Rx Drugs Info

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use truvada safely and effectively. See full prescribing information for truvada.
truvada (emtricitabine and tenofovir disoproxil fumaratetablet, film coated for oral use
Initial U.S. Approval: 2004

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

See full prescribing information for complete boxed warning.

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. ( 5.1)
  • TRUVADA 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 HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, the components of TRUVADA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-Hepatitis B therapy may be warranted. ( 5.2)

INDICATIONS AND USAGE

TRUVADA, a combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. ( 1)


DOSAGE AND ADMINISTRATION

  • Recommended dose: One tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. ( 2.1)
  • Dose recommended in renal impairment:
    Creatinine clearance 30–49 mL/min: 1 tablet every 48 hours ( 2.2)
    CrCl <30 mL/min or hemodialysis: Do not use TRUVADA ( 2.2)

DOSAGE FORMS AND STRENGTHS

Tablets: 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. ( 3)


CONTRAINDICATIONS

TRUVADA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. ( 4)


WARNINGS AND PRECAUTIONS

  • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TRUVADA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. ( 5.3)
  • Products with same or similar active ingredients: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, EMTRIVA, VIREAD; or with drugs containing lamivudine. ( 5.4)
  • Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or who are at risk for osteopenia. ( 5.5)
  • Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.6)
  • Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.7)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥10%) 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


DRUG INTERACTIONS

  • 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. ( 7.1)
  • Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with TRUVADA only with ritonavir; monitor for evidence of tenofovir toxicity. ( 7.2)
  • Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. ( 7.2)

USE IN SPECIFIC POPULATIONS

  • Nursing mothers: Women infected with HIV should be instructed not to breast feed. ( 8.3)
  • Pediatrics: Safety and efficacy not established in patients less than 18 years of age. ( 8.4)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 06/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Adjustment for Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

5.2 Patients Coinfected with HIV-1 and HBV

5.3 New Onset or Worsening Renal Impairment

5.4 Coadministration with Related Products

5.5 Decreases in Bone Mineral Density

5.6 Fat Redistribution

5.7 Immune Reconstitution Syndrome

6 ADVERSE REACTIONS

6.1 Adverse Reactions from Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Didanosine

7.2 Atazanavir

7.3 Lopinavir/Ritonavir

7.4 Drugs Affecting Renal Function

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Impaired Renal Function

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Study 934

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

17.2 FDA-Approved Patient Labeling


FULL PRESCRIBING INFORMATION

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals [See Warnings and Precautions (5.1)].

TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of TRUVADA 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 EMTRIVA or VIREAD, the components of TRUVADA. 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 TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

TRUVADA®, a combination of EMTRIVA® and VIREAD®, is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

Additional important information regarding the use of TRUVADA for the treatment of HIV-1 infection:

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The dose of TRUVADA is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

2.2 Dose Adjustment for Renal Impairment

Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to patients with moderate to severe renal impairment [see EMTRIVA or VIREAD Package Insert]. Therefore, the dosing interval of TRUVADA should be adjusted in patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].

Table 1 Dosage Adjustment for Patients with Altered Creatinine Clearance
Creatinine Clearance (mL/min)*
≥50 30–49 <30
(Including Patients Requiring Hemodialysis)
*
Calculated using ideal (lean) body weight
Recommended Dosing Interval Every 24 hours Every 48 hours TRUVADA should not be administered.

3 DOSAGE FORMS AND STRENGTHS

TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side and with "701" on the other side.

4 CONTRAINDICATIONS

TRUVADA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA 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).

5.2 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic Hepatitis B virus (HBV) before initiating antiretroviral therapy. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA 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 EMTRIVA or VIREAD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of Hepatitis B were associated with liver decompensation and liver failure. 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 TRUVADA. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

5.3 New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment.

Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min, [See Dosage and Administration (2.2)]. No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with creatinine clearance <30 mL/min or patients requiring hemodialysis.

TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent.

5.4 Coadministration with Related Products

TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

5.5 Decreases in Bone Mineral Density

Bone mineral density monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. 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

Tenofovir Disoproxil Fumarate: In a 144-week study of treatment naive patients, decreases in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz compared with patients receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated patients vs. 21% of the comparator patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the VIREAD group and 6 patients in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in patients receiving VIREAD. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].

5.6 Fat Redistribution

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

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA and VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

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.

