SIDE EFFECTS
Clinical Trials: 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 Phase I每III clinical trials and expanded access studies. A total of 1,544 patients have received VIREAD 300 mg once daily in Phase I每III clinical trials; over 11,000 patients have received VIREAD in expanded access studies.
Treatment-Naïve Patients
Study 903 - Treatment-Emergent Adverse Events: 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 events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse events are summarized in Table 9.
|
Table 9 Selected Treatment-Emergent Adverse Events (Grades 2每4) Reported in ³5% in Any Treatment Group in Study 903 (0每144 Weeks) |
| |
VIREAD + 3TC + EFV |
d4T + 3TC + EFV |
|
N=299 |
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 |
| Lipodystrophy1 |
1% |
8% |
| Musculoskeletal |
| Arthralgia |
5% |
7% |
| Myalgia |
3% |
5% |
| Nervous System |
| Depression |
11% |
10% |
| Insomnia |
5% |
8% |
| Dizziness |
3% |
6% |
| Peripheral neuropathy2 |
1% |
5% |
| Anxiety |
6% |
6% |
| Respiratory |
| Pneumonia |
5% |
5% |
| Skin and Appendages |
| Rash event3 |
18% |
12% |
| 1 Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. |
| 2Peripheral neuropathy includes peripheral neuritis and neuropathy. |
| 3Rash 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 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 10.
|
Table 10 Grade 3/4 Laboratory Abnormalities Reported in ³1% of VIREAD-Treated Patients in Study 903 (0每144 Weeks) |
| |
VIREAD + 3TC + EFV |
d4T + 3TC + EFV |
|
N=299 |
N=301 |
| Any ³Grade 3 Laboratory Abnormality |
36% |
42% |
| Fasting Cholesterol (>240 mg/dL) |
19% |
40% |
| Creatine Kinase |
| (M: >990 U/L) |
12% |
12% |
| (F:>845 U/L) |
| Serum Amylase (>175 U/L) |
9% |
8% |
| AST |
| (M: >180 U/L) |
5% |
7% |
| (F: >170 U/L) |
| ALT |
| (M:>215 U/L) |
4% |
5% |
| (F: >170 U/L) |
| Hematuria (>100 RBC/HPF) |
7% |
7% |
| Neutrophil (<750/mm3) |
3% |
1% |
| Fasting Triglyceride (>750mg/dL) |
1% |
9% |
Study 934 - Treatment Emergent Adverse Events: 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 events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 11).
|
Table 11 Selected Treatment-Emergent Adverse Events (Grades 2每4) Reported in ³3% in Any Treatment Group in Study 934 (0每48 Weeks) |
| |
VIREAD + FTC + EFV |
AZT/3TC + EFV |
| |
N=257 |
N=254 |
| Gastrointestinal Disorder |
| Diarrhea |
7% |
4% |
| Nausea |
8% |
6% |
| Vomiting |
1% |
4% |
| General Disorders and Administration Site Condition |
| Fatigue |
7% |
6% |
| Infections and Infestations |
| Sinusitis |
4% |
2% |
| Upper respiratory tract infections |
3% |
3% |
| Nasopharyngitis |
3% |
1% |
| Nervous System Disorders |
| Somnolence |
3% |
2% |
| Headache |
5% |
4% |
| Dizziness |
8% |
7% |
| Psychiatric Disorders |
| Depression |
4% |
7% |
| Insomnia |
4% |
5% |
| Abnormal dreams |
4% |
3% |
| Skin and Subcutaneous Tissue Disorders |
| Rash |
5% |
4% |
Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 12).
|
Table 12 Significant Laboratory Abnormalities Reported in ³1% of Patients in Any Treatment Group in Study 934 (0每48 Weeks) |
| |
VIREAD + FTC + EFV |
AZT/3TC + EFV |
| |
N=257 |
N=254 |
| Any ³Grade 3 Laboratory Abnormality |
25% |
22% |
| Fasting Cholesterol (>240 mg/dL) |
15% |
17% |
| Creatine Kinase |
| (M: >990 U/L) |
7% |
6% |
| (F: >845 U/L) |
| Serum Amylase (>175 U/L) |
7% |
3% |
| Alkaline Phosphatase (>550 U/L) |
1% |
0% |
| AST |
| (M: >180 U/L) |
3% |
2% |
| (F: >170 U/L) |
| ALT |
| (M:>215 U/L) |
2% |
2% |
| (F: >170 U/L) |
| Hemoglobin (<8.0 mg/dL) |
0% |
3% |
| Hyperglycemia (>250 mg/dL) |
1% |
1% |
| Hematuria (>75 RBC/HPF) |
2% |
2% |
| Neutrophil (<750/mm3) |
3% |
4% |
| Fasting Triglyceride (>750 mg/dL) |
4% |
2% |
Treatment-Experienced Patients
Treatment-Emergent Adverse Events: 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 events (Study 907).
