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lamivudine hbv 100 mg tablet generic epivir hbv

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Uses

Treatment of HIV Infection

Lamivudine is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 3 months of age or older.

Lamivudine usually is used in multiple-drug regimens that include another HIV nucleoside reverse transcriptase inhibitor (NRTI) (dual NRTIs) and an HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens.

If the dual NRTI option of lamivudine and zidovudine is used in conjunction with other antiretrovirals for treatment of HIV-1 infection, a fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) is commercially available and can be used in adults, adolescents, and pediatric patients weighing 30 kg or more to decrease pill burden and improve adherence.

If the dual NRTI option of lamivudine and abacavir is used in conjunction with other antiretrovirals for treatment of HIV-1 infection, a fixed-combination preparation containing both drugs (abacavir/lamivudine; Epzicom) is commercially available and can be used in adults to decrease pill burden and improve adherence. Abacavir/lamivudine must be used in conjunction with other antiretrovirals for treatment of HIV-1 infection and should be used with a drug from another class (not another NRTI).

Lamivudine has been used in triple NRTI regimens (i.e., single-class NRTI regimens) that include lamivudine and 2 other NRTIs. A fixed-combination preparation containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir) is commercially available and can be used in adults and adolescents weighing 40 kg or more to provide a triple NRTI regimen and to decrease pill burden and improve adherence.(See All-NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the individual patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

Dual NRTI Options

For initial treatment regimens in HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is the recommended dual NRTI option for use in most INSTI-, NNRTI-, and PI-based regimens recommended for initial treatment. These experts state that abacavir and lamivudine (or emtricitabine) also is a recommended dual NRTI option for use in some initial treatment regimens in antiretroviral-naive adults and adolescents, but should be used only in those who are negative for human leukocyte antigen (HLA)-B*5701. These recommendations are based on safety and efficacy data from clinical trials, long-term clinical experience, and availability of fixed-combination preparations containing NRTIs.

The HHS panel states that recommended regimens for initial treatment in antiretroviral-naive adults and adolescents that can be used regardless of baseline plasma HIV RNA levels or CD4 T-cell counts include the dual NRTI option of tenofovir DF and emtricitabine (or lamivudine) in conjunction with efavirenz, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, dolutegravir, or raltegravir. In addition, the dual NRTI option of abacavir and lamivudine (or emtricitabine) in conjunction with dolutegravir is a recommended regimen that can be used for initial treatment in antiretroviral-naive adults and adolescents regardless of baseline plasma HIV RNA levels or CD4 T-cell counts in those who are negative for HLA-B*5701.

Tenofovir DF and emtricitabine (or lamivudine) is the preferred dual NRTI option for antiretroviral regimens used in HIV-infected patients coinfected with hepatitis B virus (HBV). All 3 of these NRTIs (tenofovir DF, emtricitabine, lamivudine) have activity against both HIV and HBV, and regimens that contain only 1 of these 3 antiretrovirals are not recommended in HIV-infected patients coinfected with HBV.

When the dual NRTI option of abacavir and lamivudine is used, the fixed-combination preparation containing both drugs (abacavir/lamivudine; Epzicom) can be used in adults. Abacavir/lamivudine must be used in conjunction with other antiretrovirals for treatment of HIV-1 infection and should be used with a drug from a different class (not another NRTI).

The dual NRTI option of zidovudine and lamivudine is no longer recommended for initial treatment regimens in nonpregnant antiretroviral-naive adults and adolescents because it has greater toxicity than the dual NRTI options of tenofovir DF and emtricitabine or abacavir and lamivudine and requires twice-daily dosing. However, the dual NRTI option of zidovudine and lamivudine is one of several preferred dual NRTI options for initial treatment regimens in antiretroviral-naive pregnant women(see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation) and for initial treatment regimens in pediatric patients(see Pediatric Patients under Uses: Treatment of HIV Infection). When the dual NRTI option of lamivudine and zidovudine is used in conjunction with other antiretrovirals, the fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) can be used in adults and adolescents weighing 30 kg or more.

A dual NRTI option of didanosine and lamivudine (or emtricitabine) is not recommended for initial antiretroviral regimens because of inferior virologic efficacy and limited clinical trial experience in antiretroviral-naive patients.

A dual NRTI option of stavudine and lamivudine is not recommended for initial antiretroviral regimens because of reported toxicities.

Lamivudine and emtricitabine should not be used concomitantly at any time since the drugs have similar resistance profiles and minimal additive antiretroviral activity.

All-NRTI Regimens

Lamivudine has been included in NRTI regimens that include 3 or 4 NRTIs (without any drugs from another class). However, triple and quadruple NRTI regimens are not usually recommended for treatment of HIV-1 infection in antiretroviral-naive adults or adolescents because such regimens have inferior virologic efficacy or have not been adequately studied. In addition, regimens that only include NRTIs are not usually recommended in antiretroviral-experienced patients.(See Antiretroviral-experienced Adults and Adolescents under Uses: Treatment of HIV Infection.)

Lamivudine has been used in a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine. The fixed-combination preparation containing these 3 NRTIs (abacavir/lamivudine/zidovudine; Trizivir) can be used in adults and adolescents weighing 40 kg or more. Abacavir/lamivudine/zidovudine is intended only for regimens that require all 3 drugs, and clinicians should consider that data are limited regarding use of this fixed-combination preparation in patients with baseline viral loads exceeding 100,000 copies/mL. Although a triple NRTI regimen of abacavir, lamivudine, and zidovudine offers the advantages of fewer drug interactions, low pill burden, and ease of administration (because of the commercially available fixed-combination preparation), and spares patients from potential adverse effects associated with PIs and NNRTIs, there is evidence that triple NRTI regimens have inferior virologic efficacy. Therefore, experts state that a triple NRTI regimen that includes abacavir, lamivudine, and zidovudine is not recommended for initial therapy in antiretroviral-naive adults and adolescents and should be used only when other regimens cannot be used.

A triple NRTI regimen of lamivudine, zidovudine, and tenofovir DF has been used and has been shown to have antiretroviral activity; however, this regimen should be used only when other regimens cannot be used.

A triple NRTI regimen of abacavir, lamivudine, and tenofovir DF is not recommended at any time in antiretroviral-naive or antiretroviral-experienced patients because of a high rate of virologic failure. Interim analysis of a randomized, open-label study evaluating efficacy of a once-daily regimen of abacavir, lamivudine, and tenofovir DF compared with an NNRTI-based once-daily regimen of efavirenz, abacavir, and lamivudine in treatment-naive patients (ESS30009) indicated a high rate of early virologic nonresponse in those receiving the triple NRTI regimen (almost 50%). Based on these results, the abacavir, lamivudine, and tenofovir DF arm of the study was terminated. A high rate of virologic nonresponse also was reported in a pilot study evaluating this triple NRTI regimen. Several possible reasons for the poor response to this regimen have been proposed, but the ESS30009 investigators suggest that the most likely cause is a low genetic barrier to resistance because of synergistic selection from all 3 NRTIs for 2 specific resistance mutations (M184V and K65R).

A quadruple NRTI regimen of abacavir, lamivudine, tenofovir DF, and zidovudine is not recommended for initial therapy in antiretroviral-naive HIV-infected adults and adolescents because of inferior virologic efficacy. In an open-label pilot study, a quadruple NRTI regimen was compared with an NNRTI-based regimen of efavirenz with lamivudine and zidovudine, and both regimens had similar efficacy and tolerability. However, a larger, open-label study comparing a similar quadruple NRTI regimen (abacavir, emtricitabine, tenofovir DF, zidovudine) with a standard NNRTI- or PI-based regimen found that substantially fewer patients receiving the quadruple NRTI regimen achieved HIV-1 RNA levels below 200 copies/mL.