The most common adverse reactions (incidence ≥ 10%, any severity) occurring in Study 934, an active-controlled clinical study of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 2 for the frequency of treatment-emergent adverse reactions (Grade 2–4) occurring in ≥ 5% of patients treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate in this study.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in other studies in treatment-experienced or treatment-naïve patients receiving VIREAD and/or EMTRIVA (Table 2).

Table 2 Selected Treatment-Emergent Adverse Reactions* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)
FTC + TDF + EFV AZT/3TC + EFV
N=257 N=254
*
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
From Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.
Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.
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
  Depression 9% 7%
  Insomnia 5% 7%
Skin and Subcutaneous Tissue Disorders
  Rash event 7% 9%

Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in other studies of VIREAD and/or EMTRIVA (Table 3).

Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Group in Study 934 (0–144 Weeks)
FTC + TDF + EFV* AZT/3TC + EFV
N=257 N=254
*
From Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.
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%

In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of patients receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.

In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 elevations of bilirubin (>2.5 × ULN), pancreatic amylase (>2.0 × ULN), serum glucose (<40 or >250 mg/dL), and serum lipase (>2.0 × ULN) occurred in up to 3% of patients treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VIREAD. 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.

Immune System Disorders
allergic reaction

Metabolism and Nutrition Disorders
hypophosphatemia, lactic acidosis

Respiratory, Thoracic, and Mediastinal Disorders
dyspnea

Gastrointestinal Disorders
abdominal pain, increased amylase, pancreatitis

Hepatobiliary Disorders
increased liver enzymes (most commonly increased AST, ALT, Gamma GT), hepatitis

Skin and Subcutaneous Tissue Disorders
rash

Musculoskeletal and Connective Tissue Disorders
myopathy, osteomalacia (both associated with proximal renal tubulopathy)

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

General Disorders and Administration Site Conditions
asthenia

7 DRUG INTERACTIONS

No drug interaction studies have been conducted using TRUVADA tablets. Drug interaction studies have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of TRUVADA. This section describes clinically relevant drug interactions observed with emtricitabine and tenofovir disoproxil fumarate [See Clinical Pharmacology (12.3)].

7.1 Didanosine

Coadministration of TRUVADA 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.

When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.

In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When coadministered, TRUVADA and Videx EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions.

7.2 Atazanavir

Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving atazanavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions.

Tenofovir decreases the AUC and Cmin of atazanavir [See Clinical Pharmacology (12.3)]. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with TRUVADA.

7.3 Lopinavir/Ritonavir

Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions.

7.4 Drugs Affecting Renal Function

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [See Clinical Pharmacology (12.3)]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.

Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

8.4 Pediatric Use

Truvada is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, VIREAD, for which safety and efficacy have not been established in this age group.

8.5 Geriatric Use

Clinical studies of EMTRIVA or VIREAD 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 the 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 Patients with Impaired Renal Function

It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

10 OVERDOSAGE

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. 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 Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir disoproxil fumarate was administered to 8 patients 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 VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

TRUVADA tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (tenofovir DF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

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:

Chemical Structure

Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (logp) for emtricitabine is -0.43 and the pKa is 2.65.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate 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:

Chemical Structure

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

TRUVADA is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

TRUVADA: One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 4. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and 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. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 4. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and 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. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 4 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults*
Emtricitabine Tenofovir
*
NC = Not calculated
Median (range)
Mean (± SD)
§
Data presented as steady state values.
Fasted Oral Bioavailability (%) 92 (83.1–106.4) 25 (NC–45.0)
Plasma Terminal Elimination Half-Life (hr) 10 (7.4–18.0) 17 (12.0–25.7)
Cmax (µg/mL) 1.8 ± 0.72§ 0.30 ± 0.09
AUC (µghr/mL) 10.0 ± 3.12§ 2.29 ± 0.69
CL/F (mL/min) 302 ± 94 1043 ± 115
CLrenal (mL/min) 213 ± 89 243 ± 33

Effects of Food on Oral Absorption

TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy studies, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.

Special Populations

Race

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

Tenofovir Disoproxil Fumarate: 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 VIREAD.

Gender

Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

Pediatric and Geriatric Patients

Pharmacokinetic studies of tenofovir have not been performed in pediatric patients (<18 years). Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years).

