Viraday

When are you taking this medicine? Empty stomach Before food After food With a meal

Viraday uses

• Warning: posttreatment exacerbation of hepatitis b
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Viraday reviews

WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS B

Viraday is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Viraday have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, which are components of Viraday. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Viraday. If appropriate, initiation of anti-hepatitis B therapy may be warranted .

WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS B

See full prescribing information for complete boxed warning.

Viraday is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 who have discontinued EMTRIVA or VIREAD, two of the components of Viraday. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)

Boxed Warning, Lactic Acidosis/Severe Hepatomegaly with Steatosis	Removed 04/2017
Warnings and Precautions, Lactic Acidosis/Severe Hepatomegaly with Steatosis (5.3)	04/2017
Warnings and Precautions, Coadministration with Related Products (5.4)	04/2017
Warnings and Precautions, QTc Prolongation (5.5)	04/2017
Warnings and Precautions, Psychiatric Symptoms (5.6)	04/2017
Warnings and Precautions, Fat Redistribution (5.15)	04/2017

1 INDICATIONS AND USAGE

Viraday^® is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

Viraday, a combination of 2 nucleoside analog HIV-1 reverse transcriptase inhibitors and 1 non-nucleoside HIV-1 reverse transcriptase inhibitor, is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION

• Recommended dose in adults and pediatric patients (12 years of age and older and weighing at least 40 kg): One tablet once daily taken orally on an empty stomach, preferably at bedtime. (2)
• Dose in renal impairment: Should not be administered in patients with estimated creatinine clearance below 50 mL/min. (2)
• With rifampin coadministration, an additional 200 mg/day of Viraday is recommended for patients weighing 50 kg or more. (2)

Adults and pediatric patients 12 years of age and older with body weight at least 40 kg (at least 88 lbs): The dose of Viraday is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Renal impairment: Because Viraday is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment, such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

Rifampin coadministration: When Viraday is administered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of Viraday is recommended .

3 DOSAGE FORMS AND STRENGTHS

Viraday is available as tablets. Each tablet contains 600 mg of Viraday, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate (tenofovir DF), which is equivalent to 245 mg of tenofovir disoproxil. The tablets are pink, capsule shaped, film coated, debossed with "123" on one side, and plain faced on the other side.

Tablet containing 600 mg of Viraday, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. (3)

4 CONTRAINDICATIONS

• Previously demonstrated hypersensitivity to Viraday, a component of Viraday. (4.1)
• Coadministration with voriconazole due to a significant drug interaction with Viraday, a component of Viraday, that may decrease the therapeutic effectiveness of voriconazole and increase the risk of efavirenz-associated side effects. (4.2)

4.1 Hypersensitivity

Viraday is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to Viraday, a component of Viraday.

4.2 Contraindicated Drugs

Coadminstration of Viraday with voriconazole is contraindicated. Viraday, a component of Viraday, significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases Viraday plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because Viraday is a fixed-dose combination product, the dose of Viraday cannot be altered .

5 WARNINGS AND PRECAUTIONS

• Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
• QTc prolongation: Consider alternatives to Viraday in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. (5.5)
• Serious psychiatric symptoms: Immediate medical evaluation is recommended. (5.6, 6.1)
• Nervous system symptoms (NSS): NSS are frequent, usually begin 1–2 days after initiating therapy, and resolve in 2–4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (2, 5.7)
• New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with Viraday. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein before initiating treatment with Viraday and periodically during treatment. Avoid administering Viraday with concurrent or recent use of nephrotoxic drugs. (5.8)
• Pregnancy: Fetal harm may occur when administered to a pregnant woman during the first trimester. Women should be apprised of the potential harm to the fetus. A pregnancy registry is available. (5.9, 8.1)
• Rash: Discontinue if severe rash develops. (5.10, 6.1)
• Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. (5.11, 6.3, 8.6)
• Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathological fracture or other risk factors for osteoporosis or bone loss. (5.12)
• Convulsions: Use caution in patients with a history of seizures. (5.12)
• Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.14)
• Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.15)
• Coadministration with other products: Do not use with drugs containing emtricitabine, tenofovir disoproxil fumarate, or tenofovir alafenamide, including COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or with drugs containing lamivudine. SUSTIVA (efavirenz) should not be coadministered with Viraday unless required for dose-adjustment when coadministered with rifampin. (5.4) Do not administer in combination with HEPSERA. (5.1)

5.1 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. Viraday is not approved for the treatment of chronic HBV infection, and the safety and efficacy of Viraday have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of Viraday. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with Viraday. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Viraday should not be administered with HEPSERA^® (adefovir dipivoxil).

5.2 Drug Interactions

Viraday plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, Viraday may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of Viraday at steady state is induction of CYP3A and CYP2B6 .

5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF and emtricitabine, components of Viraday, alone or in combination with other antiretrovirals. Treatment with Viraday 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).

5.4 Coadministration with Related Products

Viraday is a fixed-dose combination of Viraday, emtricitabine, and tenofovir DF. Do not coadminister Viraday with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including COMPLERA^®, DESCOVY^®, EMTRIVA^®, GENVOYA^®, ODEFSEY^®, STRIBILD^®, TRUVADA^®, VEMLIDY^®, or VIREAD^®. SUSTIVA^® should not be coadministered with Viraday unless needed for dose-adjustment (e.g., with rifampin) . Due to similarities between emtricitabine and lamivudine, Viraday should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

5.5 QTc Prolongation

QTc prolongation has been observed with the use of Viraday . Consider alternatives to Viraday when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

5.6 Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with Viraday. In controlled trials of 1008 subjects treated with regimens containing Viraday for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency of specific serious psychiatric events among subjects who received Viraday or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with Viraday was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at trial entry; similar associations were observed in both the Viraday and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both efavirenz-treated and control-treated subjects. One percent of efavirenz-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, and catatonia, although a causal relationship to the use of Viraday cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of Viraday, and if so, to determine whether the risks of continued therapy outweigh the benefits .

5.7 Nervous System Symptoms

Fifty-three percent (531/1008) of subjects receiving Viraday in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2–4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing Viraday and from 3% to 5% in subjects treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms . Dosing at bedtime may improve the tolerability of these nervous system symptoms .

Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with Viraday + zidovudine + lamivudine, Viraday + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated subjects were generally similar to those in the indinavir-containing control arm.

Patients receiving Viraday should be alerted to the potential for additive central nervous system effects when Viraday is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

5.8 New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney; however, Viraday is not. Since Viraday is a combination product and the dose of the individual components cannot be altered, patients with estimated creatinine clearance below 50 mL/min should not receive Viraday.

Renal impairment, including cases of acute renal failure and Fanconi syndrome has been reported with the use of tenofovir DF .

It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Viraday. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Viraday and periodically during Viraday therapy.

Viraday should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

5.9 Reproductive Risk Potential

Pregnancy Category D: Viraday may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving Viraday. Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives). Because of the long half-life of Viraday, use of adequate contraceptive measures for 12 weeks after discontinuation of Viraday is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of Viraday. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

There are no adequate and well-controlled trials of Viraday in pregnant women. Viraday should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options .

5.10 Rash

In controlled clinical trials, 26% of adult subjects treated with 600 mg Viraday experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with Viraday. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with Viraday in all trials and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with Viraday (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with Viraday, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1008). Viraday can be reinitiated in patients interrupting therapy because of rash. Viraday should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered .

Experience with Viraday in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with Viraday. Nine of these subjects developed mild-to-moderate rash while receiving therapy with Viraday, and two of these subjects discontinued because of rash.

Rash was reported in 59 of 182 pediatric subjects (32%) treated with Viraday . Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3−1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with Viraday in pediatric patients should be considered.

5.11 Hepatotoxicity

Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity . A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors . Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Viraday needs to be weighed against the unknown risks of significant liver toxicity.

5.12 Bone Effects of Tenofovir DF

Bone Mineral Density

In clinical trials in HIV-1 infected adults, tenofovir DF was associated with slightly greater decreases in bone mineral density and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.

Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis-B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information.

The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such 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 tenofovir DF . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF .

5.13 Convulsions

Convulsions have been observed in adult and pediatric patients receiving Viraday, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels .

5.14 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Viraday. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections, 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.