NNRTI-based Regimens

The comparative efficacy of a once- or twice-daily lamivudine regimen used in conjunction with zidovudine in an NNRTI-based regimen was evaluated in a 48-week double-blind, randomized study (EPV20001) in 554 antiretroviral-naive adults (79% male, 50% Caucasian, median age 35 years, baseline CD4 T-cell count 69-1089/mm [median 362/mm], median baseline plasma HIV-1 RNA level 4.66 log10 copies/mL). Patients were randomized to receive efavirenz (600 mg once daily) with zidovudine (300 mg twice daily) and either lamivudine 300 mg once daily or lamivudine 150 mg twice daily. Plasma HIV-1 RNA levels were less than 50 copies/mL through week 48 in 61% of patients receiving the once-daily lamivudine regimen and in 63% of those receiving the twice-daily lamivudine regimen. At week 48, the median increase in CD4 T-cell count was 144 cells/mm or 146 cells/mm in those receiving the once- or twice-daily lamivudine regimen, respectively. The virologic failure rate was 8% in both groups.

Antiretroviral-experienced Adults and Adolescents

Although monotherapy or 2-drug regimens that include only NRTIs no longer are recommended for treatment of HIV infection, early studies evaluating the safety and efficacy of lamivudine in antiretroviral-experienced (previously-treated) patients used such regimens. These studies showed that patients who received lamivudine (150 or 300 mg every 12 hours) in conjunction with zidovudine (200 mg 3 times daily) for 24 weeks experienced greater increases in CD4 T-cell counts than those who received zidovudine monotherapy (200 mg 3 times daily) or zidovudine (200 mg 3 times daily) in conjunction with zalcitabine (0.75 mg 3 times daily; no longer commercially available in the US).

Lamivudine has been evaluated in a randomized, double-blind study (study NUCB3007; CAESAR study) in 1816 HIV-infected patients (baseline CD4 T-cell count 25-250/mm [median 122/mm], 84% nucleoside-experienced, 16% treatment-naive). Oral lamivudine (with or without an NNRTI) was added to the patient's existing regimen (i.e., monotherapy with zidovudine [62%], a 2-drug regimen of zidovudine and didanosine or zalcitabine [38%]) and efficacy was assessed by disease progression or death over the following 12 months. The 12-month cumulative incidence of disease progression or death was 8.9-9.6% in patients randomized to receive lamivudine (with or without an NNRTI) in conjunction with their existing regimen and 19.6% in patients randomized to receive placebo in conjunction with their existing regimen. The 12-month cumulative mortality was 2.6-3 or 5.9% in patients randomized to receive lamivudine (with or without an NNRTI) or placebo, respectively, in conjunction with their existing regimen.

Based on interim analysis of a study evaluating a triple NRTI regimen of abacavir, lamivudine, and tenofovir DF that indicated a high rate of early virologic nonresponse in antiretroviral-naive patients receiving this regimen, a triple NRTI regimen of abacavir, lamivudine, and tenofovir DF is not recommended in either antiretroviral-naive or antiretroviral-experienced patients.(See All NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

Pediatric Patients

Lamivudine is used in conjunction with other antiretroviral agents for treatment of HIV-1 infection in children 3 months of age or older.

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or NNRTI and 2 NRTIs (dual NRTIs). These experts state that the preferred dual NRTI options for initial treatment regimens in pediatric patients are zidovudine and either lamivudine or emtricitabine (can be used in pediatric patients of any age) or abacavir and either lamivudine or emtricitabine (can be used in those 3 months of age or older who are negative for HLA-B*5701).

For adolescents at Tanner stage 4 or 5, the preferred dual NRTI options for initial treatment regimens are abacavir and either lamivudine or emtricitabine (only in those negative for HLA-B*5701), tenofovir DF and either lamivudine or emtricitabine, or zidovudine and either lamivudine or emtricitabine. Tenofovir DF and either lamivudine or emtricitabine is considered an alternative (not a preferred) dual NRTI option for initial treatment regimens in children and adolescents at Tanner stage 3, but should be used only in special circumstances in prepubertal children 2 years of age or older and adolescents at Tanner stage 1 or 2.

When the dual NRTI option of lamivudine and zidovudine is used, the fixed-combination preparation containing both drugs (lamivudine/zidovudine; Combivir) can be used in pediatric patients weighing 30 kg or more.

Didanosine and lamivudine (or emtricitabine) is an alternative (not a preferred) dual NRTI option for initial treatment regimens in children 2 weeks of age or older.

Because of a high incidence of toxicity, a dual NRTI option of stavudine and lamivudine (or emtricitabine) should be used in initial treatment regimens in children only in special circumstances.

Emtricitabine and lamivudine should not be used concomitantly at any time since the drugs have similar resistance profiles and minimal additive antiretroviral activity.

Antiretroviral regimens containing only NRTIs are not recommended for initial treatment in antiretroviral-naive pediatric patients because of inferior virologic efficacy.

A triple NRTI regimen that includes abacavir, tenofovir DF, and either lamivudine or emtricitabine or a triple NRTI regimen that includes tenofovir DF, didanosine, and either lamivudine or emtricitabine should not be used at any time in pediatric patients because of the high rate of early virologic failure reported in antiretroviral-naive adults.

For further information on treatment of HIV infection in pediatric patients,

Prevention of Perinatal HIV Transmission

Lamivudine has been used in some antepartum, intrapartum, and neonatal antiretroviral prophylaxis regimens used for prevention of perinatal HIV transmission.

In the US, multiple-drug antiretroviral regimens are considered the standard of care for treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission. The HHS Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that all pregnant HIV-infected women in the US should receive multiple-drug antiretroviral therapy, regardless of the woman's plasma HIV-1 RNA level or CD4 T-cell count. In addition, to decrease the risk of perinatal HIV transmission, the HHS panel states that pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or with unknown HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an oral or IV zidovudine prophylaxis regimen. In certain situations (e.g., infant born to a woman who did not receive antepartum or intrapartum antiretrovirals or received only intrapartum antiretrovirals), a 3-dose nevirapine prophylaxis regimen is recommended in the neonate in addition to the usual neonatal zidovudine prophylaxis regimen. Combined antepartum, intrapartum, and neonatal antiretroviral prophylaxis is recommended since this strategy reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant. Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries (e.g., resource-limited countries).

Lamivudine is a component of several preferred dual NRTI options that are used in conjunction with other antiretrovirals for treatment of HIV-1 infection in pregnant women (see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation). Although lamivudine has been included in some intrapartum antiretroviral regimens and also has been used in some neonatal prophylaxis regimens for prevention of perinatal HIV transmission, higher rates of hematologic toxicity have been reported in infants receiving a prophylaxis regimen of zidovudine and lamivudine compared with those receiving zidovudine alone or zidovudine in conjunction with nevirapine. The HHS panel states that, for US patients, decisions to include any additional antiretrovirals for prophylaxis with the recommended intrapartum and neonatal zidovudine prophylaxis regimens should be made in consultation with a pediatric HIV specialist (preferably before delivery) and should be accompanied by maternal counseling regarding the potential risks and benefits. These experts also state that, because safety and dosage data are not available, use of antiretrovirals other than zidovudine and nevirapine cannot be recommended for prophylaxis in premature HIV-exposed neonates.

For information on the risk of perinatal transmission of HIV and some additional information regarding recommendations for use of antiretroviral agents for prevention of perinatal HIV transmission, In addition, clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.

Postexposure Prophylaxis following Occupational Exposure to HIV

Lamivudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care workers and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs). The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure chemoprophylaxis, and recommendations regarding postexposure prophylaxis,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Lamivudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Chronic Hepatitis B Virus Infection

Lamivudine is used for treatment of chronic hepatitis B virus (HBV) infection associated with evidence of HBV replication and active liver inflammation.

The American Association for the Study of Liver Diseases (AASLD) states that lamivudine is not considered a preferred antiviral for long-term treatment of chronic HBV because a high rate of lamivudine resistance has been reported with such treatment. The manufacturer states that lamivudine should be considered for treatment of chronic HBV infection only when alternative antiviral agents associated with a higher genetic barrier to resistance are not available or appropriate.

Safety and efficacy of lamivudine for treatment of chronic HBV infection have not been established in patients with decompensated liver disease, liver transplant recipients, HBV-infected patients coinfected with HIV (see HIV-infected Individuals under Uses: Chronic Hepatitis B Virus Infection), HBV-infected patients coinfected with hepatitis C virus (HCV) or hepatitis D virus (HDV), or pediatric patients younger than 2 years of age.

