VIREAD SIDE EFFECTS

SIDE EFFECTS

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

• Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection
• New Onset or Worsening Renal Impairment
• Immune Reconstitution Syndrome
• Bone Loss and Mineralization Defects
• Lactic Acidosis/Severe Hepatomegaly with Steatosis

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.

Adverse Reactions From Clinical Trials Experience In HIV-1 Infected Adults

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.

Clinical Trials In Treatment-Naive HIV-1 Infected Adult Subjects

In Trial 903, 600 antiretroviral-naive subjects received VIREAD (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions 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. Table 4 provides the treatment-emergent adverse reactions (Grades 2- 4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 1 : Selected Adverse Reactions* (Grades 2-4) Reported in ≥5% in Any Treatment Group in Trial 903 (0-144 Weeks)

	VIRE AD+3T C+EF V N=299	d4T+3TC+EFV N=301
	VIRE AD+3T C+EFV N=299	d4T+3TC+EFV N=301
Rash event†	18%	12%
Headache	14%	17%
Pain	13%	12%
Diarrhea	11%	13%
Depression	11%	10%
Back pain	9%	8%
Nausea	8%	9%
Fever	8%	7%
Abdominal pain	7%	12%
Asthenia	6%	7%
Anxiety	6%	6%
Vomiting	5%	9%
Insomnia	5%	8%
Arthralgia	5%	7%
Pneumonia	5%	5%
Dyspepsia	4%	5%
Dizziness	3%	6%
Myalgia	3%	5%
Lipodystrophy‡	1%	8%
Peripheral neuropathy§	1%	5%
*Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. ‡Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. §Peripheral neuropathy includes peripheral neuritis and neuropathy.

 

Laboratory Abnormalities

Table 2 provides a list of laboratory abnormalities (Grades 3-4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the VIREAD group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and d4T treatment arms.

Table 2 : Grades 3-4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Trial 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 LI/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%

 

Changes In Bone Mineral Density

In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-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 d4T 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 VIREADtreated subjects vs. 21% of d4T-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 d4T 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 d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range.

In Trial 934, 511 antiretroviral-naive subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + VIREAD (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 6 provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 3 : Selected Adverse Reactions (Grades 2-4) Reported in ≥5% in Any Treatment Group in Trial 934 (0-144 Weeks)

	VIREAD†+FTC+EFV N=257	AZT/3TC+EFV N=254
Fatigue	9%	8%
Depression	9%	7%
Nausea	9%	7%
Diarrhea	9%	5%
Dizziness	8%	7%
Upper respiratory tract infections	8%	5%
Sinusitis	8%	4%
Rash event‡	7%	9%
Headache	6%	5%
Insomnia	5%	7%
Nasopharyngitis	5%	3%
Vomiting	2%	5%
*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 trial, subjects received TRUVADA with EFV in place of VIREAD ® + FTC with EFV. ‡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 4).

Table 4 : Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Trial 934 (0- 144 Weeks)

	VIREAD + FTC + EFV* N=257	AZT/3TC + EFV N=254
Aliy ≥ 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 LI/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%
*From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of VIREAD + FTC with EFV.

 

Clinical Trials In Treatment-Experienced HIV-1 Infected Adult Subjects

In Trial 907, the adverse reactions seen in HIV-1 infected treatment-experienced subjects were generally consistent with those seen in treatment-naive 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. Table 5 provides the treatment-emergent adverse reactions (Grades 2-4) occurring in greater than or equal to 3% of subjects treated in any treatment group.

Table 5 : Selected Adverse Reactions (Grades 2-4) Reported in ≥3% in Any Treatment Group in Trial 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 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%
* 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.

 

Laboratory Abnormalities

Table 6 provides a list of Grade 3-4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the VIREAD and placebo groups.