Patients with Impaired Renal Function

The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal impairment [See Warnings and Precautions (5.3)]. In patients with creatinine clearance <50 mL/min, Cmax, and AUC0– of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate 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.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 5 and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, adefovir dipivoxil, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir in studies conducted in healthy volunteers (see Tables 7 and 8).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug*
Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Emtricitabine Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.

↑ = Increase; ↓ = Decrease; Symbol = No Effect; NA = Not Applicable

Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 Symbol Symbol ↑ 20
(↑ 12 to ↑ 29)
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 Symbol Symbol Symbol
Indinavir 800 × 1 200 × 1 12 Symbol Symbol NA
Famciclovir 500 × 1 200 × 1 12 Symbol Symbol NA
Stavudine 40 × 1 200 × 1 6 Symbol Symbol NA

Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine*
Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.

↑ = Increase; ↓ = Decrease; Symbol = No Effect; NA = Not Applicable

Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 Symbol Symbol Symbol
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 ↑ 17
(↑ 0 to ↑ 38)
↑ 13
(↑ 5 to ↑ 20)
Symbol
Indinavir 800 × 1 200 × 1 12 Symbol Symbol NA
Famciclovir 500 × 1 200 × 1 12 Symbol Symbol NA
Stavudine 40 × 1 200 × 1 6 Symbol Symbol NA
Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir* in the Presence of the Coadministered Drug
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters
(90% CI)
Cmax AUC Cmin
*
Patients received VIREAD 300 mg once daily.

Increase = ↑; Decrease = ↓; No Effect = Symbol; NC = Not Calculated

Reyataz Prescribing Information
Abacavir 300 once 8 Symbol Symbol NC
Adefovir dipivoxil 10 once 22 Symbol Symbol NC
Atazanavir 400 once daily × 14 days 33 ↑ 14
(↑ 8 to ↑ 20)
↑ 24
(↑ 21 to ↑ 28)
↑ 22
(↑ 15 to ↑ 30)
Didanosine (enteric-coated) 400 once 25 Symbol Symbol Symbol
Didanosine (buffered) 250 or 400 once daily × 7 days 14 Symbol Symbol Symbol
Efavirenz 600 once daily × 14 days 29 Symbol Symbol Symbol
Emtricitabine 200 once daily × 7 days 17 Symbol Symbol Symbol
Indinavir 800 three times daily × 7 days 13 ↑ 14
(↓ 3 to ↑ 33)
Symbol Symbol
Lamivudine 150 twice daily × 7 days 15 Symbol Symbol Symbol
Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 Symbol ↑ 32
(↑ 25 to ↑ 38)
↑ 51
(↑ 37 to ↑ 66)
Nelfinavir 1250 twice daily × 14 days 29 Symbol Symbol Symbol
Saquinavir/Ritonavir 1000/100 twice daily × 14 days 35 Symbol Symbol ↑ 23
(↑ 16 to ↑ 30)
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters*
(90% CI)
Cmax AUC Cmin
*

Increase = ↑; Decrease = ↓; No Effect = Symbol; NA = Not Applicable

Reyataz Prescribing Information
In 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.
§
R-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD.
Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
#
Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
Þ
Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
Abacavir 300 once 8 ↑ 12
(↓ 1 to ↑ 26)
Symbol NA
Adefovir dipivoxil 10 once 22 Symbol Symbol NA
Atazanavir 400 once daily × 14 days 34 ↓ 21
(↓ 27 to ↓ 14)
↓ 25
(↓ 30 to ↓ 19)
↓ 40
(↓ 48 to ↓ 32)
Atazanavir Atazanavir/Ritonavir 300/100 once daily × 42 days 10 ↓ 28
(↓ 50 to ↑ 5)
↓ 25
(↓ 42 to ↓ 3)
↓ 23
(↓ 46 to ↑ 10)
Efavirenz 600 once daily × 14 days 30 Symbol Symbol Symbol
Emtricitabine 200 once daily × 7 days 17 Symbol Symbol ↑ 20
(↑ 12 to ↑ 29)
Indinavir 800 three times daily × 7 days 12 ↓ 11
(↓ 30 to ↑ 12)
Symbol Symbol
Lamivudine 150 twice daily × 7 days 15 ↓ 24
(↓ 34 to ↓ 12)
Symbol Symbol
Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 Symbol Symbol Symbol
Ritonavir Symbol Symbol Symbol
Methadone§ 40–110 once daily × 14 days 13 Symbol Symbol Symbol
Nelfinavir 1250 twice daily × 14 days 29 Symbol Symbol Symbol
M8 metabolite Symbol Symbol Symbol
Oral Contraceptives# Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) Once daily × 7 days 20 Symbol Symbol Symbol
Ribavirin 600 once 22 Symbol Symbol NA
Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22
(↑ 6 to ↑41)
↑ 29Þ
(↑ 12 to ↑ 48)
↑ 47Þ
(↑ 23 to ↑ 76)
Ritonavir Symbol Symbol ↑ 23
(↑ 3 to ↑ 46)

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

Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, 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. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.