The goal of antiviral therapy in patients with chronic HBV infection is to achieve sustained suppression of HBV replication and remission of liver disease. The long-term goal of therapy is to prevent cirrhosis, hepatic failure, and hepatocellular carcinoma. Currently available therapies for chronic HBV infection (e.g., interferon alfa, peginterferon alfa, adefovir, entecavir, lamivudine, telbivudine, tenofovir) do not eradicate HBV and may have only limited long-term efficacy. Decisions on the appropriate time to initiate therapy and which drug to use should take into consideration the patient's age, severity of liver disease, likelihood of response, safety and efficacy of the drug, potential for selection of resistant HBV strains, potential for adverse reactions, costs, patient's pregnancy potential, and patient and provider preferences.

The AASLD states that treatment of HBV infection is indicated if the risk of liver-related morbidity and mortality in the near future (5-10 years) and the likelihood of achieving sustained HBV suppression during continued treatment are high. Treatment also is indicated if the risk of liver-related morbidity and mortality in the foreseeable future (10-20 years) and the likelihood of achieving sustained HBV suppression after a defined course of therapy are high. These experts state that treatment is not indicated if both the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving sustained HBV suppression after a defined course of treatment are low.

Treatment of chronic HBV infection is complex and rapidly evolving. Specialized references should be consulted for specific information regarding the evaluation and management of individuals with chronic HBV infection, including information on the choice of treatment regimens.

Adults

Safety and efficacy of lamivudine for treatment of HBV infection were evaluated in 3 controlled studies in adults 16 years of age or older with compensated chronic HBV infection (serum HBsAg positive for at least 6 months) accompanied by evidence of HBV replication (positive for serum hepatitis B e antigen [HBeAg] and positive for serum HBV DNA as measured by a research solution hybridization assay) and persistently elevated serum ALT concentrations and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. Lamivudine treatment in patients with chronic HBV infection has been associated with histologic improvement on liver biopsy, decreases in HBV DNA, normalization of serum ALT concentrations, and HBeAg seroconversion (loss of HBeAg and development of antibody to HBeAg).

In a controlled study in Chinese patients with chronic HBV infection who received lamivudine 100 mg once daily, lamivudine 25 mg once daily, or placebo for 12 months, hepatic necroinflammatory activity improved in 56, 49, or 25% and deteriorated in 7, 8, or 26% of patients, respectively. Therapy with lamivudine 100 mg daily was associated with a reduction in the progression of fibrosis compared with placebo. At 12 months, HBeAg seroconversion occurred in 16, 13, or 4%, respectively, of patients receiving lamivudine 100 mg daily, 25 mg daily, or placebo. Therapy with lamivudine 100 mg daily was associated with a rapid and sustained reduction in HBV DNA (97% reduction at week 2, 98% reduction at week 52 compared with baseline) and sustained serum ALT response in 72% of patients; therapy with lamivudine 25 mg daily or placebo was associated with a 93 or 54% reduction in HBV DNA at week 52 and sustained ALT response in 65 or 24% of patients, respectively. In this study, therapy with lamivudine 100 mg daily was more effective than lamivudine 25 mg daily or placebo.

While therapy with lamivudine is associated with histologic improvement in most patients and is well tolerated, the optimum duration of therapy, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis remain to be determined. There is some evidence that efficacy of lamivudine may not be sustained during continued therapy. Results from 52-week studies in adults indicate that HBV DNA levels decrease to below the limits of detection in the majority of lamivudine-treated patients early in the course of treatment; however, assay-detectable HBV DNA reappears during treatment in approximately one-third of those who had an initial response. Strains of HBV with resistance to lamivudine have emerged during therapy with the drug, especially during long-term treatment.(See Resistance: Resistance in HBV.) Development of lamivudine-resistant HBV during treatment with the drug has been associated with decreased treatment responses evidenced by lower rates of HBeAg seroconversion and HBeAg loss and more frequent increases in HBV DNA levels and serum ALT concentrations after an initial response. Progression of HBV infection, including death, has been reported in some patients with lamivudine-resistant HBV.

Pediatric Patients

Lamivudine is used for treatment of chronic HBV infection in children 2 years of age or older. Safety and efficacy of lamivudine was evaluated in a double-blind clinical study in 286 children and adolescents 2-17 years of age with compensated chronic HBV infection accompanied by evidence of HBV replication (positive serum HBeAg and positive for serum HBV DNA as measured by a research branched DNA [bDNA] assay) and persistently elevated serum ALT concentrations. Loss of HBeAg and reduction of HBV DNA to below the limits of detection of the research assay (evaluated at week 52) occurred in 23% of children who received 52 weeks of lamivudine (3 mg/kg once daily; maximum 100 mg once daily) compared with 13% of those who received placebo. In addition, normalization of serum ALT concentrations was achieved and maintained to week 52 more frequently in patients treated with lamivudine (55%) compared with placebo (13%). As in the controlled studies in adults, most lamivudine-treated pediatric patients had decreases in serum HBV DNA concentrations below the limits of detection early in treatment, but about one-third of subjects with this initial response had reappearance of detectable HBV DNA during treatment. Adolescents (13-17 years of age) showed less evidence of this treatment effect than younger children.

HIV-infected Individuals

Safety and efficacy of lamivudine for treatment of chronic HBV infection in patients coinfected with HIV have not been established.

HIV-infected patients coinfected with HBV often have higher HBV viral loads and are more likely to have detectable HBeAg, lower rates of HBeAg seroconversion, and an increased risk for and more rapid progression to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma compared with individuals not infected with HIV. Decisions to initiate HBV treatment in patients coinfected with HIV and HBV and the most appropriate drugs for HBV treatment in such patients depend on various factors, including the possible effects on replication of both HIV and HBV and whether the patient is currently receiving antiretroviral therapy. Specialized references should be consulted for specific information regarding the evaluation and management of chronic HBV infection in HIV-infected patients.

Although lamivudine is active against both HBV and HIV, it should not be used for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy since dosages used for treatment of HBV infection are lower than those recommended for treatment of HIV infection and use of suboptimal dosages in HIV-infected individuals may allow for the selection of lamivudine-resistant HIV. In addition, emergence of lamivudine-resistant HBV has been reported in HIV-infected individuals who were coinfected with HBV and receiving lamivudine-containing antiretroviral regimens. Although a high rate of emergence of lamivudine-resistant HBV has been reported with long-term lamivudine therapy in HBV-infected patients without HIV infection, there is some evidence that the rate of emergence of HBV resistance may be even higher in HIV-infected individuals who receive the drug. Reactivation of chronic HBV has been reported in some HIV-infected patients who received long-term lamivudine therapy, and fulminant and fatal reactivation of chronic HBV infection as the result of emergence of lamivudine-resistant HBV has been reported.(See Precautions Related to Treatment of Chronic HBV Infection under Cautions: Precautions and Contraindications.)

Transplant Recipients

Safety and efficacy of lamivudine have not been established for treatment of HBV infection in organ transplant recipients. There is some evidence that lamivudine appears to reduce the risk of HBV reinfection in orthotopic liver transplant recipients. However, further study is needed to define the role of lamivudine and other therapies for prevention and control of HBV recurrence in transplant recipients.

Dosage and Administration

Administration

Lamivudine is administered orally once or twice daily without regard to meals.

For treatment of human immunodeficiency virus type 1 (HIV-1) infection, lamivudine is commercially available as an oral solution containing 10 mg/mL or tablets containing 150 or 300 mg of the drug (Epivir). The 150-mg scored tablets may be used in children who weigh 14 kg or more and can swallow tablets. The oral solution should be used in children unable to reliably swallow tablets. Lamivudine is used in conjunction with other antiretrovirals for treatment of HIV-1 infections.

For treatment of chronic hepatitis B virus (HBV) infection, lamivudine is commercially available as an oral solution containing 5 mg/mL or film-coated tablets containing 100 mg of the drug (Epivir-HBV). The oral solution should be used in patients requiring a dosage less than 100 mg and in children unable to reliably swallow tablets. Because Epivir-HBV preparations contain a lower dosage of lamivudine than Epivir, they should not be used in patients with HIV infection. If Epivir-HBV is used for the management of chronic HBV infection in 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 for HIV-infected individuals.(See Chronic Hepatitis B Virus Infection under Dosage and Administration: Dosage.)