5.15 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," has been observed in patients receiving antiretroviral therapy, including Viraday. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 ADVERSE REACTIONS

Most common adverse reactions observed in an active-controlled clinical trial of Viraday, emtricitabine, and tenofovir disoproxil fumarate are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6)

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

Viraday, Emtricitabine and Tenofovir DF: The following adverse reactions are discussed in other sections of the labeling:

• Severe Acute Exacerbations of Hepatitis B .
• Lactic Acidosis/Severe Hepatomegaly with Steatosis .
• QTc Prolongation.
• Psychiatric Symptoms .
• Nervous System Symptoms .
• New Onset or Worsening Renal Impairment .
• Rash .
• Hepatotoxicity .
• Bone Effects of Tenofovir DF .
• Immune Reconstitution Syndrome .
• Fat Redistribution .
• Drug Interactions .

For additional safety information about SUSTIVA (efavirenz), EMTRIVA (emtricitabine), or VIREAD (tenofovir DF) in combination with other antiretroviral agents, consult the prescribing information for these products.

6.1 Adverse Reactions from 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 Adult Subjects

Study 934

Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either emtricitabine + tenofovir DF administered in combination with Viraday (N=257) or zidovudine/lamivudine administered in combination with Viraday (N=254).

The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1).

	FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with Viraday in place of emtricitabine + tenofovir DF with Viraday.	AZT/3TC+EFV
	N=257	N=254
Gastrointestinal Disorder
Diarrhea	9%	5%
Nausea	9%	7%
Vomiting	2%	5%
General Disorders and Administration Site Condition
Fatigue	9%	8%
Infections and Infestations
Sinusitis	8%	4%
Upper respiratory tract infections	8%	5%
Nasopharyngitis	5%	3%
Nervous System Disorders
Headache	6%	5%
Dizziness	8%	7%
Psychiatric Disorders
Anxiety	5%	4%
Depression	9%	7%
Insomnia	5%	7%
Skin and Subcutaneous Tissue Disorders
Rash EventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.	7%	9%

Study 073

In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive Viraday or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of Viraday when each was administered in combination with other antiretroviral agents.

Viraday, Emtricitabine, or Tenofovir DF

In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of Viraday, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.

Viraday: The most significant adverse reactions observed in subjects treated with Viraday were nervous system symptoms , psychiatric symptoms, and rash .

Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of efavirenz-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.

Pancreatitis has also been reported, although a causal relationship with Viraday has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with Viraday 600 mg than in control subjects.

Emtricitabine and Tenofovir DF: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials included arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis, and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction).

Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Clinical Trials in Pediatric Subjects

Viraday: Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects 3 months to 21 years of age who received Viraday in combination with other antiretroviral agents for a median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults . For additional information, please consult the SUSTIVA prescribing information.

Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with emtricitabine in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information.

Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with tenofovir DF were consistent with those observed in clinical trials of tenofovir DF in adults .

6.2 Laboratory Abnormalities

Viraday, Emtricitabine and Tenofovir DF: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials.

	FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with Viraday in place of emtricitabine + tenofovir DF with Viraday.	AZT/3TC+EFV
	N=257	N=254
Any ≥ Grade 3 Laboratory Abnormality	30%	26%
Fasting Cholesterol (>240 mg/dL)	22%	24%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	9%	7%
Serum Amylase (>175 U/L)	8%	4%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%
ALT (M: >215 U/L) (F: >170 U/L)	2%	3%
Hemoglobin (<8.0 mg/dL)	0%	4%
Hyperglycemia (>250 mg/dL)	2%	1%
Hematuria (>75 RBC/HPF)	3%	2%
Glycosuria (≥3+)	<1%	1%
Neutrophils (<750/mm3)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934.

In addition to the laboratory abnormalities described for Study 934 (Table 2), Grade 3/4 laboratory abnormalities of increased bilirubin (greater than 2.5 × upper limit of normal (ULN)), increased pancreatic amylase (greater than 2.0 × ULN), increased or decreased serum glucose (less than 40 or greater than 250 mg/dL), and increased serum lipase (greater than 2.0 × ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.

Hepatic Events: In Study 934, 19 subjects treated with Viraday, emtricitabine, and tenofovir DF and 20 subjects treated with Viraday and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (1/19) in the Viraday, emtricitabine, and tenofovir DF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders .

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Viraday, emtricitabine, or tenofovir DF. Because postmarketing reactions 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.

Viraday:

Cardiac Disorders

Palpitations

Ear and Labyrinth Disorders

Tinnitus, vertigo

Endocrine Disorders

Gynecomastia

Eye Disorders

Abnormal vision

Gastrointestinal Disorders

Constipation, malabsorption

General Disorders and Administration Site Conditions

Asthenia

Hepatobiliary Disorders

Hepatic enzyme increase, hepatic failure, hepatitis. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Immune System Disorders

Allergic reactions

Metabolism and Nutrition Disorders

Redistribution/accumulation of body fat , hypercholesterolemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders

Arthralgia, myalgia, myopathy

Nervous System Disorders

Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

Psychiatric Disorders

Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

Skin and Subcutaneous Tissue Disorders

Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome

Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir DF:

Immune System Disorders

Allergic reaction, including angioedema

Metabolism and Nutrition Disorders

Lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnea

Gastrointestinal Disorders

Pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT)

Skin and Subcutaneous Tissue Disorders

Rash

Musculoskeletal and Connective Tissue Disorders

Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders

Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

Asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

7 DRUG INTERACTIONS

This section describes clinically relevant drug interactions with Viraday. Drug interaction trials are described elsewhere in the labeling .

• Viraday: Coadministration of Viraday can alter the concentrations of other drugs, and other drugs may alter the concentrations of Viraday. The potential for drug-drug interactions must be considered before and during therapy. (4.2, 7.1, 12.3)
• Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. (7.2)
• HIV-1 protease inhibitors: Coadministration of Viraday with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of Viraday with either atazanavir or atazanavir and ritonavir is not recommended. (7.3)

7.1 Viraday

Viraday has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with Viraday.

Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of Viraday, resulting in lowered plasma concentrations .

There is limited information available on the potential for a pharmacodynamic interaction between Viraday and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of Viraday . Consider alternatives to Viraday when coadministered with a drug with a known risk of Torsade de Pointes.

7.2 Emtricitabine and Tenofovir DF

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Viraday with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides, and high-dose or multiple NSAIDs .

Coadministration of tenofovir DF and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions (for didanosine dosing adjustment recommendations, see Table 3). Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

Darunavir with ritonavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. Tenofovir DF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When tenofovir DF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving darunavir with ritonavir and Viraday, or lopinavir/ritonavir with Viraday, should be monitored for tenofovir-associated adverse reactions. Viraday should be discontinued in patients who develop tenofovir-associated adverse reactions (Table 3).

Coadministration of atazanavir with Viraday is not recommended, as coadministration of atazanavir with either Viraday or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with Viraday (Table 3).

7.3 Viraday, Emtricitabine and Tenofovir DF

Other important drug interaction information for Viraday is summarized in Table 3. The drug interactions described are based on trials conducted with either Viraday, the components of Viraday (efavirenz, emtricitabine, or tenofovir DF) as individual agents, or are potential drug interactions [for pharmacokinetic data see Clinical Pharmacology (12.3) , Tables 4−7. The tables include potentially significant interactions, but are not all inclusive].

Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with Viraday is not recommended. Coadministration of atazanavir with either Viraday or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of Viraday plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with Viraday.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and Viraday with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when Viraday is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when Viraday is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with Viraday, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to Viraday.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with Viraday. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as Viraday. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ Viraday	When ritonavir 500 mg every 12 hours was coadministered with Viraday 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Viraday is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of Viraday and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Viraday decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with Viraday.
NRTI: didanosine	↑ didanosine	Coadministration of Viraday and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ Viraday and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. Viraday contains Viraday and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Viraday reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with Viraday, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: simeprevir	↓ simeprevir ↔ Viraday	Concomitant administration of simeprevir with Viraday is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitors/NS5B polymerase inhibitors: ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving Viraday and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
sofosbuvir/velpatasvir	↑ tenofovir ↓ velpatasvir	Coadministration of efavirenz-containing regimens and EPCLUSA® (sofosbuvir/velpatasvir) is not recommended.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by Viraday.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ Viraday	There are insufficient data to make a dose recommendation for Viraday. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ Viraday	Potential for reduction in anticonvulsant and/or Viraday plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of Viraday on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with Viraday and ketoconazole have not been conducted. Viraday has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ Viraday	If Viraday is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of Viraday is recommended.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation.
atovaquone/proguanil	↓ atovaquone ↓ proguanil	Concomitant administration of atovaquone/proguanil with Viraday is not recommended.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of Viraday is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of Viraday with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with Viraday. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Viraday had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on Viraday plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and Viraday has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by Viraday. These immunosuppressants are not anticipated to affect exposure of Viraday. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with Viraday.
Narcotic analgesic: methadone	↓ methadone	Coadministration of Viraday in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

7.4 Viraday Assay Interference

Cannabinoid Test Interaction: Viraday does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving Viraday. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Women should avoid pregnancy while receiving Viraday and for 12 weeks after discontinuation.
• Nursing mothers: Women infected with HIV should be instructed not to breastfeed. (8.3)
• Hepatic impairment: Viraday is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (5.11, 8.6)
• Pediatrics: The incidence of rash was higher than in adults. (5.10, 6.1)

8.1 Pregnancy

Pregnancy Category D

Antiretroviral Pregnancy Registry:

To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.

Viraday: As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to Viraday has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Viraday has not been established, similar defects have been observed in preclinical studies of Viraday.

Animal Data

Effects of Viraday on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, Viraday 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, Viraday was administered either during organogenesis (gestation Days 7 to 18) or from gestation Day 7 through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation Day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, Viraday was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in humans have shown that Viraday, tenofovir, and emtricitabine are excreted in human milk. Because the risks of low-level exposure to Viraday, emtricitabine, and tenofovir to infants are unknown, and because of the potential for HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving Viraday.

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.

Tenofovir DF

Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.

8.4 Pediatric Use

Viraday should only be administered to pediatric patients 12 years of age and older with a body weight greater than or equal to 40 kg. Because Viraday is a fixed-dose combination tablet, the dose adjustments recommended for pediatric patients younger than 12 years of age for each individual component cannot be made with Viraday .

8.5 Geriatric Use

Clinical trials of Viraday, emtricitabine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Viraday is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine an appropriate dose. Patients with mild hepatic impairment may be treated with Viraday at the approved dose. Because of the extensive cytochrome P450-mediated metabolism of Viraday and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Viraday to these patients .

8.7 Renal Impairment

Because Viraday is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) .

10 OVERDOSAGE

If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital signs and observation of the patient's clinical status; standard supportive treatment should then be applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed Viraday. Hemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information below), but is unlikely to significantly remove Viraday from the blood.

Viraday: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology trial single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.

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/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir DF: Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one trial, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Viraday is a fixed-dose combination tablet containing Viraday, emtricitabine, and tenofovir DF. SUSTIVA is the brand name for Viraday, a non-nucleoside reverse transcriptase inhibitor (NNRTI). EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. VIREAD is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. VIREAD and EMTRIVA are the components of TRUVADA.

Viraday tablets are for oral administration. Each tablet contains 600 mg of Viraday, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Viraday: Viraday is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C₁₄H₉ClF₃NO₂ and its structural formula is:

Viraday is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (less than 10 µg/mL).

Chemical Structure

Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. 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 crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C.

Chemical Structure

Tenofovir DF: Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C₁₉H₃₀N₅O₁₀P ∙ C₄H₄O₄ and a molecular weight of 635.52. It has the following structural formula:

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C.

Chemical Structure

12 CLINICAL PHARMACOLOGY

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA, and VIREAD prescribing information.

12.1 Mechanism of Action

Viraday is a fixed-dose combination of antiviral drugs Viraday, emtricitabine, and tenofovir DF .

12.2 Pharmacodynamics

Cardiac Electrophysiology

Viraday: The effect of Viraday on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean C_max of Viraday in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C_max observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between Viraday concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days .

12.3 Pharmacokinetics

Viraday: One Viraday tablet is bioequivalent to one SUSTIVA tablet plus one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).

Viraday: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving Viraday 600 mg once daily, steady-state C_max was 12.9 ± 3.7 µM (mean ± SD), C_min was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM∙hr. Viraday is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of ¹⁴C-labeled Viraday, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for Viraday metabolism. Viraday has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Viraday has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.

Emtricitabine: Following oral administration, emtricitabine is rapidly absorbed, with peak plasma concentrations occurring at 1–2 hours postdose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the steady-state plasma emtricitabine C_max was 1.8 ± 0.7 µg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 µg∙hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 µg/mL. The mean absolute bioavailability of emtricitabine was 93%. Less than 4% of emtricitabine binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir DF: Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C_max) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C_max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng∙hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion, with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.

Effects of Food on Oral Absorption

Viraday has not been evaluated in the presence of food. Administration of Viraday tablets with a high-fat meal increased the mean AUC and C_max of Viraday by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high-fat meal or a light meal increased the mean AUC and C_max of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures .

Specific Populations

Race

Viraday: The pharmacokinetics of Viraday in HIV-1 infected subjects appear to be similar among the racial groups studied.

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.

Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir DF.

Gender

Viraday, Emtricitabine, and Tenofovir DF: Viraday, emtricitabine, and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

Viraday should only be administered to pediatric patients 12 years of age and weighing greater than or equal to 40 kg (greater than or equal to 88 lb).

Viraday: In an open-label trial in NRTI-experienced pediatric subjects (mean age 8 years, range 3−16), the pharmacokinetics of Viraday in pediatric subjects were similar to the pharmacokinetics in adults who received a 600 mg daily dose of Viraday. Based on mean steady-state predicted population pharmacokinetic modeling in pediatric subjects weighing >40 kg receiving the 600 mg dose of Viraday, C_max was 6.57 µg/mL, C_min was 2.82 µg/mL, and AUC_(0–24) was 254.78 µM∙hr.

Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1 infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean ± SD C_max and AUC were 2.7 ± 0.9 µg/mL and 12.6 ± 5.4 µg∙hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean ± SD C_max and AUC_tau are 0.38 ± 0.13 µg/mL and 3.39 ± 1.22 µg∙hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Geriatric Patients

Pharmacokinetics of Viraday, emtricitabine, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) .

Patients with Impaired Renal Function

Viraday: The pharmacokinetics of Viraday have not been studied in subjects with renal insufficiency; however, less than 1% of Viraday is excreted unchanged in the urine, so the impact of renal impairment on Viraday elimination should be minimal.

Emtricitabine and Tenofovir DF: The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min, C_max and AUC_0–∞ of emtricitabine and tenofovir were increased .

Patients with Hepatic Impairment

Viraday: A multiple-dose trial showed no significant effect on Viraday pharmacokinetics in subjects with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects Viraday pharmacokinetics .

Emtricitabine: The pharmacokinetics of emtricitabine have 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 DF: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

Assessment of Drug Interactions

The drug interaction trials described were conducted with either Viraday or the components of Viraday (efavirenz, emtricitabine, or tenofovir DF) as individual agents.

Viraday: The steady-state pharmacokinetics of Viraday and tenofovir were unaffected when Viraday and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with Viraday and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways.

Viraday has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that Viraday inhibited CYP isozymes 2C9 and 2C19 with K_i values (8.5–17 µM) in the range of observed Viraday plasma concentrations. In in vitro studies, Viraday did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K_i values 82–160 µM) only at concentrations well above those achieved clinically. Coadministration of Viraday with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of Viraday resulting in lowered plasma concentrations.

Drug interaction trials were performed with Viraday and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between Viraday and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on Viraday exposures. The effects of coadministration of Viraday on C_max, AUC, and C_min are summarized in Table 4 (effect of other drugs on Viraday) and Table 5 (effect of Viraday on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7)].