Table 9 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD
Didanosine* Dose (mg)/Method of Administration* VIREAD Method of Administration* N % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted
Cmax AUC
*
Administration with food was with a light meal (~373 kcal, 20% fat).

Increase = ↑; Decrease = ↓; No Effect = Symbol

Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily × 7 days Fasted 1 hour after didanosine 14 ↑ 28
(↑ 11 to ↑ 48)
↑ 44
(↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted With food, 2 hours after didanosine 26 ↑ 48
(↑ 25 to ↑ 76)
↑ 48
(↑ 31 to ↑ 67)
400 once, with food Simultaneously with didanosine 26 ↑ 64
(↑ 41 to ↑ 89)
↑ 60
(↑ 44 to ↑ 79)
250 once, fasted With food, 2 hours after didanosine 28 ↓ 10
(↓ 22 to ↑ 3)
Symbol
250 once, fasted Simultaneously with didanosine 28 Symbol ↑ 14
(0 to ↑ 31)
250 once, with food Simultaneously with didanosine 28 ↓ 29
(↓ 39 to ↓ 18)
↓ 11
(↓ 23 to ↑ 2)

12.4 Microbiology

Mechanism of Action

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (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 polymerase α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate 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

Emtricitabine and Tenofovir Disoproxil Fumarate: In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.

Emtricitabine: The antiviral activity 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 nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, 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 Disoproxil Fumarate: The antiviral activity 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 nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, 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 µM to 5.5 µM).

Resistance

Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.

In a clinical study of treatment-naïve patients [Study 934, see Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed patient isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed patient isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no patients have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. 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 Disoproxil Fumarate: 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 2–4 fold reduction in susceptibility to tenofovir.

In treatment-naïve patients, isolates from 8/47 (17%) analyzed patients developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced patients, 14/304 (5%) isolates from patients failing VIREAD through Week 96 showed >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.

Cross Resistance

Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. 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.

Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

Tenofovir Disoproxil Fumarate: HIV-1 isolates from patients (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. Multinucleoside resistant HIV-1 with a T69S double insertion substitution in the RT showed reduced susceptibility to tenofovir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine: In long-term oral 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/kg/day (31 times the human systemic exposure at the therapeutic dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate 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 disoproxil fumarate 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 disoproxil fumarate was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate 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 seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Tenofovir and tenofovir disoproxil fumarate 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. 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) 2–20 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 TRUVADA tablets for the treatment of HIV-1 infection. Additional data in support of the use of TRUVADA are derived from Study 903, in which lamivudine and tenofovir disoproxil fumarate (tenofovir DF) were used in combination in treatment-naïve adults, and clinical Study 303 in which emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these studies, please consult the prescribing information for tenofovir DF and emtricitabine.

14.1 Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. From Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Patients 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). Patients were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 10.

Table 10 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)
Outcomes At Week 48 At Week 144
FTC + TDF
+ EFV
(N=244)
AZT/3TC
+ EFV
(N=243)
FTC + TDF
+ EFV
(N=227)*
AZT/3TC
+ EFV
(N=229)*
*
Patients who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.
Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.
§
Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Responder 84% 73% 71% 58%
Virologic failure 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 reasons§ 10% 14% 20% 22%

Through Week 48, 84% and 73% of patients 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 patients 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 study. In addition, 80% and 70% of patients 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 patients in the emtricitabine + tenofovir DF group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 patients through 144 weeks).

16 HOW SUPPLIED/STORAGE AND HANDLING

The blue, capsule-shaped, film-coated, tablets contain 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil), are debossed with "GILEAD" on one side and with "701" on the other side, and are available in unit of use bottles (containing a dessicant [silica gel canister or sachet] and closed with a child-resistant closure) of:

Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (17.2)

17.1 Information for Patients

Patients should be advised that:

17.2 FDA-Approved Patient Labeling

TRUVADA® (tru-VAH-dah) tablets

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

Read the Patient Information that comes with TRUVADA before you start taking it and each time you get a refill. 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 TRUVADA. 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 TRUVADA.