Fixed Combinations Containing Lamivudine

For treatment of HIV infection, lamivudine is commercially available in fixed-combination tablets containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir), fixed-combination tablets containing abacavir and lamivudine (abacavir/lamivudine; Epzicom), and fixed-combination tablets containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir).

Lamivudine/zidovudine (Combivir) tablets are administered orally twice daily without regard to meals. A fixed-combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine is bioequivalent to one 150-mg tablet of lamivudine and one 300-mg tablet of zidovudine given simultaneously. Lamivudine/zidovudine is used in conjunction with other antiretrovirals. The fixed combination should not be used in pediatric patients weighing less than 30 kg, patients with renal impairment (i.e., creatinine clearance 50 mL/minute or less), patients with hepatic impairment, patients who experience dose-limiting adverse effects, or others requiring dosage adjustment.

Abacavir/lamivudine (Epzicom) tablets are administered orally once daily without regard to meals. A fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine is bioequivalent to two 300-mg tablets of abacavir and two 150-mg tablets of lamivudine given simultaneously. Abacavir/lamivudine is used in conjunction with other antiretrovirals. The fixed combination should not be used in patients younger than 18 years of age, patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute), patients with hepatic impairment, or others requiring dosage adjustment.

Abacavir/lamivudine/zidovudine (Trizivir) tablets are administered orally twice daily without regard to meals. A fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine is bioequivalent to a 300-mg abacavir tablet, a 150-mg lamivudine tablet, and a 300-mg zidovudine tablet given simultaneously. Abacavir/lamivudine/zidovudine can be used alone as a complete treatment regimen or can be used in conjunction with other antiretrovirals. The fixed combination should not be used in pediatric patients, adolescents weighing less than 40 kg, patients with renal impairment (i.e., creatinine clearance 50 mL/minute or less), patients with hepatic impairment, or others requiring dosage adjustment.

Because the antiretroviral agents contained in lamivudine/zidovudine, abacavir/lamivudine, and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated when any of these fixed combinations are used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Dosage

Treatment of HIV Infection

Adult Dosage

The usual dosage of lamivudine (Epivir) for treatment of HIV-1 infection in adults older than 16 years of age is 150 mg twice daily or 300 mg once daily.

When lamivudine/zidovudine (Combivir) is used for treatment of HIV-1 infection, adults weighing 30 kg or more should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily.

When abacavir/lamivudine (Epzicom) is used for treatment of HIV-1 infection, adults should receive 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily.

When abacavir/lamivudine/zidovudine (Trizivir) is used for treatment of HIV-1 infection, adults should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

Pediatric Dosage

When lamivudine oral solution (Epivir) is used for treatment of HIV-1 infection in infants and children 3 months to 16 years of age, the recommended dosage is 4 mg/kg (up to 150 mg) twice daily.

When lamivudine 150-mg tablets (Epivir) are used in infants and children 3 months to 16 years of age who weigh 14 kg or more and can swallow tablets, the recommended dosage is 75 mg (half tablet) twice daily for those who weigh 14-21 kg, 75 mg (half tablet) in the morning and 150 mg in the evening for those who weigh more than 21 to less than 30 kg, and 150 mg twice daily for those who weigh 30 kg or more.

Some experts state that adolescents 16 years of age or older weighing less than 50 kg should receive lamivudine in a dosage of 4 mg/kg (up to 150 mg) twice daily and those weighing 50 kg or more may receive 150 mg twice daily or 300 mg once daily.

Although safety and efficacy of lamivudine in infants younger than 3 months of age have not been established, some experts suggest that neonates younger than 4 weeks of age can receive lamivudine oral solution (Epivir) in a dosage of 2 mg/kg twice daily and infants 4 weeks of age or older can receive a dosage of 4 mg/kg (up to 150 mg) twice daily.

When lamivudine/zidovudine (Combivir) is used for treatment of HIV-1 infection, children and adolescents weighing 30 kg or more should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily.

Although not labeled for use in patients younger than 18 years of age, some experts suggest that adolescents 16 years of age or older can receive abacavir/lamivudine (Epzicom) in a dosage of 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily for treatment of HIV-1 infection.

When abacavir/lamivudine/zidovudine (Trizivir) is used for treatment of HIV-1 infection, adolescents weighing 40 kg or more should receive 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, the preferred dosage of lamivudine is 300 mg once daily. Alternatively, lamivudine can be given in a dosage of 150 mg twice daily. Lamivudine usually is used with tenofovir DF or zidovudine in conjunction with a recommended HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

When lamivudine/zidovudine (Combivir) is used as the dual NRTI option in PEP regimens, adults should receive 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily in conjunction with a recommended INSTI, NNRTI, or PI.(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP), the usual adult dosage of lamivudine is 150 mg twice daily or 300 mg once daily in conjunction with other antiretrovirals.(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)

The nPEP regimen should be initiated as soon as possible following nonoccupational exposure to HIV (preferably within 72 hours) and continued for 28 days.

Chronic Hepatitis B Virus Infection

For treatment of chronic hepatitis B virus (HBV) infection in adults, lamivudine should be administered as the oral solution containing 5 mg/mL or tablets containing 100 mg of the drug (Epivir-HBV). Prior to and periodically during lamivudine therapy for treatment of chronic HBV infection, the HIV status of the patient should be determined since the dosage of the drug used for treatment of HBV infection is lower than the dosage used for treatment of HIV infection and use of suboptimal dosages in HIV-infected individuals may allow for the selection of lamivudine-resistant HIV isolates.(See Precautions Related to Treatment of Chronic HBV Infection under Cautions: Precautions and Contraindications.)

Adult Dosage

When lamivudine (Epivir-HBV) is used for treatment of chronic HBV infection in adults, the recommended dosage is 100 mg once daily.

Pediatric Dosage

When lamivudine (Epivir) is used for treatment of chronic HBV infection in children 2-17 years of age, the recommended dosage is 3 mg/kg (up to 100 mg) once daily.

Duration of Therapy and Clinical and Laboratory Monitoring

The optimum duration of lamivudine therapy for treatment of chronic HBV infection is not known. The manufacturer states that safety and efficacy of the drug administered for longer than 1 year for treatment of chronic HBV infection have not been established. The American Association for the Study of Liver Diseases (AASLD) recommends that lamivudine treatment be continued for at least 12 months; in HBsAg-positive patients, these experts recommend that treatment be continued for at least 6 months after HBeAg seroconversion (loss of HBeAg and detection of anti-HBe).

Patients receiving lamivudine for treatment of chronic HBV infection should be monitored regularly during treatment by a clinician experienced in the management of chronic HBV infection. During lamivudine therapy, events that may be considered as potentially reflecting loss of therapeutic response include combinations of such events as return of persistently elevated serum ALT concentrations, increasing levels of HBV DNA over time after an initial decline below the limits of detection of the assay, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings. Such events should be taken into consideration when determining the advisability of continuing therapy with lamivudine.

Patients should be informed that deterioration of liver disease has occurred in some cases following discontinuance of lamivudine therapy, and that they should discuss any change in regimen with their clinician. Patients should be informed that emergence of resistant HBV and worsening of disease can occur during treatment, and they should promptly report any new symptoms to their clinician.(See Cautions: Precautions and Contraindications.)

Dosage in Renal and Hepatic Impairment

Because lamivudine pharmacokinetics are not affected by hepatic impairment, dosage of the drug does not need to be adjusted in patients with hepatic impairment. However, safety and efficacy have not been established in patients with decompensated liver disease.

Because elimination of lamivudine may be reduced in patients with renal impairment, dosage of the drug should be decreased in adults 16 years of age and older with creatinine clearances less than 50 mL/minute.

Treatment of HIV Infection

For treatment of HIV infection in adults older than 16 years of age who weigh 30 kg or more with impaired renal function, the manufacturer recommends a lamivudine (Epivir) dosage of 150 mg once daily in those with creatinine clearances of 30-49 mL/minute. Those with creatinine clearances of 15-29 mL/minute may receive a single 150-mg dose on the first day, then 100 mg once daily thereafter, and those with creatinine clearances of 5-14 mL/minute may receive a single 150-mg dose on the first day, then 50 mg once daily thereafter. Adults 16 years of age and older with creatinine clearances less than 5 mL/minute may receive a single 50-mg dose on the first day, then 25 mg once daily thereafter. The manufacturer states that dosage modifications in addition to those based on creatinine clearance are unnecessary in HIV-infected patients undergoing routine (4-hour) hemodialysis or peritoneal dialysis. The manufacturer states that data are insufficient to make dosage recommendations for HIV-infected pediatric patients with renal impairment; however, a reduction in the dose and/or an increase in the dosing interval should be considered.

