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

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Severe Acute Exacerbation of Hepatitis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
• Decreases in Bone Mineral Density [See WARNINGS AND PRECAUTIONS].
• Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].

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 Patients with HIV-1 Infection

More than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access programs.

The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Treatment-Naive Patients

Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.

Table 2 : Selected Treatment-Emergent Adverse Reactions^a (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0–144 Weeks)

Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.

Table 3 : Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Subjects in Study 903 (0–144 Weeks)

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaïve subjects 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 trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 4).

Table 4 : Selected Treatment-Emergent Adverse Reactions^a (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Study 934 (0–144 Weeks)

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 5).

Table 5 : Significant Laboratory Abnormalities Reported in ≥ 1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks)

Treatment-Experienced Patients

Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced subjects were generally consistent with those seen in treatment naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).

A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 6.

Table 6 : Selected Treatment-Emergent Adverse Reactions^a (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in Study 907 (0–48 Weeks)

Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 7.

Table 7 : Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Subjects in Study 907 (0–48 Weeks)

Clinical Trials in Pediatric Subjects 12 Years of Age and Older with HIV-1 Infection

Assessment of adverse reactions is based on one randomized trial (Study 321) in 87 HIV-1 infected pediatric subjects (12 to less than 18 years of age) who received treatment with VIREAD (N=45) or placebo (N=42) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults.

Bone effects observed in pediatric subjects 12 years of age and older were consistent with those observed in adult clinical trials [See WARNINGS AND PRECAUTIONS].

Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease

Treatment-Emergent Adverse Reactions: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48week double-blind period experienced nausea: 9% with VIREAD versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

During the open-label phase of treatment with VIREAD (weeks 48-192) in Studies 0102 and 0103, less than 1% of subjects (5/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 192 weeks.

Laboratory Abnormalities: A summary of Grade 3 and 4 laboratory abnormalities through Week 48 is provided in Table 8. Grade 3/4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 192 weeks in these trials.

Table 8 : Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Subjects in Studies 0102 and 0103 (0-48 Weeks)

The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease

In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks [see Clinical Studies]. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain.

One of 45 subjects experienced an on-treatment hepatic flare during the 48 Week trial.

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, 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.

This section describes clinically relevant drug interactions with VIREAD. Drug interactions trials are described elsewhere in the labeling [See CLINICAL PHARMACOLOGY].

Didanosine

Coadministration of VIREAD 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 administered with VIREAD, Cmax and AUC of didanosine (administered as either the buffered or enteric-coated formulation) increased significantly [See CLINICAL PHARMACOLOGY]. 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 disoproxil fumarate (tenofovir DF) with didanosine 400 mg daily.

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

Atazanavir

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

VIREAD decreases the AUC and Cmin of atazanavir [See CLINICAL PHARMACOLOGY]. When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD.

Lopinavir/Ritonavir

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

Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys [See CLINICAL PHARMACOLOGY], coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir.

In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

Last reviewed on RxList: 12/6/2011
This monograph has been modified to include the generic and brand name in many instances.