				Mean % Change of Viraday Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	Viraday Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
Lopinavir/ritonavir	400/100 mg q12h × 9 days	600 mg qd × 9 days	11, 12Parallel-group design; N for Viraday + lopinavir/ritonavir, N for Viraday alone.	↔	↓ 16 (↓ 38 to ↑ 15)	↓ 16 (↓ 42 to ↑ 20)
Nelfinavir	750 mg q8h × 7 days	600 mg qd × 7 days	10	↓ 12 (↓ 32 to ↑13)95% CI	↓ 12 (↓ 35 to ↑ 18)	↓ 21 (↓ 53 to ↑ 33)
Ritonavir	500 mg q12h × 8 days	600 mg qd × 10 days	9	↑ 14 (↑ 4 to ↑ 26)	↑ 21 (↑ 10 to ↑ 34)	↑ 25 (↑ 7 to ↑ 46)
Boceprevir	800 mg tid × 6 days	600 mg qd × 16 days	NA	↑11 (↑ 2 to ↑ 20)	↑ 20 (↑ 15 to ↑ 26)	NA
Rifabutin	300 mg qd × 14 days	600 mg qd × 14 days	11	↔	↔	↓ 12 (↓ 24 to ↑ 1)
Rifampin	600 mg × 7 days	600 mg qd × 7 days	12	↓ 20 (↓ 11 to ↓ 28)	↓ 26 (↓ 15 to ↓ 36)	↓ 32 (↓ 15 to ↓ 46)
Artemether/Lumefantrine	Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)	600 mg qd × 26 days	12	↔	↓17	NA
Simvastatin	40 mg qd × 4 days	600 mg qd × 15 days	14	↓ 12 (↓ 28 to ↑ 8)	↔	↓ 12 (↓ 25 to ↑ 3)
Carbamazepine	200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 15 days	600 mg qd × 35 days	14	↓ 21 (↓ 15 to ↓ 26)	↓ 36 (↓ 32 to ↓ 40)	↓ 47 (↓ 41 to ↓ 53)
Diltiazem	240 mg × 14 days	600 mg qd × 28 days	12	↑ 16 (↑ 6 to ↑ 26)	↑ 11 (↑ 5 to ↑ 18)	↑ 13 (↑ 1 to ↑ 26)
Voriconazole	400 mg po q12h × 1 day then 200 mg po q12h × 8 days	400 mg qd × 9 days	NA	↑ 3890% CI not available	↑ 44	NA
	300 mg po q12h days 2–7	300 mg qd × 7 days	NA	↓ 14Relative to steady-state administration of Viraday (600 mg once daily for 9 days). (↓ 7 to ↓ 21)	↔	NA
	400 mg po q12h days 2–7	300 mg qd × 7 days	NA	↔	↑ 17 (↑ 6 to ↑ 29)	NA

No effect on the pharmacokinetic parameters of Viraday was observed with the following coadministered drugs: indinavir, saquinavir soft gelatin capsule, simeprevir, ledipasvir/sofosbuvir, sofosbuvir, clarithromycin, itraconazole, atorvastatin, pravastatin, or sertraline.

				Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	Viraday Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
Atazanavir	400 mg qd with a light meal d 1–20	600 mg qd with a light meal d 7–20	27	↓ 59 (↓ 49 to ↓ 67)	↓ 74 (↓ 68 to ↓78)	↓ 93 (↓ 90 to ↓ 95)
	400 mg qd d 1–6, then 300 mg qd d 7–20 with ritonavir 100 mg qd and a light meal	600 mg qd 2 h after atazanavir and ritonavir d 7–20	13	↑ 14Compared with atazanavir 400 mg qd alone. (↓ 17 to ↑ 58)	↑ 39 (↑ 2 to ↑ 88)	↑ 48 (↑ 24 to ↑ 76)
	300 mg qd/ritonavir 100 mg qd d 1–10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11–24 (pm) (simultaneous with Viraday)	600 mg qd with a light snack d 11–24 (pm)	14	↑ 17 (↑ 8 to ↑ 27)	↔	↓ 42 (↓ 31 to ↓ 51)
Indinavir	1000 mg q8h × 10 days	600 mg qd × 10 days	20
	After morning dose			↔Comparator dose of indinavir was 800 mg q8h × 10 days.	↓ 33 (↓ 26 to ↓ 39)	↓ 39 (↓ 24 to ↓ 51)
	After afternoon dose			↔	↓ 37 (↓ 26 to ↓ 46)	↓ 52 (↓ 47 to ↓ 57)
	After evening dose			↓ 29 (↓ 11 to ↓ 43)	↓ 46 (↓ 37 to ↓ 54)	↓ 57 (↓ 50 to ↓ 63)
Lopinavir/ritonavir	400/100 mg q12h × 9 days	600 mg qd × 9 days	11, 7Parallel-group design; N for Viraday + lopinavir/ritonavir, N for lopinavir/ritonavir alone.	↔Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent Viraday.	↓ 19 (↓ 36 to ↑ 3)	↓ 39 (↓ 3 to ↓ 62)
Nelfinavir	750 mg q8h × 7 days	600 mg qd × 7 days	10	↑ 21 (↑ 10 to↑ 33)	↑ 20 (↑ 8 to ↑ 34)	↔
Metabolite AG-1402				↓ 40 (↓ 30 to ↓ 48)	↓ 37 (↓ 25 to ↓ 48)	↓ 43 (↓ 21 to ↓ 59)
Ritonavir	500 mg q12h × 8 days	600 mg qd × 10 days	11
	After AM dose			↑ 24 (↑ 12 to ↑ 38)	↑ 18 (↑ 6 to ↑ 33)	↑ 42 (↑ 9 to ↑ 86)95% CI
	After PM dose			↔	↔	↑ 24 (↑ 3 to ↑ 50)
Saquinavir SGCSoft Gelatin Capsule	1200 mg q8h × 10 days	600 mg qd × 10 days	12	↓ 50 (↓ 28 to ↓ 66)	↓ 62 (↓ 45 to ↓74)	↓ 56 (↓ 16 to ↓ 77)
Maraviroc	100 mg bid	600 mg qd	12	↓ 51 (↓ 37 to ↓ 62)	↓ 45 (↓ 38 to ↓ 51)	↓ 45 (↓ 28 to ↓ 57)
Raltegravir	400 mg single dose	600 mg qd	9	↓ 36 (↓ 2 to ↓ 59)	↓ 36 (↓ 20 to ↓ 48)	↓ 21 (↓ 51 to ↑ 28)
Boceprevir	800 mg tid × 6 days	600 mg qd × 16 days	NA	↓ 8 (↓ 22 to ↑ 8)	↓ 19 (↓ 11 to ↓25)	↓ 44 (↓ 26 to ↓ 58)
Simeprevir	150 mg qd × 14 days	600 mg qd × 14 days	23	↓ 51 (↓ 46 to ↓ 56)	↓ 71 (↓ 67 to ↓ 74)	↓ 91 (↓ 88 to ↓ 92)
Ledipasvir/SofosbuvirStudy conducted with Viraday coadministered with HARVONI.	90/400 mg qd × 14 days	600 mg qd × 14 days	15
Ledipasvir				↓ 34 (↓ 25 to ↓ 41)	↓ 34 (↓ 25 to ↓ 41)	↓ 34 (↓ 24 to ↓ 43)
Sofosbuvir				↔	↔	NA
GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.				↔	↔	↔
SofosbuvirStudy conducted with Viraday coadministered with SOVALDI® (sofosbuvir).	400 mg qd single dose	600 mg qd × 14 days	16	↓ 19 (↓ 40 to ↑ 10)	↔	NA
GS-331007				↓ 23 (↓ 16 to ↓ 30)	↓ 16 (↓ 24 to ↓ 8)	NA
Sofosbuvir/VelpatasvirStudy conducted with Viraday coadministered with EPCLUSA.	400/100 mg qd × 14 days	600 mg qd × 14 days	14
Sofosbuvir				↑ 38 (↑ 14 to ↑ 67)	↔	NA
GS-331007				↓ 14 (↓ 20 to ↓ 7)	↔	↔
Velpatasvir				↓ 47 (↓ 57 to ↓ 36)	↓ 53 (↓ 61 to ↓ 43)	↓ 57 (↓ 64 to ↓ 48)
Clarithromycin	500 mg q12h × 7 days	400 mg qd × 7 days	11	↓ 26 (↓ 15 to ↓ 35)	↓ 39 (↓ 30 to ↓ 46)	↓ 53 (↓ 42 to ↓ 63)
14-OH metabolite				↑ 49 (↑ 32 to ↑ 69)	↑ 34 (↑ 18 to ↑ 53)	↑ 26 (↑ 9 to ↑ 45)
Itraconazole	200 mg q12h × 28 days	600 mg qd × 14 days	18	↓ 37 (↓ 20 to ↓ 51)	↓ 39 (↓ 21 to ↓ 53)	↓ 44 (↓ 27 to ↓ 58)
Hydroxy-itraconazole				↓ 35 (↓ 12 to ↓ 52)	↓ 37 (↓ 14 to ↓ 55)	↓ 43 (↓ 18 to ↓ 60)
Posaconazole	400 mg (oral suspension) bid × 10 and 20 days	400 mg qd × 10 and 20 days	11	↓ 45 (↓ 34 to ↓ 53)	↓ 50 (↓ 40 to ↓ 57)	NA
Rifabutin	300 mg qd × 14 days	600 mg qd × 14 days	9	↓ 32 (↓ 15 to ↓ 46)	↓ 38 (↓ 28 to ↓ 47)	↓ 45 (↓ 31 to ↓ 56)
Artemether/lumefantrine	Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)	600 mg qd × 26 days	12
Artemether				↓ 21	↓ 51	NA
dihydroartemisinin				↓ 38	↓ 46	NA
lumefantrine				↔	↓ 21	NA
Atorvastatin	10 mg qd × 4 days	600 mg qd × 15 days	14	↓ 14 (↓ 1 to ↓ 26)	↓ 43 (↓ 34 to ↓ 50)	↓ 69 (↓ 49 to ↓ 81)
Total active (including metabolites)				↓ 15 (↓ 2 to ↓ 26)	↓ 32 (↓ 21 to ↓ 41)	↓ 48 (↓ 23 to ↓ 64)
Pravastatin	40 mg qd × 4 days	600 mg qd × 15 days	13	↓ 32 (↓ 59 to ↑ 12)	↓ 44 (↓ 26 to ↓ 57)	↓ 19 (↓ 0 to ↓ 35)
Simvastatin	40 mg qd × 4 days	600 mg qd × 15 days	14	↓ 72 (↓ 63 to ↓ 79)	↓ 68 (↓ 62 to ↓ 73)	↓ 45 (↓ 20 to ↓ 62)
Total active (including metabolites)				↓ 68 (↓ 55 to ↓ 78)	↓ 60 (↓ 52 to ↓ 68)	NANot available because of insufficient data.
Carbamazepine	200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 29 days	600 mg qd × 14 days	12	↓ 20 (↓ 15 to ↓ 24)	↓ 27 (↓ 20 to ↓ 33)	↓ 35 (↓ 24 to ↓ 44)
Epoxide metabolite				↔	↔	↓ 13 (↓ 30 to ↑ 7)
Diltiazem	240 mg × 21 days	600 mg qd × 14 days	13	↓ 60 (↓ 50 to ↓ 68)	↓ 69 (↓ 55 to ↓ 79)	↓ 63 (↓ 44 to ↓ 75)
Desacetyl diltiazem				↓ 64 (↓ 57 to ↓ 69)	↓ 75 (↓ 59 to ↓ 84)	↓ 62 (↓ 44 to ↓ 75)
N-monodesmethyl diltiazem				↓ 28 (↓ 7 to ↓ 44)	↓ 37 (↓ 17 to ↓ 52)	↓ 37 (↓ 17 to ↓ 52)
Ethinyl estradiol/ Norgestimate	0.035 mg/0.25 mg × 14 days	600 mg qd × 14 days
Ethinyl estradiol			21	↔	↔	↔
Norelgestromin			21	↓ 46 (↓ 39 to ↓ 52)	↓ 64 (↓ 62 to ↓ 67)	↓ 82 (↓ 79 to ↓ 85)
Levonorgestrel			6	↓ 80 (↓ 77 to ↓ 83)	↓ 83 (↓ 79 to ↓ 87)	↓ 86 (↓ 80 to ↓ 90)
Methadone	Stable maintenance 35–100 mg daily	600 mg qd × 14–21 days	11	↓ 45 (↓ 25 to ↓ 59)	↓ 52 (↓ 33 to ↓ 66)	NA
Bupropion	150 mg single dose (sustained-release)	600 mg qd × 14 days	13	↓ 34 (↓ 21 to ↓ 47)	↓ 55 (↓ 48 to ↓ 62)	NA
Hydroxybupropion				↑ 50 (↑ 20 to ↑ 80)	↔	NA
Sertraline	50 mg qd × 14 days	600 mg qd × 14 days	13	↓ 29 (↓ 15 to ↓ 40)	↓ 39 (↓ 27 to ↓ 50)	↓ 46 (↓ 31 to ↓ 58)
Voriconazole	400 mg po q12h × 1 day then 200 mg po q12h × 8 days	400 mg qd × 9 days	NA	↓ 6190% CI not available.	↓ 77	NA
	300 mg po q12h days 2–7	300 mg qd × 7 days	NA	↓ 36Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). (↓ 21 to ↓ 49)	↓ 55 (↓ 45 to ↓ 62)	NA
	400 mg po q12h days 2–7	300 mg qd × 7 days	NA	↑ 23 (↓ 1 to ↑ 53	↓ 7 (↓ 23 to ↑ 13)	NA