Lamivudine (Epivir) dosage does not need to be adjusted in patients with hepatic impairment; however, safety and efficacy of the drug have not been established in patients with decompensated liver disease.

Fixed combinations containing lamivudine (lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine) should not be used for treatment of HIV infection in patients with creatinine clearance less than 50 mL/minute or in patients with any degree of hepatic impairment.

Chronic Hepatitis B Virus Infection

For treatment of chronic HBV infection in adults with impaired renal function, the manufacturer recommends that those with creatinine clearances of 30-49 mL/minute receive a 100-mg lamivudine dose (Epivir-HBV) on the first day, then 50 mg once daily thereafter. Those with creatinine clearances of 15-29 mL/minute should receive a 100-mg dose on the first day, then 25 mg once daily thereafter and those with creatinine clearance of 5-14 mL/minute should receive a 35-mg dose on the first day, then 15 mg once daily thereafter. Adults with creatinine clearances less than 5 mL/minute should receive a 35-mg dose on the first day, then 10 mg once daily thereafter.

The manufacturer states that data are insufficient to make specific dosage recommendations for pediatric patients with renal impairment.

The manufacturer states that supplemental doses are unnecessary in patients undergoing routine (4-hour) hemodialysis or peritoneal dialysis.

Cautions

Information on adverse effects of lamivudine has been obtained from clinical studies in adults with human immunodeficiency virus (HIV) infection who received the drug in conjunction with other antiretroviral agents (e.g., studies NUCA3001, NUCA3002, NUCB3001, NUCB3002, NUCB3007, EPV20001, EPV40001). In addition, information on adverse effects of lamivudine in patients with compensated chronic hepatitis B virus (HBV) infection has been obtained from 3 placebo-controlled studies where the drug was used alone for up to 68 weeks.

The most common adverse effects reported in HIV-infected adults receiving lamivudine in conjunction with other antiretroviral agents are nausea, fatigue and/or malaise, headache, nasal symptoms, diarrhea, and cough. The manufacturer states that the types and frequencies of adverse effects in HIV-infected patients receiving lamivudine 300 mg once daily are similar to those reported in patients receiving 150 mg twice daily. The most common adverse effects reported in clinical trials evaluating lamivudine in adults with chronic HBV infection are increased ALT concentrations; infections of the ear, nose, or throat; diarrhea; sore throat; and increased serum lipase concentrations.

Although lamivudine generally is well tolerated, serious adverse effects such as peripheral neuropathy, pancreatitis, and lactic acidosis and severe hepatomegaly with steatosis have been reported in patients receiving the drug or the fixed combination of lamivudine and zidovudine.

When the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir), fixed combination containing abacavir and lamivudine (abacavir/lamivudine; Epzicom), or fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir) is used, the adverse effects, precautions, and contraindications associated with each of the individual components should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Nervous System Effects

Peripheral neuropathy has been reported in adults receiving lamivudine, but has rarely resulted in interruption or discontinuance of therapy. In clinical studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002 in HIV-infected adults receiving lamivudine in conjunction with zidovudine, neuropathy was reported in 12% of the patients. Weakness has been reported in patients receiving lamivudine during postmarketing experience.

In HIV-infected adults receiving lamivudine in conjunction with zidovudine, headache, malaise, fatigue, insomnia and other sleep disorders, dizziness, and depressive disorders were reported in 35, 27, 27, 11, 10, and 9%, respectively.

There have been postmarketing reports of paresthesia and peripheral neuropathy in patients receiving lamivudine for treatment of chronic HBV infection.

Pancreatitis

Pancreatitis has been reported in less than 0.5% of patients receiving lamivudine for treatment of HIV infection in controlled clinical studies; pancreatitis has been reported during postmarketing experience. However, the incidence of pancreatitis was reported to be 14-18% in HIV-infected pediatric patients receiving lamivudine in open-label studies.(See Cautions: Pediatric Precautions) Increased serum amylase concentrations (greater than 2 times the upper limit of normal) were reported 4.2 % of adults receiving lamivudine in conjunction with zidovudine in clinical studies NUCA3001, NUCA3002, NUCB3001, NUCB3002 and in 2.2% of adults receiving lamivudine in conjunction with other antiretroviral agents in clinical study NUCB3007.

In clinical studies in adults who received lamivudine for treatment of chronic HBV infection, increased serum lipase concentrations (at least 2.5 times the upper limit of normal) were reported in 10% of patients. There also have been postmarketing reports of pancreatitis.

Hepatic Effects and Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported rarely in patients receiving lamivudine and also have been reported in patients receiving other HIV nucleoside reverse transcriptase inhibitors (NRTIs). Most reported cases have involved women; obesity and long-term therapy with NRTIs also may be risk factors. Lamivudine should be used with caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.(See Cautions: Precautions and Contraindications).

Increased serum concentrations of AST (SGOT), ALT (SGPT), and bilirubin have been reported in patients receiving lamivudine in conjunction with other antiretroviral agents for treatment of HIV infection. In clinical studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002, increased serum concentrations of ALT (greater than 5 times the upper limit of normal), AST (greater than 5 times the upper limit of normal), or bilirubin (greater than 2.5 times the upper limit of normal) were reported in 3.7, 1.7, and 0.8% of patients, respectively. In another study (NUCB3007) evaluating patients receiving lamivudine in conjunction with other antiretroviral agents, the overall incidence of increased serum concentrations of ALT or AST (greater than 5 times the upper limit of normal) was 3.8 or 4%, respectively. The occurrence of increased levels of hepatic enzymes and bilirubin in these patients appears to be transient and resolves without dosage modification or discontinuance of therapy.

In clinical studies in adults who received 52 weeks of lamivudine for treatment of chronic HBV infection, serum ALT concentrations at least 2 times greater than baseline were reported in 27% and serum ALT concentrations at least 3 times greater than baseline were reported in 21% of patients during 16 weeks of follow-up after the drug was discontinued. Increased serum concentrations of ALT (at least 2 times greater than baseline) and absolute serum ALT concentrations exceeding 500 IU/L were reported in 15% of patients evaluated for up to 16 weeks after discontinuance of the drug; increased serum concentrations of ALT (at least 2 times greater than baseline) and increased serum bilirubin concentrations (greater than 2 times the upper limit of normal and at least 2 times greater than baseline) were reported in 0.7% of patients.

Hepatic decompensation, sometimes fatal, has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) receiving antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin. (See Precautions Related to Treatment of HIV Infection under Cautions: Precautions and Contraindications and see Drug Interactions.)

GI Effects

The most frequently occurring adverse effects associated with lamivudine therapy involve the GI tract, particularly early in therapy. In clinical studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002 in HIV-infected adults, nausea, diarrhea, vomiting, anorexia and/or decreased appetite, abdominal pain, abdominal cramps, and dyspepsia were reported in 33, 18, 13, 10, 9, 6, and 5% of patients, respectively.

In clinical studies in adults receiving lamivudine for treatment of chronic HBV infection, diarrhea was reported in 14% of patients. There also have been postmarketing reports of stomatitis.

Dermatologic and Sensitivity Reactions

In studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002 in HIV-infected adults receiving lamivudine in conjunction with zidovudine, rash was reported in 9% of patients. Anaphylaxis, urticaria, alopecia, rash, pruritus, erythema multiforme, and Stevens-Johnson syndrome have been reported in patients who received lamivudine or the fixed combination of lamivudine and zidovudine during postmarketing experience.

There have been postmarketing reports of alopecia, pruritus, and rash in patients receiving lamivudine for treatment of chronic HBV infection.

