WARNINGS
In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, EPIVIR should be used with caution. Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur (see ADVERSE REACTIONS).
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering EPIVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with EPIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Important Differences Among Lamivudine-Containing Products
EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than in EPIVIR-HBV Tablets and Oral Solution. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients dually infected with HIV and HBV. Lamivudine has not been adequately studied for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV treatment. If a decision is made to administer lamivudine to patients dually infected with HIV and HBV, EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR® (lamivudine/zidovudine) Tablets, or EPZICOM™ (abacavir sulfate and lamivudine) Tablets should be used as part of an appropriate combination regimen. COMBIVIR (a fixed-dose combination tablet of lamivudine and zidovudine) should not be administered concomitantly with EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR, or TRIZIVIR®.
Posttreatment Exacerbations of Hepatitis
In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.
Use With Interferon- and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and EPIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of EPIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).
PRECAUTIONS
Patients With Impaired Renal Function
Reduction of the dosage of EPIVIR is recommended for patients with impaired renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Patients With HIV and Hepatitis B Virus Co-Infection
infection
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non−HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPIVIR. 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.
Differences Between Dosing Regimens
Trough levels of lamivudine in plasma and of intracellular lamivudine triphosphate were lower with once-daily dosing than with twice-daily dosing (see CLINICAL PHARMACOLOGY). The clinical significance of this observation is not known.
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.
Information for Patients
EPIVIR is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using EPIVIR. Patients should be advised that the use of EPIVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
Patients should be advised that EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV treatment regimen of a patient dually infected with HIV and HBV, the formulation and dosage of lamivudine in EPIVIR (not EPIVIR-HBV) should be used.
Patients co-infected with HIV and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician.
Patients should be advised that the long-term effects of EPIVIR are unknown at this time.
EPIVIR Tablets and Oral Solution are for oral ingestion only.
Patients should be advised of the importance of taking EPIVIR with combination therapy on a regular dosing schedule and to avoid missing doses.
Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Diabetic patients should be advised that each 15-mL dose of EPIVIR Oral Solution contains 3 grams of sucrose.
Drug Interactions
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).
TMP 160 mg/SMX 800 mg once daily has been shown to increase lamivudine exposure (AUC) by 43% (see CLINICAL PHARMACOLOGY). 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. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times(mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.
Pregnancy
Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.
In 2 clinical studies conducted in South Africa, pharmacokinetic measurements were performed on samples from pregnant women who received lamivudine beginning at Week 38 of gestation (10 women who received 150 mg twice daily in combination with zidovudine and 10 who received lamivudine 300 mg twice daily without other antiretrovirals) or beginning at Week 36 of gestation (16 women who received lamivudine 150 mg twice daily in combination with zidovudine). These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those obtained following birth and in non-pregnant adults. Lamivudine concentrations were generally similar in maternal, neonatal, and cord serum samples. In a subset of subjects from whom amniotic fluid specimens were obtained following natural rupture of membranes, amniotic fluid concentrations of lamivudine ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily) and were typically greater than 2 times the maternal serum levels. See the ADVERSE REACTIONS section for the limited late-pregnancy safety information available from these studies. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection.
A study in lactating rats administered 45 mg/kg of lamivudine showed that lamivudine concentrations in milk were slightly greater than those in plasma. Lamivudine is also excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine.
Pediatric Use
HIV
Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old. See the ADVERSE REACTIONS section for the limited safety information available from these studies.
The safety and effectiveness of twice-daily EPIVIR in combination with other antiretroviral agents have been established in pediatric patients 3 months of age and older.
In Study A2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-infected pediatric patients (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the 9 infants and children (range: 5 months to 12 years of age) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.
Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 2.
Figure 2. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age
After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric patients ranging from 4 months to 14 years of age, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose. Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL. The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients is not known. The safety and pharmacokinetic properties of EPIVIR in combination with antiretroviral agents other than zidovudine have not been established in pediatric patients. See INDICATIONS AND USAGE: Description of Clinical Studies, CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.
HBV
See the complete prescribing information for EPIVIR-HBV Tablets and Oral Solution for additional information on the pharmacokinetics of lamivudine in HBV-infected children.
Geriatric Use
Clinical studies of EPIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).
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