformations was not increased 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.
Tenofovir Alafenamide (TAF): Embryonic fetal development studies have been performed in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus due to TAF. The embryo-fetal NOAELs in rats and rabbits occurred at TAF exposures similar to and 53 times higher than, respectively, the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir, the observed tenofovir exposure in rats and rabbits were 59 and 93 times higher than human tenofovir exposures at the recommended daily doses, respectively.
8.3 Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. It is not known whether elvitegravir, cobicistat, or TAF is excreted in human milk.
In humans, 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.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving GENVOYA.
8.4 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 (Study 106) [see Dosage and Administration (2.2), 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 have not been established.
8.5 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.
8.6 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)].
No dosage adjustment of GENVOYA is required in adult 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 (5.7), and Clinical Pharmacology (12.3)].
8.7 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
10 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.
Elvitegravir: Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. In one study, boosted elvitegravir equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Cobicistat: Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, a single dose of cobicistat 400 mg (2.7 times the dose in GENVOYA) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in GENVOYA) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the therapeutic dose of TAF. A single dose of 125 mg TAF (12.5 times the dose in GENVOYA) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.
11 DESCRIPTION
GENVOYA is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide for oral administration.
Elvitegravir is an HIV-1 integrase strand transfer inhibitor.
Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
Emtricitabine is a synthetic nucleoside analog of cytidine.
Tenofovir alafenamide is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate.
Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (equivalent to 11.2 mg of tenofovir alafenamide fumarate). The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing FD&C Blue No. 2/indigo carmine aluminum lake, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Elvitegravir: The chemical name of elvitegravir is 6-(3-chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:
Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl), 5-thiazolylmethyl ester, (3R,6R,9S).
It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:
Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide drug substance is a white to pale yellow powder with a solubility of 0.1 mg per mL in water at 20 °C.
Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:
Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
It has a molecular formula of C23H31O7N6P and a molecular weight of 534.5. It has the following structural formula:
Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].
12.2 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 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the 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.
Effects on Serum Creatinine
The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with an eGFR of at least 80 mL per minute (N=18) and with an eGFR of 50 to 79 mL per minute (N=12). A statistically significant change of eGFRCG from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with an eGFR of at least 80 mL per minute (-9.9 ± 13.1 mL/min) and subjects with an eGFR of 50 to 79 mL per minute (-11.9 ± 7.0 mL per minute). These decreases in eGFRCG were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with an eGFR of at least 50 mL per minute, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
12.3 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.
Table 6 Pharmacokinetic Properties of the Components of GENVOYA
PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1.
* Values refer to mean systemic exposure. Elvitegravir light meal=~373 kcal, 20% fat; GENVOYA light meal=~400 kcal, 20% fat; elvitegravir and GENVOYA high fat meal=~800 kcal, 50% fat. Based on the effect of food on elvitegravir, GENVOYA should be taken with food.
In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.
t 1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs.
Dosing in mass balance studies: elvitegravir (single dose administration of [ 14C] elvitegravir coadministered with 100 mg ritonavir); cobicistat (single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14C] TAF).
Table 7 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA with Food in HIV-Infected Adults
CV = Coefficient of Variation; NA = Not Applicable
* From Intensive PK analysis in Study 102, N=19
From Population PK analysis in Studies 104 and 111, N=539
From Population PK analysis in Studies 104 and 111, N=841
In Studies 104 and 111, a 10 mg oral dose of TAF in GENVOYA resulted in greater than 90% lower concentrations of tenofovir in plasma as compared to a 300 mg oral dose of TDF in STRIBILD.
Special Populations
Patients with Renal Impairment
The pharmacokinetics of GENVOYA in HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated in a subset of virologically suppressed subjects in an open-label trial, Study 112 (Table 8).
Table 8 Pharmacokinetics of GENVOYA in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function
From a phase 2 study in HIV-infected adults with normal renal function
These subjects from Study 112 had an eGFR ranging from 60 to 69 mL per minute.
Study 112
AUC last
Patients with Hepatic Impairment
Elvitegravir and Cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects [see Use in Specific Populations (8.7)].
Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Alafenamide (TAF): Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate hepatic impairment [see Use in Specific Populations (8.7)].
Hepatitis B and/or Hepatitis C Virus Co-infection
Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.
Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.
Emtricitabine and Tenofovir Alafenamide (TAF): Pharmacokinetics of emtricitabine and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Race
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.
Gender
Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.