Hematologic Effects

In studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002 in HIV-infected adults, anemia (hemoglobin concentration less than 8.0 g/dL) was reported in 2.9% of patients who received lamivudine in conjunction with zidovudine. In addition, neutropenia (neutrophil count less than 750/mm) occurred in 7.2% and thrombocytopenia (thrombocytes less than 50,000/mm) occurred in 0.4% of patients. In study NUCB3007 in HIV-infected adults, anemia (hemoglobin less than 8.0 g/dL) was reported in 2.2%, neutropenia (neutrophil count less than 750/mm) occurred in 15%, and thrombocytopenia (thrombocytes less than 50,000/mm) occurred in 2.8% of patients. The occurrence of neutropenia in these patients appears to be transient and resolves without dosage modification or discontinuation of therapy.

Thrombocytopenia has been reported in patients receiving lamivudine for treatment of chronic HBV infection. In clinical trials, thrombocytopenia (platelets less than 50,000/mm) was reported in 4% of patients receiving the drug.

Aplastic anemia, anemia (including severe anemia progressing on therapy), lymphadenopathy, pure red cell aplasia, and splenomegaly have been reported in patients receiving lamivudine or lamivudine/zidovudine during postmarketing experience.

Musculoskeletal Effects

Adverse musculoskeletal effects, including pain, myalgia, and arthralgia have been reported in 12, 8, and 5%, respectively, of HIV-infected patients who received lamivudine in studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002.

In clinical studies evaluating lamivudine for treatment of chronic HBV infection, increased concentrations of creatine kinase (CK, creatine phosphokinase, CPK) exceeding 7 times the baseline concentration were reported in 9% of patients. Myalgia and arthralgia also have been reported.

Muscle weakness, cramps, CK (CPK) elevation, and rhabdomyolysis have been reported in patients receiving lamivudine or lamivudine/zidovudine during postmarketing experience.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents, including lamivudine or the fixed combination of lamivudine and ritonavir. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Patients receiving potent antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy. Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Other Adverse Effects

Nasal signs and symptoms, cough, and fever or chills have been reported in 20, 18, and 10%, respectively, of HIV-infected patients who received lamivudine in studies NUCA3001, NUCA3002, NUCB3001, and NUCB3002. In adults who received lamivudine for treatment of chronic HBV infection, ear, nose, and throat infection was reported in 25% and sore throat was reported in 13% of patients. There also have been postmarketing reports of abnormal breath sounds/wheezing in patients receiving lamivudine for treatment of chronic HBV infection.

Hyperglycemia, cardiomyopathy, vasculitis, weakness have been reported in patients receiving lamivudine or lamivudine/zidovudine during postmarketing experience.

Precautions and Contraindications

Lamivudine and fixed combinations containing lamivudine (lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine) are contraindicated in patients with clinically important hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to lamivudine or any ingredient in the formulation.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Use of lamivudine or other HIV NRTIs has been associated with potentially fatal lactic acidosis and severe hepatomegaly with steatosis.(See Cautions: Hepatic Effects and Lactic Acidosis.) Lamivudine should be discontinued in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations). Lamivudine should be used with caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.

Patients should be advised 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 as yet unknown.(See Cautions: Adipogenic Effects.)

Patients with renal impairment (i.e., creatinine clearances less than 50 mL/minute) may be at increased risk of adverse effects during lamivudine therapy because of decreased clearance of the drug; a decrease in dosage is recommended in such patients.(See Dosage: Dosage in Renal and Hepatic Impairment.)

Individuals with diabetes mellitus and/or their caregivers should be informed that lamivudine oral solutions (Epivir, Epivir-HBV) contain 1 g of sucrose per 5 mL.

Because of similarity in spelling between lamivudine and lamotrigine (Lamictal, an anticonvulsant agent), several dispensing errors have been reported to the manufacturer. These medication errors may be associated with serious adverse effects either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or due to the risk of developing adverse effects associated with the use of lamotrigine (e.g., serious rash) in patients for whom the drug was not prescribed and consequently not properly titrated. Therefore, the manufacturer cautions that extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for lamotrigine (Lamictal) and lamivudine. The manufacturer also recommends that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another in product storage areas, patient counseling).

Precautions Related to Treatment of HIV Infection

Lamivudine in conjunction with other antiretroviral agents is not a cure for HIV infection, and patients receiving the drugs may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be informed of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician. Patients should be advised to take their antiretroviral regimen exactly as prescribed and not to alter or discontinue the regimen without consulting a clinician.

Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Lamivudine should always be administered in conjunction with other antiretroviral agents and should not be used alone for treatment of HIV infection. The usual precautions and contraindications of the other antiretrovirals in the regimen should be considered during concomitant therapy.

Patients receiving lamivudine with peginterferon alfa (or interferon alfa) with or without ribavirin should be closely monitored for toxicity, especially hepatic decompensation. Discontinuance of lamivudine should be considered as medically appropriate. Dosage reduction or discontinuance of peginterferon alfa (or interferon alfa) and/or ribavirin also should be considered if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score greater than 6), occur.

Precautions Related to Treatment of Chronic HBV Infection

Prior to and periodically during lamivudine therapy for treatment of chronic HBV infection (Epivir-HBV), all patients should be offered HIV counseling and testing. Epivir-HBV is not appropriate for treatment of chronic HBV infection in patients coinfected with HIV since it contains a lower dose of lamivudine than Epivir. Use of Epivir-HBV for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in rapid emergence of lamivudine-resistant HIV and limit antiretroviral treatment options. If a decision is made to use lamivudine in patients coinfected with HBV and HIV, Epivir should be used in dosages appropriate for treatment of HIV infection in conjunction with other antiretrovirals.

Patients receiving lamivudine for treatment of chronic HBV infection should be monitored regularly during treatment by a clinician experienced in the management of chronic HBV infection.

Posttreatment exacerbations of HBV infection and emergence of resistant strains of HBV have been reported following discontinuance of lamivudine therapy in non-HIV-infected patients. Exacerbations of HBV infection also have been reported when lamivudine was discontinued from antiretroviral regimens in HIV-infected patients coinfected with HBV. Such exacerbations of HBV infection have been detected principally by increases in serum ALT concentrations in addition to re-emergence of serum HBV DNA. Although most events appear to have been self-limited and the causal relationship to lamivudine discontinuance is unknown, some fatalities have been reported. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping lamivudine treatment. There is insufficient evidence to determine whether reinitiation of therapy alters the course of posttreatment exacerbations of hepatitis.

Patients should be advised that lamivudine is not a cure for HBV, that the long-term benefits of lamivudine therapy are unknown at this time, and that the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown.

Patients should also be advised that lamivudine therapy has not been shown to reduce the risk of transmission of HBV to others via sexual conduct or blood contamination and that practices designed to prevent transmission of HBV should be maintained during therapy. Patients should be instructed to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Lamivudine (Epivir-HBV) should not be used concomitantly with any preparation containing lamivudine or emtricitabine.

Precautions Related to Use of Fixed Combinations

When lamivudine/zidovudine, abacavir/lamivudine, or abacavir/lamivudine/zidovudine is used, the usual cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, pediatric patients, geriatric patients) should be considered for each drug.

Because the antiretrovirals contained in lamivudine/zidovudine, abacavir/lamivudine, and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if one of these fixed combinations is used in conjunction with other antiretrovirals.

Multiple lamivudine-containing preparations should not be used concomitantly.

Lamivudine and fixed combinations containing lamivudine should not be used concomitantly with any preparation containing emtricitabine.

If abacavir/lamivudine or abacavir/lamivudine/zidovudine is used, clinicians should consider that abacavir has been associated with serious and sometimes fatal hypersensitivity reactions. Because individuals with the human leukocyte antigen (HLA)-B*5701 allele are at high risk for abacavir hypersensitivity reactions, screening for the HLA-B*5701 allele is recommended prior to initiation of abacavir-containing preparations. Abacavir/lamivudine or abacavir/lamivudine/zidovudine should be discontinued as soon as a hypersensitivity reaction is suspected. Regardless of the patient's HLA-B*5701 status, the fixed combinations containing abacavir should be permanently discontinued if hypersensitivity cannot be ruled out.

If lamivudine/zidovudine or abacavir/lamivudine/zidovudine is used, clinicians should consider that zidovudine has been associated with hematologic toxicity (including neutropenia and severe anemia), particularly in those with advanced HIV-1 disease, and that prolonged zidovudine use has been associated with symptomatic myopathy. These fixed combinations should be used with caution in patients who have bone marrow compromise evidenced by a granulocyte count less than 1000 cells/mm or a hemoglobin concentration less than 9.5 g/dL.

