Viread
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Viread
SIDE EFFECTS
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-Naïve Patients
Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatmentnaïve 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 4.
Table 4 : Selected Treatment-Emergent Adverse
Reactionsa (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in
Study 903 (0–144 Weeks)
| VIREAD + 3TC + EFV N=299 |
d4T + 3TC + EFV N=301 |
|
| Body as a Whole | ||
| Headache | 14% | 17% |
| Pain | 13% | 12% |
| Fever | 8% | 7% |
| Abdominal pain | 7% | 12% |
| Back pain | 9% | 8% |
| Asthenia | 6% | 7% |
| Digestive System | ||
| Diarrhea | 11% | 13% |
| Nausea | 8% | 9% |
| Dyspepsia | 4% | 5% |
| Vomiting | 5% | 9% |
| Metabolic Disorders | ||
| Lipodystrophyb | 1% | 8% |
| Musculoskeletal | ||
| Arthralgia | 5% | 7% |
| Myalgia | 3% | 5% |
| Nervous System | ||
| Depression | 11% | 10% |
| Insomnia | 5% | 8% |
| Dizziness | 3% | 6% |
| Peripheral neuropathyc | 1% | 5% |
| Anxiety | 6% | 6% |
| Respiratory | ||
| Pneumonia | 5% | 5% |
| Skin and Appendages | ||
| Rash eventd | 18% | 12% |
| a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, regardless of relationship to study
drug. b Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. c Peripheral neuropathy includes peripheral neuritis and neuropathy. d Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
||
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 Grades 3-4 laboratory abnormalities is provided in Table 5.
Table 5 : Grades 3-4 Laboratory Abnormalities Reported
in ≥ 1% of VIREAD-Treated Subjects in Study 903 (0–144 Weeks)
| VIREAD + 3TC + EFV N=299 |
d4T + 3TC + EFV N=301 |
|
| Any ≥ Grade 3 Laboratory Abnormality | 36% | 42% |
| Fasting Cholesterol ( > 240 mg/dL) | 19% | 40% |
| Creatine Kinase (M: > 990 U/L; F: > 845 U/L) | 12% | 12% |
| Serum Amylase ( > 175 U/L) | 9% | 8% |
| AST (M: > 180 U/L; F: > 170 U/L) | 5% | 7% |
| ALT (M: > 215 U/L; F: > 170 U/L) | 4% | 5% |
| Hematuria ( > 100 RBC/HPF) | 7% | 7% |
| 3 Neutrophils ( < 750/mm³ ) | 3% | 1% |
| Fasting Triglycerides ( > 750 mg/dL) | 1% | 9% |
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 6).
Table 6 : Selected Treatment-Emergent Adverse
Reactionsa (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in
Study 934 (0–144 Weeks)
| VIREADb + FTC + EFV N=257 |
AZT/3TC + EFV 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 | ||
| Depression | 9% | 7% |
| Insomnia | 5% | 7% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash eventc | 7% | 9% |
| a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, regardless of relationship to study
drug. b From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. c Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. |
||
Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).
Table 7 : Significant Laboratory Abnormalities
Reported in ≥ 1% of Subjects in Any Treatment Group in Study 934
(0–144 Weeks)
| VIREADa + FTC + EFV N=257 |
AZT/3TC + EFV 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% |
| 3 Neutrophils ( < 750/mm ) | 3% | 5% |
| Fasting Triglycerides ( > 750 mg/dL) | 4% | 2% |
| a From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. | ||
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 8.
Table 8 : Selected Treatment-Emergent Adverse
Reactionsa (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in
Study 907 (0–48 Weeks)
| VIREAD (N=368) (Week 0-24) |
Placebo (N=182) (Week 0-24) |
VIREAD (N=368) (Week 0-48) |
Placebo Crossover to VIREAD (N=170) (Week 24-48) |
|
| Body as a Whole | ||||
| Asthenia | 7% | 6% | 11% | 1% |
| Pain | 7% | 7% | 12% | 4% |
| Headache | 5% | 5% | 8% | 2% |
| Abdominal pain | 4% | 3% | 7% | 6% |
| Back pain | 3% | 3% | 4% | 2% |
| Chest pain | 3% | 1% | 3% | 2% |
| Fever | 2% | 2% | 4% | 2% |
| Digestive System | ||||
| Diarrhea | 11% | 10% | 16% | 11% |
| Nausea | 8% | 5% | 11% | 7% |
| Vomiting | 4% | 1% | 7% | 5% |
| Anorexia | 3% | 2% | 4% | 1% |
| Dyspepsia | 3% | 2% | 4% | 2% |
| Flatulence | 3% | 1% | 4% | 1% |
| Respiratory | ||||
| Pneumonia | 2% | 0% | 3% | 2% |
| Nervous System | ||||
| Depression | 4% | 3% | 8% | 4% |
| Insomnia | 3% | 2% | 4% | 4% |
| Peripheral neuropathyb | 3% | 3% | 5% | 2% |
| Dizziness | 1% | 3% | 3% | 1% |
| Skin and Appendage | ||||
| Rash eventc | 5% | 4% | 7% | 1% |
| Sweating | 3% | 2% | 3% | 1% |
| Musculoskeletal | ||||
| Myalgia | 3% | 3% | 4% | 1% |
| Metabolic | ||||
| Weight loss | 2% | 1% | 4% | 2% |
| a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, regardless of relationship to study
drug. b Peripheral neuropathy includes peripheral neuritis and neuropathy. c Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
||||
Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grades 3-4 laboratory abnormalities is provided in Table 9.
Table 9 : Grades 3-4 Laboratory Abnormalities Reported
in ≥ 1% of VIREAD-Treated Subjects in Study 907 (0–48 Weeks)
| VIREAD (N=368) (Week 0-24) |
Placebo (N=182) (Week 0-24) |
VIREAD (N=368) (Week 0-48) |
Placebo Crossover to VIREAD (N=170) (Week 24-48) |
|
| Any ≥ Grade 3 Laboratory Abnormality | 25% | 38% | 35% | 34% |
| Triglycerides ( > 750 mg/dL) | 8% | 13% | 11% | 9% |
| Creatine Kinase (M: > 990 U/L; F: > 845 U/L) | 7% | 14% | 12% | 12% |
| Serum Amylase ( > 175 U/L) | 6% | 7% | 7% | 6% |
| Glycosuria ( ≥ 3+) | 3% | 3% | 3% | 2% |
| AST (M: >180 U/L; F: > 170 U/L) | 3% | 3% | 4% | 5% |
| ALT (M: > 215 U/L; F: > 170 U/L) | 2% | 2% | 4% | 5% |
| Serum Glucose ( > 250 U/L) | 2% | 4% | 3% | 3% |
| 3 Neutrophils ( < 750/mm³ ) | 1% | 1% | 2% | 1% |
Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection
Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with VIREAD (N=93) or placebo/active comparator (N=91) 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 2 years of age and older were consistent with those observed in adult clinical trials [See WARNINGS AND PRECAUTIONS].
Eighty-nine pediatric subjects received VIREAD in Study 352 (48 who were initially randomized to VIREAD and 41 who were initially randomized to continue stavudine or zidovudine and then received VIREAD in the extension phase) for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score [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 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week 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 48-240) 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 240 weeks.
Laboratory Abnormalities: A summary of Grades 3-4 laboratory abnormalities through Week 48 is provided in Table 10. Grades 3-4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 240 weeks in these trials.
Table 10 : Grades 3-4 Laboratory Abnormalities
Reported in ≥ 1% of VIREAD-Treated Subjects in Studies 0102 and 0103 (0-48
Weeks)
| VIREAD (N=426) | HEPSERA (N=215) | |
| Any ≥ Grade 3 Laboratory Abnormality | 19% | 13% |
| Creatine Kinase (M: > 990 U/L; F: > 845 U/L) | 2% | 3% |
| Serum Amylase ( > 175 U/L) | 4% | 1% |
| Glycosuria ( ≥ 3+) | 3% | < 1% |
| AST (M: > 180 U/L; F: > 170 U/L) | 4% | 4% |
| ALT (M: > 215 U/L; F: > 170 U/L) | 10% | 6% |
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 Trials 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 2 mg/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.
Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B
Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.
The mean rate of bone mineral density gain was less in VIREAD-treated subjects compared to placebo [See WARNINGS AND PRECAUTIONS].
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
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.
Read the Viread (tenofovir disoproxil fumarate) Side Effects Center for a complete guide to possible side effects »
DRUG INTERACTIONS
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 didanosineassociated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
When administered with VIREAD, Cmax and AUC of didanosine 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 VIREAD 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).
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 VIREADassociated 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: 4/22/2013
This monograph has been modified to include the generic and brand name in many instances.
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