ADVERSE REACTIONS
Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly withsteatosis, posttreatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response) are also described in WARNINGS and PRECAUTIONS.
Clinical Trials In Chronic Hepatitis B
Adults
Selected clinical adverse events observed with a ≥5% frequency during therapy with EPIVIR-HBV compared with placebo are listed in Table 5. Frequencies of specified laboratory abnormalities during therapy with EPIVIR-HBV compared with placebo are listed in Table 6.
Table 5. Selected Clinical Adverse Events (≥5% Frequency) in 3 Placebo-Controlled Clinical Trials in Adults During Treatment* (Studies 1-3) |
Adverse Event
|
EPIVIR-HBV (n = 332)
|
Placebo (n = 200)
|
| Non-site Specific | | |
| Malaise and fatigue | 24% | 28% |
| Fever or chills | 7% | 9% |
| Ear, Nose, and Throat | | |
|
Ear, nose, and throat infections
|
25%
|
21%
|
|
Sore throat
|
13%
|
8%
|
|
Gastrointestinal
| | |
|
Nausea and vomiting
|
15%
|
17%
|
|
Abdominal discomfort and pain
|
16%
|
17%
|
|
Diarrhea
|
14%
|
12%
|
|
Musculoskeletal
| | |
|
Myalgia
|
14%
|
17%
|
|
Arthralgia
|
7%
|
5%
|
|
Neurological
| | |
|
Headache
|
21%
|
21%
|
|
Skin
| | |
|
Skin rashes
|
5%
|
5%
|
*Includes patients treated for 52 to 68 weeks.
Table 6. Frequencies of Specified Laboratory Abnormalities in 3 Placebo-Controlled Trials in Adults During Treatment* (Studies 1-3) |
Test
|
Patients with Abnormality/Patients with Observations
|
|
(Abnormal Level)
|
EPIVIR-HBV
|
Placebo
|
|
ALT >3 x baseline†
|
37/331 (11%)
|
26/199 (13%)
|
|
Albumin <2.5 g/dL
|
0/331 (0%)
|
2/199 (1%)
|
| Amylase >3 x baseline |
2/259 (<1%)
|
4/167 (2%)
|
| Serum Lipase≥2.5 x ULN‡ |
19/189 (10%)
|
9/127 (7%)
|
|
CPK ≥7 x baseline
|
31/329 (9%)
|
9/198 (5%)
|
| Neutrophils <750/mm3 |
0/331 (0%)
|
1/199 (<1%)
|
|
Platelets <50,000/mm3
|
10/272 (4%)
|
5/168 (3%)
|
* Includes patients treated for 52 to 68 weeks.
†See Table 7 for posttreatment ALT values.
‡ Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information.
ULN = Upper limit of normal.
In patients followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in patients who had received EPIVIR-HBV than in patients who had received placebo. A comparison of ALT elevations between weeks 52 and 68 in patients who discontinued EPIVIR-HBV at week 52 and patients in the same studies who received placebo throughout the treatment course is shown in Table 7.
Table 7. Posttreatment ALT Elevations in 2 Placebo-Controlled Studies in Adults With No-Active-Treatment Follow-up (Studies 1 and 3) |
Patients with ALT Elevation/ Patients with Observations*
|
|
Abnormal Value
|
EPIVIR-HBV
|
Placebo
|
|
ALT ≥2 x baseline value
|
37/137 (27%)
|
22/116 (19%)
|
|
ALT ≥3 x baseline value†
|
29/137 (21%)
|
9/116 (8%)
|
|
ALT ≥2 x baseline value and absolute ALT >500 IU/L
|
21/137 (15%)
|
8/116 (7%)
|
|
ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value
|
1/137 (0.7%)
|
1/116 (0.9%)
|
*Each patient may be represented in one or more category.
†Comparable to a Grade 3 toxicity in accordance with modified WHO criteria.
ULN = Upper limit of normal.
Lamivudine in Patients With HIV
In HIV-infected patients, safety information reflects a higher dose of lamivudine (150 mg b.i.d.) than the dose used to treat chronic hepatitis B in HIV-negative patients. In clinical trials using lamivudine as part of a combination regimen for treatment of HIV infection, several clinical adverse events occurred more often in lamivudine-containing treatment arms than in comparator arms. These included nasal signs and symptoms (20% vs. 11%), dizziness (10% vs. 4%), and depressive disorders (9% vs. 4%). Pancreatitis was observed in 9 of the 2,613 adult patients (<0.5%) who received EPIVIR in controlled clinical trials. Laboratory abnormalities reported more often in lamivudine-containing arms included neutropenia and elevations of liver function tests (also more frequent in lamivudine-containing arms for a retrospective analysis of HIV/HBV dually infected patients in one study), and amylase elevations. Please see the complete prescribing information for EPIVIR Tablets and Oral Solution for more information.
Pediatric Patients with Hepatitis B
Most commonly observed adverse events in the pediatric trials were similar to those in adult trials; in addition, respiratory symptoms (cough, bronchitis, and viral respiratory infections) were reported in both lamivudine and placebo recipients. Posttreatment transaminase elevations were observed in some patients followed after cessation of lamivudine.
Pediatric Patients with HIV Infection
In early open-label studies of lamivudine in children with HIV, peripheral neuropathy and neutropenia were reported, and pancreatitis was observed in 14% to 15% of patients.
Observed During Clinical Practice
The following events have been identified during post-approval use of lamivudine 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 lamivudine, or a combination of these factors. Post-marketing experience with lamivudine at this time is largely limited to use in HIV-infected patients.
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 steatosis, pancreatitis, posttreatment exacerbation of hepatitis (see WARNINGS and PRECAUTIONS).
Hypersensitivity
Anaphylaxis, urticaria.
Musculoskeletal
Rhabdomyolysis.
Nervous
Paresthesia, peripheral neuropathy.
Respiratory
Abnormal breath sounds/wheezing.
Skin
Alopecia, pruritus, rash.
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