Emtricitabine and Tenofovir DF: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.

Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, sofosbuvir/velpatasvir, stavudine, tenofovir DF, and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, Viraday, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, or tacrolimus in trials conducted in healthy volunteers.

Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.

The effects of coadministered drugs on the C_max, AUC, and C_min of tenofovir are shown in Table 6. The effects of coadministration of tenofovir DF on C_max, AUC, and C_min of coadministered drugs are shown in Table 7.

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
			Cmax	AUC	Cmin
AtazanavirReyataz Prescribing Information.	400 once daily × 14 days	33	↑ 14 (↑ 8 to ↑ 20)	↑ 24 (↑ 21 to ↑ 28)	↑ 22 (↑ 15 to ↑ 30)
Atazanavir/ritonavir	300/100 once daily	12	↑ 34 (↑ 20 to ↑ 51)	↑ 37 (↑ 30 to ↑ 45)	↑ 29 (↑ 21 to ↑ 36)
Darunavir/ritonavirPrezista Prescribing Information.	300/100 twice daily	12	↑ 24 (↑ 8 to ↑ 42)	↑ 22 (↑ 10 to ↑ 35)	↑ 37 (↑ 19 to ↑ 57)
DidanosineSubjects received didanosine buffered tablets.	250 or 400 once daily × 7 days	14	↔	↔	↔
Ledipasvir/sofosbuvir	90/400 once daily	15	↑ 79 (↑ 56 to ↑ 104)	↑ 98 (↑ 77 to ↑ 123)	↑ 163 (↑ 132 to ↑ 197)
Lopinavir/ritonavir	400/100 twice daily × 14 days	24	↔	↑ 32 (↑ 25 to ↑ 38)	↑ 51 (↑ 37 to ↑ 66)
Sofosbuvir	400 once daily	16	↑ 25 (↑ 8 to ↑ 45)	↔	↔
Sofosbuvir/velpatasvir	400/100 once daily	15	↑ 77 (↑ 53 to ↑ 104)	↑ 81 (↑ 68 to ↑ 94)	↑ 121 (↑ 100 to ↑ 143)
Tipranavir/ ritonavirAptivus Prescribing Information.	500/100 twice daily	22	↓ 23 (↓ 32 to ↓ 13)	↓ 2 (↓ 9 to ↑ 5)	↑ 7 (↓ 2 to ↑ 17)
	750/200 twice daily (23 doses)	20	↓ 38 (↓ 46 to ↓ 29)	↑ 2 (↓ 6 to ↑ 10)	↑ 14 (↑ 1 to ↑ 27)

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
			Cmax	AUC	Cmin
AtazanavirReyataz Prescribing Information.	400 once daily × 14 days	34	↓ 21 (↓ 27 to ↓ 14)	↓ 25 (↓ 30 to ↓ 19)	↓ 40 (↓ 48 to ↓ 32)
	Atazanavir/ritonavir 300/100 once daily × 42 days	10	↓ 28 (↓ 50 to ↑ 5)	↓ 25In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. (↓ 42 to ↓ 3)	↓ 23 (↓ 46 to ↑ 10)
DarunavirPrezista Prescribing Information.	Darunavir/ritonavir 300/100 once daily	12	↑ 16 (↓ 6 to ↑ 42)	↑ 21 (↓ 5 to ↑ 54)	↑ 24 (↓ 10 to ↑ 69)
DidanosineVidex EC Prescribing Information. Subjects received didanosine enteric-coated capsules.	250 once, simultaneously with tenofovir DF and a light meal373 kcal, 8.2 g fat.	33	↓ 20Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. (↓ 32 to ↓ 7)	↔	NA
Lopinavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔
Ritonavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔
TipranavirAptivus Prescribing Information.	Tipranavir/ritonavir 500/100 twice daily	22	↓ 17 (↓ 26 to ↓ 6)	↓ 18 (↓ 25 to ↓ 9)	↓ 21 (↓ 30 to ↓ 10)
	Tipranavir/ritonavir 750/200 twice daily (23 doses)	20	↓ 11 (↓ 16 to ↓ 4)	↓ 9 (↓ 15 to ↓ 3)	↓ 12 (↓ 22 to 0)

Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir DF with didanosine enteric-coated capsules significantly increases the C_max and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown [for didanosine dosing adjustment recommendations see Drug Interactions (7.3), Table 3].

