Clinical Trials Experience

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

• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, WARNINGS and PRECAUTIONS].
• Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS and PRECAUTIONS].
• Pancreatitis [see WARNINGS and PRECAUTIONS].

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.

Adults - Clinical Trials in HIV-1: The safety profile of EPIVIR in adults is primarily based on 3,568 HIV-1-infected patients in 7 clinical trials.

The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough.

Selected clinical adverse reactions of in ≥ 5% of patients during therapy with EPIVIR 150 mg twice daily plus RETROVIR® 200 mg 3 times daily for up to 24 weeks are listed in Table 3.

Table 3: Selected Clinical Adverse Reactions ( ≥ 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)

Pancreatitis: 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 NUCB3007 [see WARNINGS and PRECAUTIONS].

EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in patients receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar.

Selected laboratory abnormalities observed during therapy are summarized in Table 4.

Table 4: Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Study (NUCB 3007)

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 - Clinical Trials in HIV-1: EPIVIR Oral Solution has been studied in 638 pediatric patients 3 months to 18- years of age in 3 clinical trials.

Selected clinical adverse reactions and physical findings with a ≥ 5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m² 3 times daily in therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 5.

Table 5: Selected Clinical Adverse Reactions and Physical Findings ( ≥ 5% Frequency) in Pediatric Patients in Study ACTG3QIQ

Pancreatitis: 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 (NUCA2002), 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 (NUCA2005), 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 [see WARNINGS and PRECAUTIONS].

Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study NUCA2002, 6 patients (9%) in Study NUCA2005, and 2 patients ( < 1%) in Study ACTG300.

Selected laboratory abnormalities experienced by therapy-naive ( ≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 6.

Table 6: Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Patients in Study ACTG300

Neonates - Clinical Trials in HIV-1: 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 CLINICAL PHARMACOLOGY]. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 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 limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of EPIVIR. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions 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 WARNINGS and PRECAUTIONS].

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B [see Boxed Warning, WARNINGS and PRECAUTIONS].

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus.

Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

Interferon- and Ribavirin-Based Regimens

Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1 /HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see WARNINGS and PRECAUTIONS, CLINICAL PHARMACOLOGY].

Zalcitabine

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.

Trimethoprim/Sulfamethoxazole (TMP/SMX)

No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

Drugs with No Observed Interactions With EPIVIR

A drug interaction study showed no clinically significant interaction between EPIVIR and zidovudine.

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