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Viread

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Viread

Viread

SIDE EFFECTS

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

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-Na´ve Patients

Study 903 -Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-na´ve 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%
Neutrophils ( < 750/mm³) 3% 1%
Fasting Triglycerides ( > 750 mg/dL) 1% 9%

 

Study 934 -Treatment Emergent Adverse Reactions

In Study 934, 511 antiretroviralna´ve 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-na´ve subjects (Table 6).

Changes in Bone Mineral Density

In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects 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 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the VIREAD group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [See WARNINGS AND PRECAUTIONS].

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%
Neutrophils ( < 750/mm³) 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 na´ve 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 W hole
  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%
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.

Eighty-nine pediatric subjects (2 to less than 12 years of age) received VIREAD in Study 352 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].

Changes in Bone Mineral Density

Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the VIREAD compared to the placebo treatment group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with VIREAD for 96 weeks. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the VIREAD and the d4T or AZT treatment groups. Total body BMD gain was less in the VIREAD compared to the d4T or AZT treatment groups. One VIREAD-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with VIREAD for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected [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 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 48-240) 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 Î baseline and greater than 10 Î 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.

The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults.

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.

In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were -0.43 for lumbar spine and -0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were -0.28 for lumbar spine and -0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was -0.05 for lumbar spine and -0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected [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

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.

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 once daily when it is coadministered with VIREAD. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of VIREAD and didanosine, please refer to the full prescribing information for didanosine.

HIV-1 Protease Inhibitors

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. VIREAD should not be coadministered with atazanavir without ritonavir.

Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [See CLINICAL PHARMACOLOGY]. Tenofovir disoproxil fumarate is a substrate of Pglycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir 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, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [See WARNINGS AND PRECAUTIONS].

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

Read the Viread Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 11/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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