Pediatric Patients
Exposures of TAF achieved in 24 pediatric subjects aged 12 to less than 18 years who received GENVOYA in Study 106 were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of GENVOYA, but were overall deemed acceptable based on exposure-response relationships; the other components of GENVOYA had similar exposures in adolescents compared to treatment-naïve adults [see Use in Specific Populations (8.4)].
Geriatric Patients
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of GENVOYA showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age [see Use in Specific Populations (8.5)].
Drug Interaction Studies
[see also Contraindications (4) and Drug Interactions (7)]
The drug-drug interaction studies described in Tables 9–11 were conducted with GENVOYA, elvitegravir (coadministered with cobicistat or ritonavir), cobicistat administered alone, or TAF administered alone.
As GENVOYA should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided [see Warnings and Precautions (5.3)].
The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 9. The effects of coadministered drugs on the exposure of TAF are shown in Table 10. The effects of GENVOYA or its components on the exposure of coadministered drugs are shown in Table 11. For information regarding clinical recommendations, see Drug Interactions (7).
Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug*
All interaction studies conducted in healthy volunteers.
Mean ratio of cobicistat PK parameters (90% CI) was 1.25 (1.18,1.32) for C max, 1.59 (1.49,1.70) for AUC, and 4.25 (3.47,5.22) for C min.
Study conducted with GENVOYA
Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Alafenamide (TAF) in the Presence of the Coadministered Drug*
NC = Not Calculated
* All interaction studies conducted in healthy volunteers.
Study conducted with GENVOYA.
Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of GENVOYA or the Individual Components
N/A = Not Applicable; NC = Not Calculated
All interaction studies conducted in healthy volunteers.
The predominant circulating metabolite of sofosbuvir.
Study conducted with STRIBILD.
Study conducted with GENVOYA.
Comparison based on rifabutin 300 mg once daily.
12.4 Microbiology
Mechanism of Action
Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
Tenofovir Alafenamide (TAF): TAF is a phosphonoamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.
Tenofovir has activity that is specific to human immunodeficiency virus and hepatitis B virus. Cell culture studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Antiviral Activity in Cell Culture
Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (TAF): The combination of elvitegravir, emtricitabine, and TAF was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat. In addition, elvitegravir, cobicistat, emtricitabine, and TAF were not antagonistic with a panel of representatives from the major classes of approved anti-HIV-1 agents (INSTIs, NNRTIs, NRTIs, and PIs).
Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture.
Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013–0.64 microM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 microM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 microM).
Tenofovir Alafenamide (TAF): The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for TAF ranged from 2.0 to 14.7 nM.
TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).
Resistance
In Cell Culture
Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M.
Emtricitabine: HIV-1 isolates with reduced susceptibility to emtricitabine have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V or I substitutions in HIV-1 RT.
Tenofovir Alafenamide (TAF): HIV-1 isolates with reduced susceptibility to TAF have been selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT has been observed. HIV-1 isolates with the K65R substitution have reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.
In Clinical Trials
In Treatment-Naïve Subjects:
In a pooled analysis of antiretroviral-naïve subjects receiving GENVOYA in Studies 104 and 111, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 48, or at time of early study drug discontinuation. As of Week 48, the development of genotypic resistance to elvitegravir, emtricitabine, or TAF was observed in 7 of 14 subjects with evaluable resistance data from paired baseline and GENVOYA treatment-failure isolates (7 of 866 subjects [0.8%]) compared with 6 of 17 treatment-failure isolates from subjects with evaluable resistance data in the STRIBILD treatment group (6 of 867 subjects [0.7%]). Of the 7 subjects with resistance development in the GENVOYA group, the resistance–associated substitutions that emerged were M184V/I (N=7) and K65R (N=1) in reverse transcriptase and T66T/A/I/V (N=2), E92Q (N=2), E138K (N=1), Q148Q/R (N=1) and N155H (N=1) in integrase. Three subjects had virus with emergent R, H, or E at the polymorphic Q207 residue in reverse transcriptase. Of the 6 subjects with resistance development in the STRIBILD group, the resistance-associated substitutions that emerged were M184V/I (N=5) and K65R (N=2) in reverse transcriptase and E92E/Q (N=2), E138K (N=3) and Q148R (N=2) in integrase. In both treatment groups, most subjects who developed substitutions associated with resistance to elvitegravir also developed emtricitabine resistance-associated substitutions. The genotypic resistance results were confirmed by phenotypic analyses.
