ADVERSE REACTIONS
Clinical Trials in HIV
Adults
Selected clinical adverse events with a ≥5% frequency during therapy with EPIVIR 150 mg twice daily plus RETROVIR 200 mg 3 times daily compared with zidovudine are listed in Table 5.
Table 5. Selected Clinical Adverse Events (≥5% Frequency) in Four Controlled Clinical Trials (A3001, A3002, B3001, B3002) |
Adverse Event
|
EPIVIR 150 mg
Twice Daily
plus RETROVIR
(n = 251)
|
RETROVIR*
(n = 230)
|
|
Body as a Whole
| | |
|
Headache
|
35%
|
27%
|
|
Malaise & fatigue
|
27%
|
23%
|
|
Fever or chills
|
10%
|
12%
|
|
Digestive
| | |
|
Nausea
|
33%
|
29%
|
|
Diarrhea
|
18%
|
22%
|
|
Nausea & vomiting
|
13%
|
12%
|
|
Anorexia and/or decreased appetite
|
10%
|
7%
|
|
Abdominal pain
|
9%
|
11%
|
|
Abdominal cramps
|
6%
|
3%
|
|
Dyspepsia
|
5%
|
5%
|
|
Nervous System
| | |
|
Neuropathy
|
12%
|
10%
|
|
Insomnia & other sleep disorders
|
11%
|
7%
|
|
Dizziness
|
10%
|
4%
|
|
Depressive disorders
|
9%
|
4%
|
|
Respiratory
| | |
|
Nasal signs & symptoms
|
20%
|
11%
|
|
Cough
|
18%
|
13%
|
|
Skin
| | |
|
Skin rashes
|
9%
|
6%
|
|
Musculoskeletal
| | |
|
Musculoskeletal pain
|
12%
|
10%
|
|
Myalgia
|
8%
|
6%
|
|
Arthralgia
|
5%
|
5%
|
*Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
The types and frequencies of clinical adverse events reported in patients receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. The most common adverse events in both treatment groups were nausea, dizziness, fatigue and/or malaise, headache, dreams, insomnia and other sleep disorders, and skin rash.
Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received EPIVIR in the controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and B3007.
Selected laboratory abnormalities observed during therapy are summarized in Table 6.
Table 6. Frequencies of Selected Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (A3001, A3002, B3001, B3002) and a Clinical Endpoint Study (B3007) |
Test
(Threshold Level)
|
24-Week Surrogate Endpoint Studies*
|
Clinical Endpoint
Study*
|
|
EPIVIR plus RETROVIR
|
RETROVIR†
|
EPIVIR plus
Current Therapy
|
Placebo plus
Current Therapy‡
|
|
Absolute neutrophil count (<750/mm3)
|
7.2%
|
5.4%
|
15%
|
13%
|
|
Hemoglobin (<8.0 g/dL)
|
2.9%
|
1.8%
|
2.2%
|
3.4%
|
|
Platelets (<50,000/mm3)
|
0.4%
|
1.3%
|
2.8%
|
3.8%
|
|
ALT (>5.0 x ULN)
|
3.7%
|
3.6%
|
3.8%
|
1.9%
|
|
AST (>5.0 x ULN)
|
1.7%
|
1.8%
|
4.0%
|
2.1%
|
|
Bilirubin (>2.5 x ULN)
|
0.8%
|
0.4%
|
ND
|
ND
|
|
Amylase (>2.0 x ULN)
|
4.2%
|
1.5%
|
2.2%
|
1.1%
|
* The median duration on study was 12 months.
† Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
‡ Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.
ULN = Upper limit of normal.
ND = Not done.
In small, uncontrolled studies in which pregnant women were given lamivudine alone or in combination with zidovudine beginning in the last few weeks of pregnancy (see PRECAUTIONS: Pregnancy), reported adverse events included anemia, urinary tract infections, and complications of labor and delivery. In postmarketing experience, liver function abnormalities and pancreatitis have been reported in women who received lamivudine in combination with other antiretroviral drugs during pregnancy. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared to other HIV-infected patients.
The frequencies of selected laboratory abnormalities reported in patients receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Pediatric Patients
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 7.
Table 7. 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 8.
Table 8. Frequencies of Selected Laboratory Abnormalities in Pediatric Patients in Study ACTG300 |
Test
(Threshold Level)
|
EPIVIR plus RETROVIR
|
Didanosine
|
|
Absolute neutrophil count (<400/mm3)
|
8%
|
3%
|
|
Hemoglobin (<7.0 g/dL)
|
4%
|
2%
|
|
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.
Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving EPIVIR alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (A2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with EPIVIR. Three of these patients died of complications of pancreatitis. In a second open-label study (A2005), 12 patients (18%) developed pancreatitis. In Study ACTG300, pancreatitis was not observed in 236 patients randomized to EPIVIR plus RETROVIR. Pancreatitis was observed in 1 patient in this study who received open-label EPIVIR in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy.
Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study A2002, 6 patients (9%) in Study A2005, and 2 patients (<1%) in Study ACTG300.
Limited short-term safety information is available from 2 small, uncontrolled studies in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation (see PRECAUTIONS: Pediatric Use). Adverse events reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, sepsis, and syphilis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups further limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse events comparable to those reported in pediatric and adult HIV-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.
Lamivudine in Patients With Chronic Hepatitis B
Clinical trials in chronic hepatitis B used a lower dose of lamivudine (100 mg daily) than the dose used to treat HIV. The most frequent adverse events with lamivudine versus placebo were ear, nose, and throat infections (25% versus 21%); malaise and fatigue (24% versus 28%); and headache (21% versus 21%), respectively. The most frequent laboratory abnormalities reported with lamivudine were elevated ALT, elevated serum lipase, elevated CPK, and posttreatment elevations of liver function tests. Emergence of HBV viral mutants during lamivudine treatment, associated with reduced drug susceptibility and diminished treatment response, was also reported (also see WARNINGS and PRECAUTIONS). Please see the complete prescribing information for EPIVIR-HBV Tablets and Oral Solution for more information.
Observed During Clinical Practice
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of lamivudine. 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 lamivudine.
Body as a Whole
Redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Digestive
Stomatitis.
Endocrine and Metabolic
Hyperglycemia.
General
Weakness.
Hemic and Lymphatic
Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.
Hepatic and Pancreatic
Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see WARNINGS and PRECAUTIONS).
Hypersensitivity
Anaphylaxis, urticaria.
Musculoskeletal
Muscle weakness, CPK elevation, rhabdomyolysis.
Nervous
Paresthesia, peripheral neuropathy.
Respiratory
Abnormal breath sounds/wheezing.
Skin
Alopecia, rash, pruritus.
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