Pediatric Precautions

Safety and efficacy of lamivudine (Epivir) in conjunction with other antiretroviral agents for treatment of HIV infection have been established in children 3 months of age and older.

Safety and efficacy of lamivudine (Epivir-HBV) for treatment of chronic HBV have been established in children 2-17 years of age. Adverse effects reported in HBV-infected children in this age group were similar to those reported in adults with HBV infection. Elevated serum aminotransferase (transaminase) concentrations were reported in some children after discontinuance of the drug. Safety and efficacy of lamivudine for treatment of HBV infection have not been established in children younger than 2 years of age.

In clinical studies in HIV-infected pediatric patients who received lamivudine in conjunction with zidovudine, paresthesia and peripheral neuropathies have been reported in up to 15% of patients. Pancreatitis, including some fatalities, has occurred in 14-18% of HIV-infected pediatric patients receiving lamivudine alone or in conjunction with other nucleoside antiretroviral agents. Other adverse effects reported in pediatric patients receiving lamivudine in conjunction with zidovudine were similar to those reported in adults and include GI effects, hepatic effects, sensitivity reactions, and hematologic effects.

Lamivudine should be used with caution in pediatric patients with a history of prior therapy with NRTIs, a history of pancreatitis, or significant risk factors for development of pancreatitis. If clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur, lamivudine should be discontinued immediately. Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis.

Limited data are available regarding safety of lamivudine in neonates. Adverse effects reported in neonates who received lamivudine alone or in conjunction with zidovudine during the first week of life as part of a regimen for prevention of perinatal HIV transmission in 2 small, uncontrolled studies in Africa include increased liver function test results, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, sepsis, and syphilis; 3 neonates died (one from gastroenteritis with acidosis and seizures, one from traumatic injury, and one from unknown causes). There were 2 other nonfatal gastroenteritis or diarrhea cases, including one with seizures; transient renal insufficiency associated with dehydration was reported in one infant. Because there were no control groups in these studies, causality is difficult to establish. However, it should be assumed that perinatally exposed neonates may be at risk for adverse effects similar to those reported in pediatric and adult HIV-infected patients receiving multiple-drug regimens containing lamivudine. The long-term effects of in utero and infant exposure to lamivudine are unknown.

Lamivudine/zidovudine (Combivir) should not be used in pediatric patients or adolescents weighing less than 30 kg.

Abacavir/lamivudine (Epzicom) should not be used in patients younger than 18 years of age.

Abacavir/lamivudine/zidovudine (Trizivir) should not be used in pediatric patients or in adolescents weighing less than 40 kg.

Geriatric Precautions

Clinical studies of lamivudine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Dosage for geriatric patients should be selected carefully because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Lamivudine is substantially eliminated by the kidneys, and the risk of severe adverse reactions to the drug may be increased in patients with impaired renal function. Because geriatric patients may have decreased renal function, the manufacturer states that renal function should be monitored and lamivudine dosage adjustments made when indicated.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

Lamivudine was not mutagenic 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, there was no evidence of genotoxic activity in rats given oral dosages up to 2 g/kg resulting in plasma lamivudine concentrations more than 60-70 times higher than those seen in humans receiving the usually recommended dosage for chronic HBV infection and 35-45 times higher than those seen in humans receiving the usually recommended dosage for HIV infection.

The carcinogenic potential of lamivudine has been studied in mice and rats. No evidence of carcinogenicity was seen in long-term studies in mice or rats receiving oral lamivudine dosages at exposures approximately 34 or 200 times higher, respectively, than those reported in humans receiving the recommended dosage for HBV infection and at exposures approximately 10 or 58 times higher, respectively, in humans receiving the recommended dosage for HIV infection.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats or rabbits using oral lamivudine in dosages up to 130 or 60 times the recommended human dosage for HIV infection, respectively, have not revealed evidence of teratogenicity. Although there was evidence of early embryolethality in rabbits receiving lamivudine at dosages similar to the recommended dosages in humans, this effect was not seen in rats receiving lamivudine at dosages 60 times the recommended human dosage for HBV infection and 35 times the recommended human dosage for HIV infection. Lamivudine crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.

There are no adequate and controlled studies to date using lamivudine in pregnant women, and the drug should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. In small, uncontrolled studies when lamivudine was used concomitantly with zidovudine during the last few weeks of pregnancy for prevention of perinatal transmission of HIV, adverse effects included anemia, urinary tract infections, and complications of labor and delivery. During postmarketing experience, liver function abnormalities and pancreatitis have been reported in women who received lamivudine in conjunction with other antiretroviral agents during pregnancy. It is not known whether risks for lamivudine-associated adverse effects are different in pregnant women compared with other HIV-infected patients.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that the preferred dual NRTI options for initial regimens used for treatment of HIV-1 infection in antiretroviral-naive pregnant women are zidovudine and lamivudine, abacavir and lamivudine (should be used only in those negative for HLA-B*5701), or tenofovir DF and either emtricitabine or lamivudine. Tenofovir DF and either emtricitabine or lamivudine is the preferred dual NRTI option for treatment of HIV-1 infection in pregnant women coinfected with HBV.

Some experts state that the dual NRTI option of lamivudine and abacavir or zidovudine used in conjunction with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is a preferred regimen for treatment of HIV type 2 (HIV-2) infection in pregnant women.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including lamivudine, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or http://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents.

Fertility

There was no evidence that lamivudine affected fertility in rats that received the drug in dosages up to 4 g/kg daily resulting in plasma concentrations 80-120 times higher than those seen in humans receiving the usually recommended dosage for chronic HBV infection and 47-70 times higher than those seen in those receiving the recommended dosage for HIV infection.

Lactation

Lamivudine is distributed into milk in humans.

The US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women (including those receiving antiretroviral therapy) not breast-feed infants.

If lamivudine is being used for treatment of chronic HBV infection, a decision should be made whether to discontinue nursing or the drug, taking into consideration the importance of continued HBV treatment to the mother and the known benefits of breast-feeding.

Drug Interactions

The following drug interactions are based on studies using lamivudine. Drug interaction studies have not been performed using the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir), fixed combination containing abacavir and lamivudine (abacavir/lamivudine; Epzicom), or fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

In vitro studies indicate that the antiretroviral effects of enfuvirtide and lamivudine are additive to synergistic against HIV-1.

Maraviroc

Maraviroc has no effect on the pharmacokinetics of lamivudine.

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and lamivudine.

HIV Integrase Inhibitors (INSTIs)

Raltegravir

Raltegravir does not have a clinically important effect on the pharmacokinetics of lamivudine.

In vitro studies indicate that the antiretroviral effects of raltegravir and lamivudine are additive to synergistic against HIV-1.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

In vitro studies using some HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, efavirenz, nevirapine) indicate that antiretroviral effects of lamivudine and these drugs may be additive or synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between lamivudine and etravirine or rilpivirine.

Efavirenz

In a multiple-dose pharmacokinetic study in HIV-infected patients, concomitant use of efavirenz and lamivudine did not affect lamivudine peak plasma concentrations or area under the serum concentration-time curve (AUC). Dosage adjustments are not necessary if efavirenz is used concomitantly with lamivudine.

Rilpivirine

Although not specifically studied, clinically important pharmacokinetic interactions are not expected if rilpivirine is used concomitantly with lamivudine.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies indicate that the antiretroviral effects of lamivudine and some other HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g. abacavir, emtricitabine, stavudine, tenofovir, zidovudine) are additive to synergistic against HIV-1. There is no in vitro evidence of antagonistic antiviral effects between lamivudine and tenofovir against hepatitis B virus (HBV).

Abacavir

In a crossover study evaluating concomitant use of single doses of abacavir (600 mg) and lamivudine (150 mg) in HIV-infected individuals, the AUC of lamivudine was decreased 15% and the pharmacokinetics of abacavir were not affected. This pharmacokinetic interaction is not considered clinically important.

Emtricitabine

Emtricitabine and lamivudine should not be used concomitantly. Because emtricitabine is an analog of lamivudine, the drugs have similar resistance profiles and minimal additive antiretroviral effects.