In Virologically Suppressed Subjects:
One subject was identified with emergent resistance to GENVOYA (M184M/I) out of 4 virologic failure subjects in a clinical study of virologically-suppressed subjects who switched from a regimen containing emtricitabine/TDF and a third agent to GENVOYA (Study 109, N=799).
Cross-Resistance
No cross-resistance has been demonstrated for elvitegravir-resistant HIV-1 isolates and emtricitabine or tenofovir, or for emtricitabine- or tenofovir-resistant isolates and elvitegravir.
Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravir-resistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of amino acid substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into a wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir). Some viruses expressing elvitegravir or raltegravir resistance amino acid substitutions maintain susceptibility to dolutegravir.
Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabine-resistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine.
Tenofovir Alafenamide (TAF): Tenofovir resistance substitutions, K65R and K70E, result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir.
HIV-1 with multiple TAMs (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R, showed reduced susceptibility to TAF in cell culture.
13 NONCLINICAL TOXICOLOGY
13.1 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-fold, 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-fold, 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-fold higher exposures (AUC), respectively, than in humans at the therapeutic 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-fold 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 therapeutic 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-fold 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-fold 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 therapeutic 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-fold or in male and female mice at approximately 60-fold 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-fold 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 5 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.
13.2 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
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
The efficacy and safety of GENVOYA were evaluated in the studies summarized in Table 12.
Table 12 Trials Conducted with GENVOYA in Subjects with HIV-1 Infection
Randomized, double blind, active controlled trial.
Randomized, open label, active controlled trial.
HIV-1 RNA less than 50 copies per mL.
Open label trial.
eGFR of 30 to 69 mL per minute by Cockcroft-Gault method
14.2 Clinical Trial Results in HIV-1 Treatment-Naïve Subjects
In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18–76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3 (range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm3.
Pooled treatment outcomes of Studies 104 and 111 through 48 weeks are presented in Table 13.
Table 13 Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 48* in Treatment-Naïve Subjects
Week 48 window was between Day 294 and 377 (inclusive).
Included subjects who had ≥ 50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 48 was 230 cells per mm3 in GENVOYA-treated subjects and 211 cells per mm3 in STRIBILD-treated subjects.
14.3 Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to GENVOYA
In Study 109, the efficacy and safety of switching from either ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to GENVOYA once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (1196 of 1436 enrolled and treated were evaluable for efficacy). Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of GENVOYA prior to study entry. Subjects were randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N=799), or stay on their baseline antiretroviral regimen (N=397). Subjects had a mean age of 41 years (range 21–72), 90% were male, 67% were White, and 21% were Black. The mean baseline CD4+ cell count was 705 cells per mm3 (range 79–1951).
Subjects were stratified by prior treatment regimen. At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.
Treatment outcomes of Study 109 through 48 weeks are presented in Table 14.
Table 14 Virologic Outcomes of Study 109 at Week 48* in Virologically-Suppressed Subjects who Switched to GENVOYA
Week 48 window was between Day 294 and 377 (inclusive).
† Included subjects who had ≥ 50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization. In Study 109, the mean increase from baseline in CD4+ cell count at Week 48 was 33 cells per mm3 in GENVOYA-treated subjects and 27 cells per mm3 in subjects who stayed on their baseline regimen.
14.4 Clinical Trial Results in HIV-1 Infected Subjects with Renal Impairment
In Study 112, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method). Of the 248 enrolled, 6 were treatment naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to GENVOYA [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
The mean age was 58 years (range 24–82), with 63 subjects (26%) who were 65 years of age or older. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 664 cells per mm3 (range 126–1813). At Week 24, 95% (230/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA. Three subjects had virologic failure at Week 24.
14.5 Clinical Trial Results in HIV-1 Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18
In Study 106, the efficacy, safety, and pharmacokinetics of GENVOYA were evaluated in an open-label trial in HIV-1-infected treatment-naïve adolescents aged 12 to less than 18 years. Twenty-three subjects treated with GENVOYA once daily for 24 weeks had a mean age of 14 years; 52% were male, 17% were Asian, and 83% were black. At baseline, mean plasma HIV-1 RNA was 4.8 log10 copies per mL (35% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm3 (range: 104 to 748), and median CD4+ percentage was 23% (range: 7% to 41%).
At 24 weeks, the virologic response rate to GENVOYA in treatment naïve HIV-1 infected adolescents was similar to response rates in trials of treatment naïve HIV-1 infected adults; 91% achieved HIV-1 RNA less than 50 copies per mL. The mean increase from baseline in CD4+ cell count at Week 24 was 212 cells per mm3. Two subjects had virologic failure at Week 24; neither subject had evidence of resistance to GENVOYA.