12.4 Microbiology

Mechanism of Action

Viraday: Viraday is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Viraday activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by Viraday.

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 RT 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, ε, and mitochondrial DNA polymerase γ.

Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity

Viraday, Emtricitabine, and Tenofovir DF: In combination studies evaluating the antiviral activity in cell culture of emtricitabine and Viraday together, Viraday and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.

Viraday: The concentration of Viraday inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC_90–95) ranged from 1.7–25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Viraday demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Viraday demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Viraday demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Viraday is not active against HIV-2.

Emtricitabine: The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC₅₀) values for emtricitabine were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, Viraday, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. 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 µM) and showed strain-specific activity against HIV-2 (EC₅₀ values ranged from 0.007–1.5 µM).

Tenofovir DF: The antiviral activity in cell culture of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC₅₀ values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, Viraday, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀ values ranged from 0.5–2.2 µM) and showed strain-specific activity against HIV-2 (EC₅₀ values ranged from 1.6–5.5 µM).

Resistance

Viraday, Emtricitabine, and Tenofovir DF: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir.

In a clinical trial of treatment-naïve subjects [Study 934, see Clinical Studies (14)] resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuations. Genotypic resistance to Viraday, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to Viraday occurred in 13/19 analyzed subjects in the emtricitabine + tenofovir DF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/19 analyzed subject isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

In a clinical trial of treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed greater than 1.4-fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.

Viraday: Clinical isolates with reduced susceptibility in cell culture to Viraday have been obtained. The most frequently observed amino acid substitution in clinical trials with Viraday is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in subjects failing treatment with Viraday in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).

HIV-1 isolates with reduced susceptibility to Viraday (greater than 380-fold increase in EC₉₀ value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT.

Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir DF: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir.

Cross Resistance

Viraday, Emtricitabine, and Tenofovir DF: Cross resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Viraday: Clinical isolates previously characterized as Viraday resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to Viraday in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to Viraday.

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, Viraday, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.

Tenofovir DF: Cross resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by tenofovir DF results in reduced susceptibility to abacavir, didanosine, emtricitabine, and lamivudine. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Viraday: Long-term carcinogenicity studies in mice and rats were carried out with Viraday. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered Viraday at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, Viraday showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of Viraday, the relevance to humans of neoplasms in efavirenz-treated mice is not known.

Viraday did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given Viraday was not affected. As a result of the rapid clearance of Viraday in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of Viraday.

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/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 times the human systemic exposure at the therapeutic dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), or the 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 DF: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.

There were no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through Day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Viraday: Nonsustained convulsions were observed in 6 of 20 monkeys receiving Viraday at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Tenofovir DF: Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species administered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2- to 20-times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14 CLINICAL STUDIES

Clinical Study 934 supports the use of Viraday tablets in antiretroviral treatment-naïve HIV-1 infected patients. Additional data in support of the use of Viraday in treatment- naïve patients can be found in the prescribing information for VIREAD.

Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to Viraday.

In antiretroviral treatment-experienced patients, the use of Viraday tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of Viraday as assessed by treatment history or by genotypic or phenotypic testing .

Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir DF administered in combination with Viraday versus zidovudine/lamivudine fixed-dose combination administered in combination with Viraday in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF fixed-dose combination with Viraday in place of emtricitabine + tenofovir DF with Viraday. Subjects had a mean age of 38 years (range 18–80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm³ (range 2–1191), and median baseline plasma HIV-1 RNA was 5.01 log₁₀ copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm³), and 41% had CD4+ cell counts <200 cells/mm³. Fifty-one percent (51%) of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have Viraday resistance at baseline (N=487) are presented in Table 8.

Outcomes	At Week 48		At Week 144
	FTC+TDF+EFV (N=244)	AZT/3TC+EFV (N=243)	FTC+TDF+EFV (N=227)Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue trial after Week 48 or Week 96 were excluded from analysis.	AZT/3TC+EFV (N=229)
ResponderSubjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.	84%	73%	71%	58%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.	2%	4%	3%	6%
Rebound	1%	3%	2%	5%
Never suppressed	0%	0%	0%	0%
Change in antiretroviral regimen	1%	1%	1%	1%
Death	<1%	1%	1%	1%
Discontinued due to adverse event	4%	9%	5%	12%
Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.	10%	14%	20%	22%

Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm³ in the emtricitabine + tenofovir DF group and 158 cells/mm³ in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm³ at Week 144).

Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Study 073: Study 073 was a 48-week open-label, randomized clinical trial in subjects with stable virologic suppression on combination antiretroviral therapy consisting of at least two NRTIs administered in combination with a protease inhibitor (with or without ritonavir) or a NNRTI.

To be enrolled, subjects were to have HIV-1 RNA <200 copies/mL for at least 12 weeks on their current regimen prior to trial entry with no known HIV-1 substitutions conferring resistance to the components of Viraday and no history of virologic failure.

The trial compared the efficacy of switching to Viraday or staying on the baseline antiretroviral regimen (SBR). Subjects were randomized in a 2:1 ratio to switch to Viraday (N=203) or stay on SBR (N=97). Subjects had a mean age of 43 years (range 22–73 years); 88% were male, 68% were white, 29% were Black or African-American, and 3% were of other races. At baseline, median CD4+ cell count was 516 cells/mm³, and 96% had HIV-1 RNA <50 copies/mL. The median time since onset of antiretroviral therapy was 3 years, and 88% of subjects were receiving their first antiretroviral regimen at trial enrollment.

At Week 48, 89% and 87% of subjects who switched to Viraday maintained HIV RNA <200 copies/mL and <50 copies/mL, respectively, compared to 88% and 85% who remained on SBR; this difference was not statistically significant. No changes in CD4+ cell counts from baseline to Week 48 were observed in either treatment arm.

16 HOW SUPPLIED/STORAGE AND HANDLING

Viraday tablets are pink, capsule shaped, film coated, debossed with "123" on one side and plain faced on the other side. Each bottle contains 30 tablets (NDC 15584-0101-1) and silica gel desiccant, and is closed with a child-resistant closure.

Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °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

A statement to patients and healthcare providers is included on the product's bottle labels: ALERT: Find out about medicines that should NOT be taken with Viraday. Viraday may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription or nonprescription medication, vitamins, or herbal supplements.

General Information for Patients

Inform patients that Viraday is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using Viraday.

Advise patients to avoid doing things that can spread HIV-1 to others:

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. Some of the medicines in Viraday can be passed to your baby in your breast milk. We do not know whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Advise patients that:

• The long-term effects of Viraday are unknown.
• 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 .
• Viraday should not be coadministered with COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir. SUSTIVA should not be coadministered with Viraday unless needed for dose adjustment .
• Viraday should not be administered with HEPSERA .

Patients Coinfected with HIV-1 and HBV

Advise patients that severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA (emtricitabine) or VIREAD (tenofovir DF), which are components of Viraday.

Lactic Acidosis and Severe Hepatomegaly

Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with Viraday should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity .

New Onset or Worsening Renal Impairment

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients to avoid using Viraday with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) .

Bone Effects of Tenofovir DF

Inform patients that decreases in bone mineral density have been observed with the use of tenofovir DF. Advise patients that bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss .

Dosing Instructions

Advise patients to take Viraday orally on an empty stomach and that it is important to take Viraday on a regular dosing schedule to avoid missing doses.