A summary of moderate to severe, treatment-emergent adverse events that occurred during the first 48 weeks of study 907 is provided in Table 13.
|
Table 13 Selected Treatment-Emergent Adverse Events (Grades 2每4) Reported in ³3% in Any Treatment Group in Study 907 (0每48 Weeks) |
| |
VIREAD (N=368) (Week 0每24) |
Placebo (N=182) (Week 0每24) |
VIREAD (N=368) (Week 0每48) |
Placebo Crossover to VIREAD (N=170) (Week 24每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 neuropathy1 |
3% |
3% |
5% |
2% |
| Dizziness |
1% |
3% |
3% |
1% |
| Skin and Appendage |
| Rash event2 |
5% |
4% |
7% |
1% |
| Sweating |
3% |
2% |
3% |
1% |
| Musculoskeletal |
| Myalgia |
3% |
3% |
4% |
1% |
| Metabolic |
| Weight loss |
2% |
1% |
4% |
2% |
| 1. Peripheral neuropathy includes peripheral neuritis and neuropathy. |
| 2. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
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 14.
|
Table 14 Grade 3/4 Laboratory Abnormalities Reported in ³1% of VIREAD-Treated Patients in Study 907 (0每48 Weeks) |
| |
VIREAD (N=368) (Week 0每24) |
Placebo (N=182) (Week 0每24) |
VIREAD (N=368) (Week 0每48) |
Placebo Crossover to VIREAD (N=170) (Week 24每48) |
| |
(%) |
(%) |
(%) |
(%) |
| Any ³Grade 3 Laboratory Abnormality |
25% |
38% |
35% |
34% |
| Triglycerides (>750 mg/dL) |
8% |
13% |
11% |
9% |
| Creatine Kinase |
| (M: >990U/L) |
7% |
14% |
12% |
12% |
| (F: >845 U/L) |
| Serum Amylase (>175 U/L) |
6% |
7% |
7% |
6% |
| Urine Glucose (³ 3+) |
3% |
3% |
3% |
2% |
| AST |
| (M: >180 U/L) |
3% |
3% |
4% |
5% |
| (F: >170 U/L) |
| ALT |
| (M: >215 U/L) |
2% |
2% |
4% |
5% |
| (F: >170 U/L) |
| Serum Glucose (>250 U/L) |
2% |
4% |
3% |
3% |
| Neutrophils (<750/mm3) |
1% |
1% |
2% |
1% |
Post Marketing Experience: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD.
IMMUNE SYSTEM DISORDERS
Allergic reaction
METABOLISM AND NUTRITION DISORDERS
Hypophosphatemia, Lactic acidosis
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
Dyspnea
GASTROINTESTINAL DISORDERS
Abdominal pain, Increased amylase, Pancreatitis
HEPATOBILIARY DISORDERS
Increased liver enzymes, Hepatitis
RENAL AND URINARY DISORDERS
Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Nephritis
DRUG INTERACTIONS
When administered with VIREAD, Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly (see Table 5). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. In adults weighing >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 patients weighing <60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events. Since tenofovir is primarily eliminated by the kidneys, 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 adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Higher tenofovir concentrations could potentiate VIREAD-associated adverse events, including renal disorders. Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and VIREAD should be monitored for VIREAD- associated adverse events. VIREAD should be discontinued in patients who develop VIREAD-associated adverse events.
VIREAD decreases the AUC and Cmin of atazanavir. 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.
Bone Effects
In study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz (-2.2% ㊣ 3.9) compared with patients receiving stavudine + lamivudine + efavirenz (-1.0% ㊣ 4.6). 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每48 weeks of the study and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated patients vs. 21% of the stavudine-treated patients 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 patients in the VIREAD group and 6 patients 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) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover.
Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
Animal Toxicology
Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity are unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2每20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