16 HOW SUPPLIED/STORAGE AND HANDLING
GENVOYA tablets are green, capsule-shaped, film-coated tablets, debossed with "GSI" on one side of the tablet and the number "510" on the other side. Each bottle contains 30 tablets (NDC 61958-1901-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.
Store below 30 °C (86 °F).
Keep container tightly closed.
Dispense only in original container.
Do not use if seal over bottle opening is broken or missing.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
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 [see Contraindications (4)]. Coadministration of GENVOYA with other antiretroviral products is not recommended [see Warnings and Precautions (5.3) and Drug Interactions (7)].
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) [see Boxed Warning and Warnings and Precautions (5.1)].
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 [see Boxed Warning, Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.5)].
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 [see Warnings and Precautions (5.6)].
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 [see Warnings and Precautions (5.7)].
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 considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.8)].
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 [see Use in Specific Populations (8.1)].
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 [see Use in Specific Populations (8.3)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34784acf-15ed-4715-b504-eb30430518e9&audience=consumer
美国上市包装
欧盟上市包装
四合一HIV新药Genvoya获FDA和欧盟批准上市
吉利德（Gilead）是艾滋病（HIV/AIDS）治疗领域的绝对领导者，该公司研发的四合一药物Stribild（E/C/F/TDF）在2012年和2013年相继在美欧2大市场上市后，极大地简化了HIV的治疗程序。
本月，吉利德新研发的四合一HIV新药Genvoya（E/C/F/TAF）在美国和欧盟监管方面相继传来特大喜讯：本月5号，Genvoya获得美国FDA批准；本月23号，Genvoya再获欧盟批准：
美国方面，Genvoya适用人群为：从未接受过治疗的HIV-1成人感染者，12岁及以上体重至少35公斤的HIV-1青少年感染者，以及HIV-1病毒目前被抑制的HIV-1成人感染者。
欧盟方面，Genvoya适用人群为：HIV-1成人感染者，12岁及以上体重至少35公斤的HIV-1青少年感染者，条件为不存在与整合酶抑制剂恩曲他滨或替诺福韦抗药性相关的任何突变。
在临床试验中，Genvoya（E/C/F/TAF）疗效媲美Stribild（E/C/F/TDF），同时能改善肾脏和骨骼参数，安全性更高，适用人群更广，该药将成为吉利德HIV专营权中的又一员猛将，也是全球HIV群体的新福音。
Stribild（elvitegravir 150 mg, cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg，E/C/F/TDF）是日服一次的四合一复方单片，该药由抗病毒药物elvitegravir(埃替拉韦)、emtricitabine (恩曲他滨)、药物增效剂cobicistat及tenofovir disoproxil fumarate（富马酸替诺福韦酯，TDF）组成，于2012年8月和2013年5月获美国和欧盟批准。
Genvoya（elvitegravir 150mg/cobicistat 150mg/emtricitabine 200 mg/tenofovir alafenamide 10mg，E/C/F/TAF）也是日服一次的四合一复方单片，该药由抗病毒药物elvitegravir(埃替拉韦)、emtricitabine (恩曲他滨)、药物增效剂cobicistat及tenofovir alafenamide（富马酸替诺福韦艾拉酚胺，TAF）组成。
两者的差别在于TDF和TAF。TAF是一种新型核苷类逆转录酶抑制剂（NRTI），在临床试验中已被证明在低于吉利德已上市药物Viread（富马酸替诺福韦酯，TDF）十分之一剂量时，就具有非常高的抗病毒疗效，同时可改善肾功能和骨骼方面参数。Viread也是一种新型NRTI药物，目前被广泛用于HIV（艾滋）和HBV（乙肝）的治疗，该药在2014年的销售额达到了11亿美元。而TAF有望取代TDF，成为吉利德巩固其感染性疾病治疗领域领导者地位的又一利器。
除了Genvoya（E/C/F/TAF）之外，吉利德还有另外两款基于TAF的复方药物正在接受FDA的审查，分别为F/TAF和R/F/TAF。此外，该公司还在研发另一款四合一复方产品D/C/F/TAF。值得一提的是，吉利德在去年底耗资1.25亿美元从Knight制药公司收购买进一张FDA的优先审评券（PRV），这张券在今年7月就用在了三合一HIV复方单片R/F/TAF的监管审查方面，有望使该三合一HIV新药提前4个月获批上市，造福全球艾滋病（AIDS）患者。
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