Viread Side Effects

Please note - some side effects for Viread may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Viread - for the Consumer

Viread

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Viread:

Abnormal skin sensations; back pain; diarrhea; dizziness; gas; headache; indigestion; loss of appetite; nausea; sleeplessness; sweating; vomiting; weakness; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Viread:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); anxiety; bone pain; chest pain; fever, chills, or sore throat; mental or mood changes (eg, depression); numbness, burning, pain, or tingling in the hands or feet; pneumonia; severe or persistent nausea or vomiting; shortness of breath; stomach pain; symptoms of kidney problems (eg, increased or decreased urination, increased thirst); symptoms of lactic acidosis (eg, unusual weakness or tiredness; unusual muscle pain; fast or difficult breathing; stomach pain with nausea and vomiting; feeling cold, especially in the arms and legs; dizziness or lightheadedness; fast or irregular heartbeat); symptoms of liver problems (eg, yellowing of the skin or eyes; dark urine; pale stools; persistent loss of appetite).

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Viread Side Effects - for the Professional

Viread

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

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].
• Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].
• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].
• Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].
• Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].

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 Patients with HIV Infection

More than 12,000 patients 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 studies. A total of 1,544 patients have received Viread 300 mg once daily in clinical trials; over 11,000 patients have received Viread in expanded access studies.

The most common adverse reactions (incidence ≥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 study in which 600 treatment-naïve patients 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* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 903 (0–144 Weeks)

	Viread + 3TC + EFV	d4T + 3TC + EFV
	N=299	N=301
* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. ‡ Peripheral neuropathy includes peripheral neuritis and neuropathy. § Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
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
Lipodystrophy†	1%	8%
Musculoskeletal
Arthralgia	5%	7%
Myalgia	3%	5%
Nervous System
Depression	11%	10%
Insomnia	5%	8%
Dizziness	3%	6%
Peripheral neuropathy‡	1%	5%
Anxiety	6%	6%
Respiratory
Pneumonia	5%	5%
Skin and Appendages
Rash event§	18%	12%

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 study 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 Patients in Study 903 (0–144 Weeks)

	Viread + 3TC + EFV	d4T + 3TC + EFV
	N=299	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%
Neutrophils (<750/mm3)	3%	1%
Fasting Triglycerides (>750 mg/dL)	1%	9%

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 previous studies in treatment-experienced or treatment-naïve patients (Table 4).

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

	Viread† + FTC + 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 previous studies (Table 5).

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

	Viread* + FTC + 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%

Treatment-Experienced Patients

Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced patients were generally consistent with those seen in treatment naïve patients including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies 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* (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)
* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † Peripheral neuropathy includes peripheral neuritis and neuropathy. ‡ Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
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 neuropathy†	3%	3%	5%	2%
Dizziness	1%	3%	3%	1%
Skin and Appendage
Rash event‡	5%	4%	7%	1%
Sweating	3%	2%	3%	1%
Musculoskeletal
Myalgia	3%	3%	4%	1%
Metabolic
Weight loss	2%	1%	4%	2%

Laboratory Abnormalities: Laboratory abnormalities observed in this study 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 Patients 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: >990U/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%
Neutrophils (<750/mm3)	1%	1%	2%	1%

Clinical Trials in Patients with Chronic Hepatitis B

Treatment-Emergent Adverse Reactions: In controlled clinical trials in patients with chronic hepatitis B, more patients treated with Viread experienced nausea: 9% with Viread versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in >5% of patients treated with Viread included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

Laboratory Abnormalities: A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 8.

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

	Viread (N=426)	HEPSERA (N=215)
Any ≥ Grade 3 Laboratory Abnormality	19%	13%
Creatine Kinase (M: >990U/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 elevations (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between Viread (2.6%) and HEPSERA (2%). ALT elevations generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No patient had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

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
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.

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Side Effects by Body System

General

The most common side effects (greater than or equal to 10%; Grades 2 to 4) reported during controlled clinical trials in patients with HIV infection included rash, diarrhea, headache, pain, depression, asthenia, and nausea. The most common side effects associated with tenofovir in combination with other antiretrovirals have included mild to moderate gastrointestinal events (such as nausea, diarrhea, vomiting, and flatulence) in treatment-experienced patients and mild to moderate gastrointestinal events and dizziness in treatment-naive patients. Less than 1% of patients in clinical trials discontinued treatment due to gastrointestinal side effects.