Table 6 : Grades 3-4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Trial 907 (0-48 Weeks)

	VIREAD N=368 (Week 0-24)	Placebo N=182 (Week 0-24)	VIREAD N=368 (Week 0-18)	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 LI/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 LI/L)	2%	4%	3%	3%
Neutrophils (<750/mm³)	1%	1%	2%	1%

 

Adverse Reactions From Clinical Trials Experience In HIV-1 Infected Pediatric Subjects 2 Years And Older

Assessment of adverse reactions is based on two randomized trials (Trials 352 and 321) in 184 HIV-1 infected pediatric subjects (2 years 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.

In Trial 352, 89 pediatric subjects (2 years to less than 12 years of age) received VIREAD 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.

Changes In Bone Mineral Density

In Trial 321 (12 years to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the VIREAD group compared to the placebo 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 Trial 352 (2 years to less than 12 years of age), 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 group compared to the d4T or AZT treatment group. 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 for the duration of the clinical trials.

Adverse Reactions From Clinical Trials Experience In HBV-Infected Adults

Clinical Trials In Adult Subjects With Chronic Hepatitis B And Compensated Liver Disease

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.

In Trials 0102 and 0103, during the open-label phase of treatment with VIREAD (weeks 48-384), 2% of subjects (13/585) 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 384 weeks.

Laboratory Abnormalities

Table 7 provides a list of Grade 3-4 laboratory abnormalities through Week 48. Grades 3-4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 384 weeks in these trials.

Table 7 : Grades 3-4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Subjects in Trials 0102 and 0103 (0-48 Weeks)

	VIREAD N=426	HEPSERA N=215
Aliy ≥ Grade 3 Laboratory Abnormality	19%	13%
Creatine Kinase (M: >990 U/L; F: >845 U/L)	2%	3%
Serum Amylase (>175 LI/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 x baseline and greater than 10 x ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4 to 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 HBV clinical trials in adults.

Clinical Trials In Adult Subjects With Chronic Hepatitis B And Decompensated Liver Disease

In Trial 0108, a small randomized, double-blind, active-controlled trial, subjects with chronic HBV and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. 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.

Adverse Reactions From Clinical Trials Experience In HBV-Infected Pediatric Subjects 2 Years And Older

Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on two randomized trials: Trial GS-US-174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with VIREAD (N=52) or placebo (N=54) for 72 weeks and Trial GS-US-174-0144 in 89 subjects (2 years to less than 12 years of age) receiving treatment with VIREAD (N=60) or placebo (N=29) for 48 weeks [see Clinical Studies]. 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 Trial 115 (12 years to less than 18 years of age) and Trial 144 (2 years to less than 12 years of age), both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine and total body BMD over 72 and 48 weeks, respectively, as expected for a pediatric population (Table 11). In Trial 115, the mean percentage BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects (Table 11).Three subjects (6%) in the VIREAD group and two subjects (4%) in the placebo group had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 72. In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects. At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (Table 8). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial.

Table 8 : Change in Bone Mineral Density from Baseline in Pediatric Subjects 2 Years to <12 Years of Age (Trials 115 and 144)

	Trial 115 (Week 72)		Trial 144 (Week 48)
	VIREAD (N=52)	Placebo (N=54)	VIREAD (N=60)	Placebo (N=29)
Mean percentage change in BMD
Lumbar spine	+5%	+8%	+4%	+8%
Total body	+3%	+5%	+5%	+9%
Cumulative incidence of ≥4% decrease in BMD
Lumbar spine	6%	4%	18%	7%
Total body	0%	2%	7%	0%
Baseline BMD Z-score (mean)
Lumbar spine	-0.43	-0.28	+0.02	-0.29
Total body	-0.20	-0.26	+0.11	-0.05
Mean change in BMD Z-score
Lumbar spine	-0.05	+0.07	-0.12	+0.14
Total body	-0.15	+0.06	-0.18	+0.22

 

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of longduration exposure in younger children is unknown.

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.

 

SRC: NLM .