Stavudine

In a pharmacokinetic study evaluating concomitant use of a single dose of stavudine (40 mg) and lamivudine (150 mg) in HIV-infected individuals, peak plasma concentrations of stavudine were increased 12%, but the AUC of stavudine and the peak plasma concentration and AUC of lamivudine were not affected. This pharmacokinetic interaction is not considered clinically important.

Tenofovir

In a pharmacokinetic study evaluating concomitant use of tenofovir disoproxil fumarate (300 mg once daily for 7 days) and lamivudine (150 mg twice daily for 7 days), peak plasma concentrations of lamivudine were decreased 24%, but the AUC of lamivudine and the peak plasma concentration and AUC of tenofovir were not affected.

Zidovudine

Results of a study in asymptomatic HIV-infected patients who received a single 200-mg dose of zidovudine in conjunction with multiple doses of lamivudine (300 mg every 12 hours) indicate that concomitant use of the drugs does not have a clinically important effect on the pharmacokinetics of either drug. The AUC of zidovudine was increased 13%, but lamivudine concentrations were not affected.

Dosage adjustments are not necessary in patients receiving lamivudine and zidovudine concomitantly.

HIV Protease Inhibitors (PIs)

Lamivudine and some HIV protease inhibitors (PIs) (e.g., amprenavir [commercially available as fosamprenavir], nelfinavir, ritonavir, saquinavir, tipranavir) are additive or synergistic against HIV-1 in vitro. There is no in vitro evidence of antagonistic antiretroviral effects between lamivudine and atazanavir or darunavir.

Darunavir

Pharmacokinetic interactions between ritonavir-boosted darunavir and lamivudine are not expected.

Fosamprenavir

Pharmacokinetic interactions did not occur when a single 600-mg dose of amprenavir (active metabolite of fosamprenavir) was used concomitantly with a single 150-mg dose of lamivudine.

Lopinavir

There was no evidence of clinically important pharmacokinetic interactions when the commercially available fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and lamivudine were used concomitantly.

Nelfinavir

Concomitant use of lamivudine (single 150-mg dose) and nelfinavir (750 mg every 8 hours for 7-10 days) increased the AUC and peak plasma concentration of lamivudine by 10 and 31%, respectively.

Tipranavir

In multiple-dose pharmacokinetic studies in HIV-infected individuals, concomitant use of ritonavir-boosted tipranavir and lamivudine did not have any clinically important effects on lamivudine pharmacokinetics.

Co-trimoxazole

In a crossover pharmacokinetic study in HIV-infected individuals, concomitant use of co-trimoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole once daily for 5 days) and lamivudine (single 300-mg dose) resulted in a 43% increase in the AUC of lamivudine, but did not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Data are not available regarding concomitant use of lamivudine and higher dosages of co-trimoxazole. Dosage adjustments are not necessary if lamivudine and co-trimoxazole are used concomitantly.

HCV Antivirals

HCV Protease Inhibitors

Simeprevir

No clinically important interactions are expected if simeprevir is used concomitantly with lamivudine.

Interferon and Peginterferon

In healthy adults who received multiple doses of lamivudine and a single dose of interferon, the AUC of lamivudine was decreased 10% (not considered clinically important) and there was no effect on the pharmacokinetics of interferon.

Potentially fatal hepatic decompensation has been reported in HIV-infected patients coinfected with hepatitis C virus (HCV) receiving antiretroviral therapy concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin. Patients receiving lamivudine concomitantly with interferon alfa (or peginterferon alfa) with or without ribavirin should be monitored closely for toxicities, especially hepatic decompensation, and consideration should be given to discontinuing lamivudine if medically appropriate. If worsening toxicities (e.g., hepatic decompensation with Child-Pugh scores greater than 6) occur, consideration should be given to also discontinuing or reducing dosage of interferon alfa (or peginterferon alfa) and/or ribavirin.

Opiates and Opiate Partial Agonists

Buprenorphine

There are no clinically important pharmacokinetic interactions between buprenorphine and lamivudine; dosage adjustments are not necessary if the drugs are used concomitantly.

Methadone

There are no clinically important pharmacokinetic interactions between methadone and lamivudine; dosage adjustments are not necessary if the drugs are used concomitantly.

Ribavirin

In vitro studies indicate that ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine. Although there was no evidence of pharmacokinetic or pharmacodynamic interactions (e.g., loss of virologic suppression of HIV-1 or HCV) in HIV-infected patients coinfected with HCV who were receiving both lamivudine and ribavirin, potentially fatal hepatic decompensation has been reported in patients coinfected with HIV and HCV receiving antiretroviral therapy and interferon alfa (or peginterferon alfa) with or without ribavirin.(See Drug Interactions: Interferon and Peginterferon.)

Pharmacokinetics

Absorption

Lamivudine is rapidly absorbed from the GI tract in patients with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection. In HIV-infected patients or healthy individuals, peak plasma concentrations are achieved within 0.5-2 hours after a single dose.

The absolute bioavailability of lamivudine tablets and oral solution is similar (86 and 87%, respectively, in HIV-infected adults). In HIV-infected pediatric patients 5 months to 12 years of age, the absolute bioavailability of the oral solution is 66%; the reason for lower bioavailability in infants and children compared with adults is unknown.

In a crossover study in healthy adults evaluating the steady-state pharmacokinetics of lamivudine administered in a once-daily regimen (300-mg tablet once daily) or twice-daily regimen (150-mg tablet twice daily), the area under the plasma concentration-time curve (AUC) was similar with both regimens; however, peak plasma concentrations were 66% higher and trough concentrations were 53% lower with the once-daily regimen compared with the twice-daily regimen.

Results of a single-dose study in healthy, fasting individuals indicate that the commercially available fixed-combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine (Combivir) is bioequivalent to a 150-mg lamivudine tablet and a 300-mg zidovudine tablet.

Results of a single-dose crossover study indicate that the commercially available tablet containing 300 mg of lamivudine and 600 mg of abacavir (Epzicom) is bioequivalent to two 150-mg tablets of lamivudine and two 300-mg tablets of abacavir administered at the same time.

Results of a cross-over study in fasting, healthy adults indicate that the commercially available fixed-combination tablet containing 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine (Trizivir) is bioequivalent to a 300-mg tablet of abacavir, a 150-mg tablet of lamivudine, and a 300-mg tablet of zidovudine administered simultaneously.

Food

Food does not appear to affect the AUC of lamivudine.

In a small study in HIV-infected patients, peak plasma concentrations of lamivudine were decreased 40% and the rate of absorption was reduced when lamivudine was administered with food, but clinically important decreases in systemic availability of the drug (AUC) were not observed.

Distribution

The apparent volume of distribution of lamivudine is 1.3 L/kg, suggesting that the drug distributes into extravascular spaces. The volume of distribution is independent of dose and does not correlate with body weight.

Lamivudine is distributed into CSF. In HIV-infected children who received oral lamivudine in a dosage of 8 mg/kg daily, CSF concentrations ranged from 0.04-0.3 mcg/mL and were 5.6-30.9% of concurrent serum concentrations.

Lamivudine crosses the placenta and is distributed into milk.

Lamivudine is less than 36% bound to plasma proteins.

Elimination

Metabolism is a minor route of elimination of lamivudine; the only known metabolite is the trans-sulfoxide metabolite. The majority of a lamivudine dose is eliminated unchanged in urine by active organic cationic secretion. Within 12 hours after an oral dose, approximately 5% is excreted in urine as the trans-sulfoxide metabolite.

Intracellularly, lamivudine is phosphorylated and converted by cellular enzymes to the active 5'-triphosphate metabolite.

In single-dose studies in healthy individuals or patients with HIV or HBV infection, the mean plasma half-life of lamivudine was 5-7 hours. The plasma half-life in HIV-infected children 4 months to 14 years of age is 2 hours.

The pharmacokinetics of lamivudine are not altered in patients with hepatic impairment.

In patients with impaired renal function, peak plasma concentrations, AUC, and plasma half-life of lamivudine are increased.

Hemodialysis increases lamivudine clearance; however, the length of time of hemodialysis (4 hours) is insufficient to substantially alter mean lamivudine exposure after a single dose of the drug. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. It is not known whether lamivudine is removed by continuous (24-hour) hemodialysis.

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