ADVERSE REACTIONS
Adults
The frequency and severity of adverse events associated with the use of RETROVIR are greater in patients with more advanced infection at the time of initiation of therapy.
Table 6 summarizes events reported at a statistically significant greater incidence for patients receiving RETROVIR in a monotherapy study:
Table 6. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection (ACTG019) |
Adverse Event
|
RETROVIR 500 mg/day
(n = 453)
|
Placebo
(n = 428)
|
|
Body as a whole
| | |
|
Asthenia
|
8.6%†
|
5.8%
|
|
Headache
|
62.5%
|
52.6%
|
|
Malaise
|
53.2%
|
44.9%
|
|
Gastrointestinal
| | |
|
Anorexia
|
20.1%
|
10.5%
|
|
Constipation
|
6.4%†
|
3.5%
|
|
Nausea
|
51.4%
|
29.9%
|
|
Vomiting
|
17.2%
|
9.8%
|
*Reported in ≥5% of study population.
†Not statistically significant versus placebo.
In addition to the adverse events listed in Table 6, other adverse events observed in clinical studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with RETROVIR are shown in Table 7.
Table 7. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with Asymptomatic HIV Infection (ACTG019) |
Adverse Event
|
RETROVIR 500 mg/day
(n = 453)
|
Placebo
(n = 428)
|
|
Anemia (Hgb<8 g/dL)
|
1.1%
|
0.2%
|
|
Granulocytopenia (<750 cells/mm3)
|
1.8%
|
1.6%
|
|
Thrombocytopenia (platelets<50,000/mm3)
|
0%
|
0.5%
|
|
ALT (>5 x ULN)
|
3.1%
|
2.6%
|
|
AST (>5 x ULN)
|
0.9%
|
1.6%
|
|
Alkaline phosphatase (>5 x ULN)
|
0%
|
0%
|
ULN = Upper limit of normal.
Pediatrics
Study ACTG300
Selected clinical adverse events and physical findings with a ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 8.
Table 8. Selected Clinical Adverse Events and Physical Findings (≥5% Frequency) in Pediatric Patients in Study ACTG300 |
Adverse Event
|
EPIVIR plus RETROVIR
(n = 236)
|
Didanosine
(n = 235)
|
|
Body as a whole
| | |
|
Fever
|
25%
|
32%
|
|
Digestive
| | |
|
Hepatomegaly
|
11%
|
11%
|
|
Nausea & vomiting
|
8%
|
7%
|
|
Diarrhea
|
8%
|
6%
|
|
Stomatitis
|
6%
|
12%
|
|
Splenomegaly
|
5%
|
8%
|
|
Respiratory
| | |
|
Cough
|
15%
|
18%
|
|
Abnormal breath sounds/wheezing
|
7%
|
9%
|
|
Ear, Nose, and Throat
| | |
|
Signs or symptoms of ears*
|
7%
|
6%
|
|
Nasal discharge or congestion
|
8%
|
11%
|
|
Other
| | |
|
Skin rashes
|
12%
|
14%
|
|
Lymphadenopathy
|
9%
|
11%
|
*Includes pain, discharge, erythema, or swelling of an ear.
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 9.
Table 9. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in Study ACTG300 |
Test
(Abnormal Level)
|
EPIVIR plus RETROVIR
|
Didanosine
|
|
Neutropenia (ANC<400 cells/mm3)
|
8%
|
3%
|
|
Anemia (Hgb<7.0 g/dL)
|
4%
|
2%
|
|
Thrombocytopenia (platelets<50,000/mm3)
|
1%
|
3%
|
|
ALT (>10 x ULN)
|
1%
|
3%
|
|
AST (>10 x ULN)
|
2%
|
4%
|
|
Lipase (>2.5 x ULN)
|
3%
|
3%
|
|
Total amylase (>2.5 x ULN)
|
3%
|
3%
|
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in pediatric patients.
Use for the Prevention of Maternal-Fetal Transmission of HIV
In a randomized, double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission, RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR. Neutropenia was reported with similar frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to RETROVIR are unknown.
Observed During Clinical Practice
In addition to adverse events reported from clinical trials, the following events have been identified during use of RETROVIR in clinical practice. 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 either their seriousness, frequency of reporting, potential causal connection to RETROVIR, or a combination of these factors.
Body as a Whole
Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular
Cardiomyopathy , syncope.
Endocrine
Gynecomastia.
Eye
Macular edema.
Gastrointestinal
Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General
Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic
Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas
Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
Musculoskeletal
Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous
Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.
Respiratory
Cough, dyspnea, rhinitis, sinusitis.
Skin
Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.
Special Senses
Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital
Urinary frequency, urinary hesitancy.
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