Nervous System Symptoms

• Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams, are commonly reported during the first weeks of therapy with Viraday. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy.
• Alert patients to the potential for additive effects when Viraday is used concomitantly with alcohol or psychoactive drugs.
• Instruct patients that if they experience NSS to avoid potentially hazardous tasks such as driving or operating machinery .

Psychiatric Symptoms

• Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms, and catatonia have been reported in patients receiving Viraday .
• Advise patients that if they experience severe psychiatric adverse experiences they should seek immediate medical evaluation.
• Advise patients to inform their physician of any history of mental illness or substance abuse.

Rash

Inform patients that a common side effect is rash, and that rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs.

Reproductive Risk Potential

• Instruct women receiving Viraday to avoid pregnancy . A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception. Because of the long half-life of Viraday, recommend use of adequate contraceptive measures for 12 weeks after discontinuation of Viraday.
• Advise women to notify their physician if they become pregnant or plan to become pregnant while taking Viraday.
• Apprise women of the potential harm to the fetus if Viraday is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug.

Manufactured and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

Viraday is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. COMPLERA, DESCOVY, EMTRIVA, EPCLUSA, GENVOYA, HARVONI, HEPSERA, ODEFSEY, SOVALDI, STRIBILD, TRUVADA, VEMLIDY, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. Reyataz and Videx are trademarks of Bristol-Myers Squibb Company. Pravachol is a trademark of ER Squibb & Sons, LLC. All other trademarks referenced herein are the property of their respective owners.

© 2017 Gilead Sciences, Inc. All rights reserved.

21937-GS-017

Patient Information

Viraday^® (uh TRIP luh) Tablets

ALERT: Find out about medicines that should NOT be taken with Viraday.

Please also read the section "MEDICINES YOU SHOULD NOT TAKE WITH Viraday."

Generic name: Viraday, emtricitabine, and tenofovir disoproxil fumarate (eh FAH vih renz, em tri SIT uh bean and te NOE' fo veer dye soe PROX il FYOU mar ate)

Read the Patient Information that comes with Viraday before you start taking it and each time you get a refill since there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. You should stay under a healthcare provider's care when taking Viraday. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider or pharmacist if you have any questions about Viraday.

What is the most important information I should know about Viraday?

If you also have hepatitis B virus (HBV) infection and you stop taking Viraday, you may get a "flare-up" of your hepatitis. A "flare-up" is when the disease suddenly returns in a worse way than before. Patients with HBV who stop taking Viraday need close medical follow-up for several months, including medical exams and blood tests to check for hepatitis that could be getting worse. Viraday is not approved for the treatment of HBV, so you must discuss your HBV therapy with your healthcare provider.

What is Viraday?

Viraday contains 3 medicines, SUSTIVA^® (efavirenz), EMTRIVA^® (emtricitabine), and VIREAD^® (tenofovir disoproxil fumarate also called tenofovir DF) combined in one pill. EMTRIVA and VIREAD are HIV-1 (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitors (NRTIs) and SUSTIVA is an HIV-1 non-nucleoside analog reverse transcriptase inhibitor (NNRTI). VIREAD and EMTRIVA are the components of TRUVADA^®. Viraday can be used alone as a complete regimen, or in combination with other anti-HIV-1 medicines to treat people with HIV-1 infection. Viraday is for adults and children 12 years of age and older who weigh at least 40 kg (at least 88 lbs). Viraday is not recommended for children younger than 12 years of age. Viraday has not been studied in adults over 65 years of age.

HIV infection destroys CD4+ T cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.

Viraday helps block HIV-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. Viraday lowers the amount of HIV-1 in the blood (viral load). Viraday may also help to increase the number of T cells (CD4+ cells), allowing your immune system to improve. Lowering the amount of HIV-1 in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Does Viraday cure HIV-1 or AIDS?

Viraday does not cure HIV-1 infection or AIDS and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using Viraday.

Who should not take Viraday?

Together with your healthcare provider, you need to decide whether Viraday is right for you.

Do not take Viraday if you are allergic to Viraday or any of its ingredients. The active ingredients of Viraday are Viraday, emtricitabine, and tenofovir DF. See the end of this leaflet for a complete list of ingredients.

What should I tell my healthcare provider before taking Viraday?

Tell your healthcare provider if you:

• Are pregnant or planning to become pregnant.
• Are breastfeeding.
• Have kidney problems or are undergoing kidney dialysis treatment.
• Have bone problems.
• Have liver problems, including hepatitis B virus infection. Your healthcare provider may want to do tests to check your liver while you take Viraday or may switch you to another medicine.
• Have ever had mental illness or are using drugs or alcohol.
• Have ever had seizures or are taking medicine for seizures.

What important information should I know about taking other medicines with Viraday?

Viraday may change the effect of other medicines, including the ones for HIV-1, and may cause serious side effects. Your healthcare provider may change your other medicines or change their doses. Other medicines, including herbal products, may affect Viraday. For this reason, it is very important to let all your healthcare providers and pharmacists know what medications, herbal supplements, or vitamins you are taking.

MEDICINES YOU SHOULD NOT TAKE WITH Viraday

• Viraday also should not be used with Combivir (lamivudine/zidovudine), COMPLERA^®, DESCOVY^®, EMTRIVA, Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), GENVOYA^®, ODEFSEY^®, STRIBILD^®, Trizivir (abacavir sulfate/lamivudine/zidovudine), TRUVADA, VEMLIDY^®, or VIREAD. Viraday also should not be used with SUSTIVA unless recommended by your healthcare provider.
• Vfend (voriconazole) should not be taken with Viraday since it may lose its effect or may increase the chance of having side effects from Viraday.
• Viraday should not be used with HEPSERA^® (adefovir dipivoxil).

It is also important to tell your healthcare provider if you are taking any of the following:

• Fortovase, Invirase (saquinavir), Biaxin (clarithromycin), Noxafil (posaconazole), Sporanox (itraconazole), Victrelis (boceprevir), Olysio (simeprevir), or EPCLUSA (sofosbuvir/velpatasvir); these medicines may need to be replaced with another medicine when taken with Viraday.
• Calcium channel blockers such as Cardizem or Tiazac (diltiazem), Covera HS or Isoptin (verapamil) and others; Crixivan (indinavir), Selzentry (maraviroc); the immunosuppressant medicines cyclosporine (Gengraf, Neoral, Sandimmune, and others), Prograf (tacrolimus), or Rapamune (sirolimus); Methadone; Mycobutin (rifabutin); Rifampin; cholesterol-lowering medicines such as Lipitor (atorvastatin), Pravachol (pravastatin sodium), and Zocor (simvastatin); or the anti-depressant medications bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, and Zyban) or Zoloft (sertraline); dose changes may be needed when these drugs are taken with Viraday.
• Videx, Videx EC (didanosine); tenofovir DF (a component of Viraday) may increase the amount of didanosine in your blood, which could result in more side effects. You may need to be monitored more carefully if you are taking Viraday and didanosine together. Also, the dose of didanosine may need to be changed.
• Reyataz (atazanavir sulfate), Prezista (darunavir) with Norvir (ritonavir), Kaletra (lopinavir/ritonavir), EPCLUSA^® (sofosbuvir/velpatasvir) or HARVONI^® (ledipasvir/sofosbuvir); these medicines may increase the amount of tenofovir DF (a component of Viraday) in your blood, which could result in more side effects. EPCLUSA and Reyataz are not recommended with Viraday. You may need to be monitored more carefully if you are taking Viraday, Prezista, and Norvir together, or if you are taking Viraday and Kaletra together. The dose of Kaletra should be increased when taken with Viraday.
• Medicine for seizures [for example, Dilantin (phenytoin), Tegretol (carbamazepine), or phenobarbital]; your healthcare provider may want to switch you to another medicine or check drug levels in your blood from time to time.

These are not all the medicines that may cause problems if you take Viraday. Be sure to tell your healthcare provider about all medicines that you take.

Keep a complete list of all the prescription and nonprescription medicines as well as any herbal remedies that you are taking, how much you take, and how often you take them. Make a new list when medicines or herbal remedies are added or stopped, or if the dose changes. Give copies of this list to all of your healthcare providers and pharmacists every time you visit your healthcare provider or fill a prescription. This will give your healthcare provider a complete picture of the medicines you use. Then he or she can decide the best approach for your situation.

How should I take Viraday?