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

What is TRUVADA?

TRUVADA is a type of medicine called an HIV-1 (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitor (NRTI). TRUVADA contains 2 medicines, EMTRIVA® (emtricitabine) and VIREAD® (tenofovir disoproxil fumarate, or tenofovir DF) combined in one pill. TRUVADA is always used with other anti-HIV-1 medicines to treat people with HIV-1 infection. TRUVADA is for adults age 18 and older. TRUVADA has not been studied in children under age 18 or adults over age 65.

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.

TRUVADA helps block HIV-1 reverse transcriptase, a chemical in your body (enzyme) that is needed for HIV-1 to multiply. TRUVADA lowers the amount of HIV-1 in the blood (viral load). TRUVADA may also help to increase the number of T cells (CD4+ cells). 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).

TRUVADA does not cure HIV-1 infection or AIDS. The long-term effects of TRUVADA are not known at this time. People taking TRUVADA may still get opportunistic infections or other conditions that happen with HIV-1 infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection. It is very important that you see your healthcare provider regularly while taking TRUVADA.

TRUVADA does not lower your chance of passing HIV-1 to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.

Who should not take TRUVADA?

What should I tell my healthcare provider before taking TRUVADA?

Tell your healthcare provider if you:

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:

Keep a complete list of all the medicines that you take. Make a new list when medicines are added or stopped. Give copies of this list to all of your healthcare providers and pharmacist every time you visit your healthcare provider or fill a prescription.

How should I take TRUVADA?

What should I avoid while taking TRUVADA?

What are the possible side effects of TRUVADA?

TRUVADA may cause the following serious side effects (see " What is the most important information I should know about TRUVADA?"):

Other side effects with TRUVADA when used with other anti-HIV-1 medicines include:

The most common side effects of EMTRIVA or VIREAD when used with other anti-HIV-1 medicines are: diarrhea, nausea, vomiting, dizziness and headache. Additional side effects are stomach pain, indigestion, gas, inflammation of the pancreas, increased amylase, sleeping problems, abnormal dreams, weakness, pain, low blood phosphate, shortness of breath, increase liver enzymes, inflammation of the liver, allergic reaction, muscle problems and rash. Skin discoloration (small spots or freckles) may also happen with TRUVADA.

These are not all the side effects of TRUVADA. This list of side effects with TRUVADA is not complete at this time because TRUVADA is still being studied. If you have questions about side effects, ask your healthcare provider. Report any new or continuing symptoms to your healthcare provider right away. Your healthcare provider may be able to help you manage these side effects.

How do I store TRUVADA?

General information about TRUVADA:

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

This leaflet summarizes the most important information about TRUVADA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TRUVADA that is written for health professionals. For more information, you may also call 1-800-GILEAD-5 or access the TRUVADA website at www.TRUVADA.com.

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

What are the ingredients of TRUVADA?

Active Ingredients: emtricitabine and tenofovir disoproxil fumarate

Inactive Ingredients: Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701 containing FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Rx Only

May 2008

TRUVADA, EMTRIVA, and VIREAD are registered trademarks of Gilead Sciences, Inc. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

21-752-GS-021 19MAY08


TRUVADA (emtricitabine and tenofovir disoproxil fumarate)
PRODUCT INFO
Product Code 61958-0701 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
tenofovir disoproxil fumarate (tenofovir) Active 300 MILLIGRAM  In 1 TABLET
emtricitabine (emtricitabine) Active 200 MILLIGRAM  In 1 TABLET
Croscarmellose Sodium Inactive  
Lactose Monohydrate Inactive  
Magnesium Stearate Inactive  
Microcrystalline Cellulose Inactive  
Pregelatinized Starch Inactive  
Opadry II Blue Y-30-10701 Inactive  
FD&C Blue #2 Aluminum Lake Inactive  
Hydroxypropyl Methylcellulose 2910 Inactive  
Titanium Dioxide Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color blue (blue) Score 1
Shape OVAL (capsule-shaped) Symbol false
Imprint Code GILEAD;701 Coating true
Size 19mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 61958-0701-1 30 TABLET In 1 BOTTLE, PLASTIC None

Revised: 06/2008Gilead Sciences, Inc.

Data are from FDA and U.S. National Library of Medicine.