The most common side effects (greater than 5%) reported during controlled clinical trials in patients with chronic hepatitis B included nausea, abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.

Gastrointestinal

Gastrointestinal side effects (Grades 2 to 4) have included diarrhea (up to 16%), nausea (up to 11%), vomiting (up to 7%), flatulence (up to 4%), dyspepsia (up to 4%), and anorexia (up to 4%). Pancreatitis, abdominal pain, and elevated amylase have been reported during postmarketing experience.

Metabolic

Hypokalemia and hypophosphatemia may occur due to proximal renal tubulopathy.

Metabolic side effects (Grade 3/4) have included elevated fasting cholesterol (up to 22%), creatine kinase (up to 12%), triglycerides (up to 11%), serum amylase (up to 9%), fasting triglycerides (up to 4%), serum glucose (up to 3%), alkaline phosphatase (1%), and serum lipase (1%). Additional side effects (Grades 2 to 4) have included weight loss (up to 4%) and lipodystrophy (1%). Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy, including tenofovir; however, a causal relationship has not been established. Lactic acidosis, hypokalemia, and hypophosphatemia have been reported during postmarketing experience.

Dermatologic

Dermatologic side effects (Grades 2 to 4) have included rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, exfoliative rash, generalized rash, macular rash, pruritic rash, and vesicular rash; up to 18%) and sweating (up to 3%). At least one case of lichenoid drug eruption with eosinophilia has been reported. Rash has also been reported during postmarketing experience.

Nervous system

Nervous system side effects (Grades 2 to 4) have included headache (up to 14%), dizziness (up to 8%), insomnia (up to 5%), and peripheral neuropathy (including peripheral neuritis and neuropathy; up to 5%). Somnolence and paresthesia have been reported.

Other

Other side effects (Grades 2 to 4) have included pain (up to 13%), asthenia (up to 11%), fatigue (9%), back pain (up to 9%), fever (up to 8%), abdominal pain (up to 7%), and chest pain (up to 3%).

Psychiatric

Psychiatric side effects (Grades 2 to 4) have included depression (up to 11%) and anxiety (6%). Abnormal dreams have been reported.

Hepatic

Hepatic side effects (Grade 3/4) have included elevated alanine transaminase (ALT; up to 10%) and aspartate transaminase (AST; up to 5%). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside/nucleotide analogs, including tenofovir, in combination with other antiretroviral agents. Hepatic steatosis, hepatitis, and elevated liver enzymes (primarily AST, ALT, and gamma glutamyl transferase) have been reported during postmarketing experience. Severe acute exacerbations of hepatitis have been reported in patients with hepatitis B after discontinuation of tenofovir.

Renal

Rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia may occur as a result of proximal renal tubulopathy.

Renal side effects have included new onset or worsening renal impairment, nephritis, and decreased urine volume. Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal renal tubulopathy, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, and interstitial nephritis (including acute cases) have been reported during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects (Grades 2 to 4) have included arthralgia (5%) and myalgia (up to 4%). Decreased bone mineral density and increased biochemical markers of bone metabolism have been reported. Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, and myopathy have been reported during postmarketing experience.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy may occur due to proximal renal tubulopathy.

Respiratory

Respiratory side effects (Grades 2 to 4) have included sinusitis (8%), upper respiratory tract infections (8%), nasopharyngitis (5%), and pneumonia (up to 5%). Nasal congestion has been reported. Dyspnea has been reported during postmarketing experience.

Hematologic

Hematologic side effects (Grade 3/4) have included decreased neutrophils (up to 3%).

Genitourinary

Genitourinary side effects (Grade 3/4) have included hematuria (up to 7%) and glycosuria (up to 3%). Proteinuria and polyuria have been reported during postmarketing experience.

Immunologic

Immunologic side effects have included immune reconstitution syndrome.

Hypersensitivity

Hypersensitivity side effects have included allergic reaction (including angioedema) during postmarketing experience.

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