• Take the exact amount of Viraday your healthcare provider prescribes. Never change the dose on your own. Do not stop this medicine unless your healthcare provider tells you to stop.
• You should take Viraday on an empty stomach.
• Swallow Viraday with water.
• Taking Viraday at bedtime may make some side effects less bothersome.
• Do not miss a dose of Viraday. If you forget to take Viraday, take the missed dose right away, unless it is almost time for your next dose. Do not double the next dose. Carry on with your regular dosing schedule. If you need help in planning the best times to take your medicine, ask your healthcare provider or pharmacist.
• If you believe you took more than the prescribed amount of Viraday, contact your local poison control center or emergency room right away.
• Tell your healthcare provider if you start any new medicine or change how you take old ones. Your doses may need adjustment.
• When your Viraday supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to Viraday and become harder to treat.
• Your healthcare provider may want to do blood tests to check for certain side effects while you take Viraday.

What should I avoid while taking Viraday?

• Women should not become pregnant while taking Viraday and for 12 weeks after stopping it. Serious birth defects have been seen in the babies of animals and women treated with Viraday (a component of Viraday) during pregnancy. It is not known whether Viraday caused these defects. Tell your healthcare provider right away if you are pregnant. Also talk with your healthcare provider if you want to become pregnant.
• Women should not rely only on hormone-based birth control, such as pills, injections, or implants, because Viraday may make these contraceptives ineffective. Women must use a reliable form of barrier contraception, such as a condom or diaphragm, even if they also use other methods of birth control. Viraday, a component of Viraday, may remain in your blood for a time after therapy is stopped. Therefore, you should continue to use contraceptive measures for 12 weeks after you stop taking Viraday.
• Do not breastfeed if you are taking Viraday. Some of the medicines in Viraday can be passed to your baby in your breast milk. We do not know whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Talk with your healthcare provider if you are breastfeeding. You should stop breastfeeding or may need to use a different medicine.
• Taking Viraday with alcohol or other medicines causing similar side effects as Viraday, such as drowsiness, may increase those side effects.
• Do not take any other medicines, including prescription and nonprescription medicines and herbal products, without checking with your healthcare provider.
• Avoid doing things that can spread HIV-1 to others.
  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

What are the possible side effects of Viraday?

Viraday may cause the following serious side effects:

• "Flare-ups" of hepatitis B virus (HBV) infection, in which the disease suddenly returns in a worse way than before, can occur if you have HBV and you stop taking Viraday. Your healthcare provider will monitor your condition for several months after stopping Viraday if you have both HIV-1 and HBV infection and may recommend treatment for your HBV. Viraday is not approved for the treatment of hepatitis B virus infection. If you have advanced liver disease and stop treatment with Viraday, the "flare-up" of hepatitis B may cause your liver function to decline. (See "What is the most important information I should know about Viraday?")
• 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.
• Serious psychiatric problems. A small number of patients may experience severe depression, strange thoughts, or angry behavior while taking Viraday. Some patients have thoughts of suicide and a few have actually committed suicide. These problems may occur more often in patients who have had mental illness. Contact your healthcare provider right away if you think you are having these psychiatric symptoms, so your healthcare provider can decide if you should continue to take Viraday.
• Kidney problems (including decline or failure of kidney function). If you have had kidney problems in the past or take other medicines that can cause kidney problems, your healthcare provider should do regular blood tests to check your kidneys. Symptoms that may be related to kidney problems include a high volume of urine, thirst, muscle pain, and muscle weakness.
• Serious liver problems. Some patients have experienced serious liver problems including liver failure resulting in transplantation or death. Most of these serious side effects occurred in patients with a chronic liver disease such as hepatitis infection, but there have also been a few reports in patients without any existing liver disease.
• Changes in bone mineral density (thinning bones). Laboratory tests show changes in the bones of patients treated with tenofovir DF, a component of Viraday. Some HIV patients treated with tenofovir DF developed thinning of the bones (osteopenia) which could lead to fractures. If you have had bone problems in the past, your healthcare provider may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density. Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as a consequence of kidney problems.

Common side effects:

Patients may have dizziness, headache, trouble sleeping, drowsiness, trouble concentrating, and/or unusual dreams during treatment with Viraday. These side effects may be reduced if you take Viraday at bedtime on an empty stomach. They also tend to go away after you have taken the medicine for a few weeks. If you have these common side effects, such as dizziness, it does not mean that you will also have serious psychiatric problems, such as severe depression, strange thoughts, or angry behavior. Tell your healthcare provider right away if any of these side effects continue or if they bother you. It is possible that these symptoms may be more severe if Viraday is used with alcohol or mood altering (street) drugs.

If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

Rash may be common. Rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. If you develop a rash, call your healthcare provider right away. Rash may be a serious problem in some children. Tell your child's healthcare provider right away if you notice rash or any other side effects while your child is taking Viraday.

Other common side effects include tiredness, upset stomach, vomiting, gas, and diarrhea.

Other possible side effects with Viraday:

• Changes in body fat. Changes in body fat develop in some patients taking anti HIV-1 medicine. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), in the breasts, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these fat changes are not known.
• Skin discoloration (small spots or freckles) may also happen with Viraday.
• 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. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.
• Additional side effects are inflammation of the pancreas, allergic reaction (including swelling of the face, lips, tongue, or throat), shortness of breath, pain, stomach pain, weakness and indigestion.

Tell your healthcare provider or pharmacist if you notice any side effects while taking Viraday.

Contact your healthcare provider before stopping Viraday because of side effects or for any other reason.

This is not a complete list of side effects possible with Viraday. Ask your healthcare provider or pharmacist for a more complete list of side effects of Viraday and all the medicines you will take.

How do I store Viraday?

• Keep Viraday and all other medicines out of reach of children.
• Store Viraday at room temperature 77 °F (25 °C).
• Keep Viraday in its original container and keep the container tightly closed.
• Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.

General information about Viraday:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Viraday for a condition for which it was not prescribed. Do not give Viraday to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Viraday. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Viraday that is written for health professionals.

Do not use Viraday if the seal over bottle opening is broken or missing.

What are the ingredients of Viraday?

Active Ingredients: Viraday, emtricitabine, and tenofovir disoproxil fumarate

Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, and sodium lauryl sulfate. The film coating contains black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Revised: April 2017

Manufactured and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

Viraday is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. COMPLERA, DESCOVY, EMTRIVA, EPCLUSA, GENVOYA, HARVONI, HEPSERA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. Reyataz and Videx are trademarks of Bristol-Myers Squibb Company. Pravachol is a trademark of ER Squibb & Sons, LLC. All other trademarks referenced herein are the property of their respective owners.

© 2017 Gilead Sciences, Inc. All rights reserved.

21937-GS-017

PRINCIPAL DISPLAY PANEL - Representative Label - 30 Tablet Bottle Label

NDC 15584-0101-1

Viraday^®

(efavirenz 600 mg/emtricitabine 200 mg/

tenofovir disoproxil fumarate 300 mg)

Tablets

30 tablets

Note to pharmacist: Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Viraday^®

Viraday pharmaceutical active ingredients containing related brand and generic drugs:

• Efavirenz
• Emtricitabine
• Tenofovir Disoproxil Fumarate

Viraday available forms, composition, doses:

• Tablets; Oral; Efavirenz 600 mg; Emtricitabine 200 mg; Tenofovir Disoproxil Fumarate 300 mg

Viraday destination | category:

• Human:
• Antivirals
• Nonnucleoside reverse transcriptase inhibitors
• Nucleoside and nucleotide reverse transcriptase inhibitors

Viraday Anatomical Therapeutic Chemical codes:

• J05AR06 - Emtricitabine, Tenofovir Disoproxil and Efavirenz

Viraday pharmaceutical companies:

• Cipla

References

1. Dailymed."EMTRIVA (EMTRICITABINE) CAPSULE EMTRIVA (EMTRICITABINE) SOLUTION [GILEAD SCIENCES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."VIREAD (TENOFOVIR DISOPROXIL FUMARATE) TABLET, COATED VIREAD (TENOFOVIR DISOPROXIL FUMARATE) POWDER [GILEAD SCIENCES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. Dailymed."SUSTIVA (EFAVIRENZ) TABLET, FILM COATED [PHYSICIANS TOTAL CARE, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Viraday?

Depending on the reaction of the Viraday after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Viraday not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Viraday addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Viraday, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Viraday consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology