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lamivudine 300 mg tablet generic epivir

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Uses

Treatment of HIV Infection

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

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.(See Dual NRTI Options under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

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

If the dual NRTI option of lamivudine and abacavir is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection, a fixed-combination preparation containing both drugs (abacavir/lamivudine; Epzicom, generic) is commercially available and can be used in adults, adolescents, and pediatric patients weighing 25 kg or more.

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, generic) is commercially available and can be used alone or in conjunction with other antiretrovirals in adults, adolescents, and pediatric patients weighing 40 kg or more.(See All-NRTI Regimens under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.)

The fixed-combination preparation containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) is used alone as a complete treatment regimen or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adults, adolescents, and pediatric patients weighing 40 kg or more.

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

The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that the preferred dual NRTI options for use in most INSTI-, NNRTI-, and PI-based regimens recommended for initial treatment of HIV infection in antiretroviral-naive adults and adolescents are a tenofovir prodrug (either tenofovir alafenamide or tenofovir disoproxil fumarate [tenofovir DF]) and emtricitabine (or lamivudine). 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. If the dual NRTI option of abacavir and lamivudine is used in conjunction with other antiretrovirals, the fixed combination containing both drugs (abacavir/lamivudine) can be used in adults and adolescents weighing 25 kg or more.

The HHS panel states that 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 currently recommended dual NRTI options. However, zidovudine and lamivudine is recommended as an alternative (not a preferred) dual NRTI option for initial treatment regimens in antiretroviral-naive pregnant women(see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation) and is a preferred dual NRTI option for initial treatment regimens in certain 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) can be used in adults and adolescents weighing 30 kg or more.

A dual NRTI option of didanosine and lamivudine is not recommended for initial antiretroviral regimens because of inferior virologic efficacy, limited clinical trial experience in antiretroviral-naive patients, and didanosine-associated toxicities (e.g., pancreatitis, peripheral neuropathy).

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.

A tenofovir prodrug (either tenofovir alafenamide or 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, 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.

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 recommended for initial treatment of HIV infection in antiretroviral-naive adults or adolescents because such regimens have inferior virologic efficacy. 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. However, this triple NRTI regimen is not recommended for initial therapy in antiretroviral-naive adults and adolescents because of inferior virologic efficacy. If a triple NRTI regimen of abacavir, lamivudine, and zidovudine is used, the fixed-combination preparation containing these 3 NRTIs (abacavir/lamivudine/zidovudine) can be used in adults and adolescents weighing 40 kg or more. Clinicians should consider that data are limited regarding use of abacavir/lamivudine/zidovudine in patients with baseline viral loads exceeding 100,000 copies/mL.

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 suggested 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.

Once-daily Versus Twice-daily Lamivudine Regimen

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 are no longer 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.

All-NRTI Regimens

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 antiretrovirals for the treatment of HIV-1 infection in children 3 months of age or older. In addition, the drug is recommended for use in conjunction with other antiretrovirals for the treatment of HIV infection in neonates and infants younger than 3 months of age and for empiric HIV therapy for prevention of perinatal HIV transmission in neonates.(See Uses: Prevention of Perinatal HIV Transmission.)

Lamivudine/zidovudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients weighing 30 kg or more.

Abacavir/lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients weighing 25 kg or more.

Abacavir/lamivudine/zidovudine is used alone or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients weighing 40 kg or more.

Abacavir/dolutegravir/lamivudine is used alone or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients weighing 40 kg or more.

For initial treatment in antiretroviral-naive HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a ritonavir-boosted PI, NNRTI, or INSTI in conjunction with 2 NRTIs (dual NRTIs).

The HHS panel states that zidovudine and lamivudine (or emtricitabine) is a preferred dual NRTI option for use in initial treatment regimens in neonates, infants, and children younger than 12 years of age and an alternative dual NRTI option for use in adolescents 12 years of age or older with sexual maturity rating (SMR) 3. When the dual NRTI option of lamivudine and zidovudine is used, the fixed-combination preparation containing both drugs (lamivudine/zidovudine) can be used in pediatric patients weighing 30 kg or more.

These experts state that abacavir and lamivudine (or emtricitabine) is a preferred dual NRTI option in pediatric patients 3 months of age or older, including adolescents 12 years of age or older with SMR 1-3, but should be used only in those who are negative for HLA-B*5701.

The HHS panel states that tenofovir DF and lamivudine (or emtricitabine) is an alternative dual NRTI option for use in initial treatment regimens in adolescents with SMR 3. These experts state that, in special circumstances, tenofovir DF and lamivudine (or emtricitabine) also can be used in conjunction with other antiretrovirals for initial treatment regimens in children 2 years of age or older and in adolescents with SMR 1 or 2.

The HHS panel states that, in special circumstances, the dual NRTI option of didanosine and lamivudine (or emtricitabine) can be considered for initial treatment regimens in children 2 years of age or older and in adolescents with SMR 1 or 2.

Emtricitabine and lamivudine should not be used concomitantly at any time since the drugs have similar resistance profiles and no additive benefit.

Antiretroviral regimens that contain only NRTIs should not be used at any time for treatment of HIV infection in 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 is used in conjunction with other antiretrovirals for empiric HIV therapy in neonates for prevention of perinatal HIV transmission.

Although lamivudine has been used in some antepartum, intrapartum, and neonatal antiretroviral prophylaxis regimens for prevention of perinatal HIV transmission (e.g., resource-limited countries), lamivudine is not a component of intrapartum or neonatal prophylaxis regimens recommended in the US for prevention of perinatal HIV transmission. Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.

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 Pregnant Women with HIV Infection 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 further decrease the risk of perinatal HIV transmission, the HHS panel states that all pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated) and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an antiretroviral regimen (either prophylaxis or empiric HIV therapy) initiated as soon as possible after birth (preferably within 6-12 hours) and continued for 4-6 weeks. HIV-exposed neonates at low risk of perinatal HIV acquisition (e.g., those born to an HIV-infected mother who received standard multiple-drug antiretroviral treatment during pregnancy with sustained viral suppression near the time of delivery and with no concerns related to maternal adherence to the treatment regimen) can receive a prophylaxis regimen that includes only zidovudine. However, a combination antiretroviral regimen that includes zidovudine and 1 or 2 additional antiretrovirals should be used in neonates at higher risk of HIV acquisition, including those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery (i.e., detectable plasma HIV RNA levels), or had primary or acute HIV infection during pregnancy or during breast-feeding. This strategy of combined antepartum, intrapartum, and neonatal antiretrovirals reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant.

Antiretrovirals in HIV-exposed Neonates

The choice of a neonatal antiretroviral prophylaxis regimen or a neonatal empiric HIV therapy regimen should be based on an assessment of the likelihood of perinatal HIV transmission.

Although the HHS panel states that a 4-week zidovudine prophylaxis regimen can be used alone in HIV-exposed neonates at low risk, those at higher risk of HIV acquisition (e.g., those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, or received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery) should receive a 2-drug prophylaxis regimen that includes a 6-week zidovudine prophylaxis regimen and a 3-dose nevirapine prophylaxis regimen. Alternatively, the HHS panel states that neonates at highest risk can receive empiric HIV therapy with a 3-drug regimen of zidovudine, lamivudine, and nevirapine. The 3-drug empiric HIV therapy regimen serves as antiretroviral prophylaxis to prevent acquisition of HIV and also serves as early treatment for neonates who are later confirmed to have acquired HIV. The optimal duration of empiric HIV therapy in neonates at highest risk of HIV acquisition is unknown. Many experts recommend that the 3-drug regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if results of the neonate's HIV nucleic acid amplification test (NAAT) are negative, but recommend continuing zidovudine for 6 weeks.

Because safety and dosage data are not available, the HHS panel states that use of antiretrovirals other than zidovudine, lamivudine, and nevirapine cannot be recommended for premature HIV-exposed neonates (gestational age less than 37 weeks).

For information on the risk of perinatal transmission of HIV and additional information regarding recommendations for use of antiretroviral agents for prevention of perinatal HIV transmission,

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). 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); 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 that might contain HIV when that exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF). In adults and adolescents 13 years of age or older with impaired renal function (creatinine clearance 59 mL/minute or less), CDC recommends a regimen of either raltegravir or dolutegravir used in conjunction with zidovudine and lamivudine.

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 if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

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

Chronic Hepatitis B Virus Infection

Lamivudine is used for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of HBV replication and active liver inflammation in adults, adolescents, and pediatric patients 2 years of age or older.

Experts state that lamivudine is not considered a preferred antiviral for treatment of chronic HBV infection because a high rate of lamivudine-resistant HBV has been reported. 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 the 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), or HBV-infected patients coinfected with hepatitis C virus (HCV) or hepatitis D virus (HDV).

The goal of antiviral therapy in patients with chronic HBV infection is to decrease the morbidity and mortality related to the infection (e.g., cirrhosis, hepatic failure, hepatocellular carcinoma). Sustained suppression of HBV replication has been associated with normalization of serum ALT concentrations, loss of hepatitis B e antigen (HBeAg) with or without detection of antibody to HBeAg (anti-HBe), and improvement in liver histology. Currently available therapies for chronic HBV infection (e.g., adefovir, entecavir, lamivudine, telbivudine, tenofovir alafenamide, tenofovir DF, interferon alfa, peginterferon alfa) are used in an attempt to provide an immunologic cure (hepatitis B surface antigen [HBsAg] loss and sustained HBV DNA suppression), but cannot provide a virologic cure (eradication of HBV).

Treatment of chronic HBV infection is complex and evolving, and specialized references and experts should be consulted. Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of HBV infection, including recommendations for initial treatment, is available at https://www.aasld.org.

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 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 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 the 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, generic). The 150-mg scored tablets are the preferred preparation in pediatric patients who weigh 14 kg or more and can swallow tablets.(See Cautions: Pediatric Precautions.) The oral solution should be used in those unable to safely and reliably swallow tablets. Lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection.

For the 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, generic). The 5-mg/mL oral solution should be used in patients requiring a dosage less than 100 mg and in children unable to reliably swallow tablets.

Lamivudine preparations labeled by FDA for treatment of chronic HBV infection should not be used in HIV-infected patients because they contain a lower dosage of the drug than that required for treatment of HIV-1 infection. If such preparations are 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 the treatment of HIV infection, lamivudine is commercially available in fixed-combination tablets containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir, generic), fixed-combination tablets containing abacavir and lamivudine (abacavir/lamivudine; Epzicom, generic), fixed-combination tablets containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir, generic), and fixed-combination tablets containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq).

Lamivudine/zidovudine 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 less than 50 mL/minute), patients with hepatic impairment, or patients who experience dose-limiting adverse effects.

Abacavir/lamivudine 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 pediatric patients weighing less than 25 kg, patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute), or patients with hepatic impairment (contraindicated in those with moderate or severe hepatic impairment).

Abacavir/lamivudine/zidovudine 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 one 300-mg abacavir tablet, one 150-mg lamivudine tablet, and one 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 weighing less than 40 kg, patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute), patients with hepatic impairment (contraindicated in those with moderate or severe hepatic impairment), or others requiring dosage adjustment.

Abacavir/dolutegravir/lamivudine tablets are administered orally once daily without regard to meals. A fixed-combination tablet containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine is bioequivalent to one 50-mg tablet of dolutegravir administered simultaneously with one fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine. Abacavir/dolutegravir/lamivudine 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 weighing less than 40 kg, patients with renal impairment (i.e., creatinine clearance less than 50 mL/minute), or patients with hepatic impairment (contraindicated in those with moderate or severe hepatic impairment).

Dosage

Treatment of HIV Infection

Adult Dosage

The usual dosage of lamivudine for the treatment of HIV-1 infection in adults is 150 mg twice daily or 300 mg once daily.

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

When abacavir/lamivudine is used for the treatment of HIV-1 infection in adults, the recommended dosage is 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily.

When abacavir/lamivudine/zidovudine is used for the treatment of HIV-1 infection in adults weighing 40 kg or more, the recommended dosage is 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) twice daily.

When abacavir/dolutegravir/lamivudine is used for the treatment of HIV-1 infection in adults weighing 40 kg or more, the recommended dosage is 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily. If abacavir/dolutegravir/lamivudine is used in those receiving concomitant therapy with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin, patients should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.

Pediatric Dosage

When lamivudine oral solution containing 10 mg/mL is used for the treatment of HIV-1 infection in pediatric patients 3 months of age or older, the recommended dosage is 5 mg/kg twice daily or 10 mg/kg once daily (up to 300 mg daily).

When lamivudine 150-mg scored tablets are used in pediatric patients 3 months of age or older who weigh 14 kg or more and are able to swallow tablets, the recommended dosage is based on weight (see Table 1 and Table 2). Data regarding efficacy of the once-daily regimen of lamivudine given as 150-mg scored tablets in pediatric patients 3 months of age or older is limited to those who transitioned from a twice-daily regimen to a once-daily regimen after 36 weeks of treatment.

Table 1. Twice-daily Lamivudine for Treatment of HIV-1 Infection in Pediatric Patients Weighing at least 14 kg (150-mg Tablets)[1 ]
Weight (kg) AM Dose PM Dose
14 to <20 75 mg (half of 150-mg tablet) 75 mg (half of 150-mg tablet)
20 to <25 75 mg (half of 150-mg tablet) 150 mg (one 150-mg tablet)
>=25 150 mg (one 150-mg tablet) 150 mg (one 150-mg tablet)
Table 2. Once-daily Lamivudine for Treatment of HIV-1 Infection in Pediatric Patients Weighing at least 14 kg (150-mg Tablets)[1 ]
Weight (kg) Once-daily Dose
14 to <20 150 mg (one 150-mg tablet)
20 to <25 225 mg (one and one-half 150-mg tablets)
>=25 300 mg (two 150-mg tablets or one 300-mg tablet)

Some experts state that adolescents weighing less than 25 kg should receive lamivudine in a dosage of 4 mg/kg (up to 150 mg) twice daily and those weighing 25 kg or more should 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 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. These experts state that once-daily regimens of lamivudine oral solution are not generally recommended in infants and young children.

When lamivudine/zidovudine is used for the treatment of HIV-1 infection in pediatric patients weighing 30 kg or more, the recommended dosage is 1 tablet (150 mg of lamivudine and 300 mg of zidovudine) twice daily.

When abacavir/lamivudine/zidovudine is used for the treatment of HIV-1 infection in pediatric patients weighing 40 kg or more, the recommended dosage is 1 tablet (300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine) orally twice daily.

When abacavir/lamivudine is used for the treatment of HIV-1 infection in pediatric patients weighing 25 kg or more, the recommended dosage is 1 tablet (600 mg of abacavir and 300 mg of lamivudine) once daily.

When abacavir/dolutegravir/lamivudine is used for the treatment of HIV-1 infection in pediatric patients weighing 40 kg or more, the recommended dosage is 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) orally once daily. If abacavir/dolutegravir/lamivudine is used in those receiving concomitant therapy with efavirenz, ritonavir-boosted fosamprenavir, ritonavir-boosted tipranavir, carbamazepine, or rifampin, patients should receive 1 tablet of the fixed combination (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir given once daily 12 hours after the daily dose of the fixed combination.

Prevention of Perinatal HIV Transmission

Pediatric Dosage

When empiric HIV therapy is used for prevention of perinatal HIV transmission in neonates at highest risk of HIV acquisition (see Uses: Prevention of Perinatal HIV Transmission), a 3-drug antiretroviral regimen of zidovudine, lamivudine, and nevirapine is recommended and should be initiated as soon as possible after birth (within 6-12 hours).

For empiric HIV therapy in HIV-exposed neonates, experts recommend that lamivudine be given in a dosage of 2 mg/kg twice daily from birth to 4 weeks of age followed by 4 mg/kg twice daily from 4-6 weeks of age.

Optimal duration of empiric HIV therapy in HIV-exposed neonates at highest risk of HIV acquisition is unknown. Many experts recommend that the 3-drug regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if results of the neonate's HIV nucleic acid amplification test (NAAT) are negative, but recommend continuing zidovudine for 6 weeks.

Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding selection of antiretrovirals, including dosage considerations, for prevention of perinatal HIV transmission.

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 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) in individuals with impaired renal function (creatinine clearance 59 mL/minute or less), lamivudine usually is used in conjunction with zidovudine and either raltegravir or dolutegravir.(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.) Lamivudine dosage should be adjusted based on the degree of renal impairment.

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days. If it has been more than 72 hours since the exposure, nPEP is not recommended.

Chronic Hepatitis B Virus Infection

For the 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. 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 (100-mg tablets or oral solution containing 5 mg/mL) is used for the treatment of chronic HBV infection in adults, the recommended dosage is 100 mg once daily.

Pediatric Dosage

When lamivudine (100-mg tablets or oral solution containing 5 mg/mL) is used for the treatment of chronic HBV infection in children 2 years of age or older, 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.

Patients receiving lamivudine for treatment of chronic HBV infection should be monitored regularly 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 lamivudine therapy.

Patients should be informed that deterioration of liver disease has been reported following discontinuance of lamivudine therapy, and that they should discuss any change in regimen with their clinician. Patients also should be informed that emergence of lamivudine-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

Treatment of HIV Infection

Because lamivudine pharmacokinetics are not affected by hepatic impairment, dosage adjustments are not necessary when lamivudine is used for the treatment of HIV infection in patients with hepatic impairment. However, safety and efficacy have not been established in those with decompensated liver disease.

Because elimination of lamivudine may be reduced in patients with renal impairment, dosage of the drug should be decreased in those with creatinine clearances less than 50 mL/minute. If lamivudine is used for the treatment of HIV infection in adults and adolescents weighing 25 kg or more with impaired renal function, dosage of the drug should be adjusted based on creatinine clearance.(See Table 3.) 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.

Table 3. Lamivudine Dosage for Treatment of HIV-1 Infection in Adults and Adolescents with Renal Impairment Weighing 25 kg or More.[1 ]
Creatinine Clearance (mL/minute) Dosage
30-49 150 mg once daily
15-29 150 mg first dose, then 100 mg once daily
5-14 150 mg first dose, then 50 mg once daily
<5 50 mg first dose, then 25 mg once daily
Hemodialysis patients Supplemental doses unnecessary after routine (4-hour) hemodialysis
Peritoneal dialysis patients Supplemental doses unnecessary after peritoneal dialysis

Lamivudine/zidovudine should not be used for the treatment of HIV infection in patients with renal impairment (creatinine clearance less than 50 mL/minute) or in patients with hepatic impairment.

Abacavir/lamivudine, abacavir/lamivudine/zidovudine, and abacavir/dolutegravir/lamivudine should not be used for the treatment of HIV infection in patients with renal impairment (creatinine clearance less than 50 mL/minute) or in patients with hepatic impairment. Abacavir/lamivudine, abacavir/lamivudine/zidovudine, and abacavir/dolutegravir/lamivudine are contraindicated in those with moderate or severe hepatic impairment.

Chronic Hepatitis B Virus Infection

Dosage adjustments are not necessary when lamivudine is used for the treatment of chronic HBV infection in patients with hepatic impairment. However, safety and efficacy have not been established in those with decompensated liver disease.

If lamivudine is used for treatment of chronic HBV infection in adults with impaired renal function, dosage of the drug should be adjusted based on creatinine clearance.(See Table 4.) The manufacturer states that data are insufficient to make specific dosage recommendations for pediatric patients with renal impairment.

Table 4. Lamivudine Dosage for the Treatment of Chronic HBV Infection in Adults with Renal Impairment.[18 ]
Creatinine Clearance (mL/minute) Dosage
30-49 100 mg first dose, then 50 mg once daily
15-29 100 mg first dose, then 25 mg once daily
5-14 35 mg first dose, then 15 mg once daily
<5 35 mg first dose, then 10 mg once daily
Hemodialysis patients Supplemental doses unnecessary after routine (4-hour) hemodialysis
Peritoneal dialysis patients Supplemental doses unnecessary after 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.

When the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir, generic), fixed combination containing abacavir and lamivudine (abacavir/lamivudine; Epzicom, generic), fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine; Trizivir, generic), or fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq) 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) and other antiretrovirals. 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

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) also have been reported to occur in the setting of immune reconstitution; however, 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 is contraindicated in patients with a history of hypersensitivity to the drug.

Lamivudine/zidovudine is contraindicated in patients with a history of hypersensitivity to lamivudine or zidovudine.

Abacavir/lamivudine is contraindicated in patients who have the human leukocyte antigen (HLA)-B*5701 allele; patients with a history of hypersensitivity to abacavir or lamivudine; and patients with moderate or severe hepatic impairment.

Abacavir/lamivudine/zidovudine is contraindicated in patients who have the HLA-B*5701 allele; patients with a history of hypersensitivity to abacavir, lamivudine, or zidovudine; and patients with moderate or severe hepatic impairment.

Abacavir/dolutegravir/lamivudine is contraindicated in patients who have the HLA-B*5701 allele; patients with a history of hypersensitivity to abacavir, dolutegravir, or lamivudine; patients receiving dofetilide; and patients with moderate or severe hepatic impairment.

Because lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving nucleoside analogs and other antiretrovirals (see Cautions: Hepatic Effects and Lactic Acidosis), lamivudine and fixed combinations containing lamivudine should be discontinued 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 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 to immediately contact a clinician if they have any signs or symptoms of infection since inflammation from previous infections may occur soon after antiretroviral therapy is initiated.(See Cautions: Immune Reconstitution Syndrome.)

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; decreased dosage is recommended in such patients. Lamivudine dosage adjustments are recommended based on the degree of renal impairment.(See Dosage: Dosage in Renal and Hepatic Impairment.)

Individuals with diabetes mellitus and/or their caregivers should be informed that lamivudine oral solutions contain 200 mg of sucrose per 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

Patients should be advised of the importance of adhering to the prescribed antiretroviral regimen and the importance of remaining under the care of 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., consistent use of condoms).

Patients receiving lamivudine with peginterferon alfa (or interferon alfa) with or without ribavirin should be closely monitored for toxicity, especially hepatic decompensation, neutropenia, and anemia. HIV-infected patients coinfected with HCV should be informed that hepatic decompensation (sometimes fatal) has been reported when antiretrovirals were used concomitantly with interferon alfa with or without ribavirin.(See Drug Interactions: Interferon Alfa and Peginterferon Alfa.)

Precautions Related to Treatment of Chronic HBV Infection

Prior to and periodically during lamivudine therapy for treatment of chronic HBV infection, all patients should be offered HIV counseling and testing. Lamivudine preparations labeled by FDA for treatment of chronic HBV infection should not be used in patients coinfected with HIV since they contain a lower dose of lamivudine than preparations labeled for treatment of HIV-1 infection. If lamivudine preparations labeled for treatment of chronic HBV infection are used in patients with unrecognized or untreated HIV infection, rapid emergence of lamivudine-resistant HIV may occur and limit antiretroviral treatment options. If a decision is made to use lamivudine in patients coinfected with HBV and HIV, the drug should be used in dosages recommended for treatment of HIV infection and in conjunction with other antiretrovirals.

Patients receiving lamivudine for treatment of chronic HBV infection should be monitored regularly 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 the long-term benefits of lamivudine therapy in patients with chronic HBV infection are unknown at this time and that the relationship between treatment response and 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.

Lamivudine should not be used concomitantly with any preparation containing lamivudine or emtricitabine.

Precautions Related to Use of Fixed Combinations

When lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine, or abacavir/dolutegravir/lamivudine 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. For cautionary information related to , , or , see Cautions in the individual drug monographs.

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

If abacavir/lamivudine, abacavir/lamivudine/zidovudine, or abacavir/dolutegravir/lamivudine is used, clinicians should consider that serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have been reported in patients receiving abacavir or fixed combinations containing abacavir. Prior to initiation or reinitiation of abacavir/lamivudine, abacavir/lamivudine/zidovudine, or abacavir/dolutegravir/lamivudine, all patients should be screened for the HLA-B*5701 allele, unless there is documentation of a previous HLA-B*5701 allele assessment. The patient's medical history also should be reviewed for prior exposure to any abacavir-containing preparation. Abacavir-containing preparations are contraindicated in individuals who test positive for HLA-B*5701. Such individuals are at higher risk for hypersensitivity reactions; however, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele. Abacavir/lamivudine, abacavir/lamivudine/zidovudine, or abacavir/dolutegravir/lamivudine should be discontinued immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even if other diagnoses are possible. 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 (150-mg scored tablets, 300-mg tablets, oral solution containing 10 mg/mL) in conjunction with other antiretroviral agents for treatment of HIV infection have been established in children 3 months of age or older. Because there is some evidence that use of lamivudine oral solution in pediatric patients is associated with lower rates of virologic suppression, lower plasma lamivudine exposures, and more frequent emergence of lamivudine-resistant HIV-1, the 150-mg scored tablets are the preferred preparation in pediatric patients who weigh 14 kg or more and can swallow tablets.

Safety and efficacy of lamivudine (100-mg tablets, oral solution containing 5 mg/mL) for treatment of chronic HBV infection have been established in children 2 years of age or older. 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 should not be used in pediatric patients weighing less than 30 kg.

Abacavir/lamivudine should not be used in pediatric patients weighing less than 25 kg.

Abacavir/lamivudine/zidovudine should not be used in pediatric patients weighing less than 40 kg.

Abacavir/dolutegravir/lamivudine should not be used in pediatric patients 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. Lamivudine and fixed combinations containing lamivudine should be used with caution in geriatric patients because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, an in vitro cell transformation assay, a rat micronucleus test, a rat bone marrow cytogenetic assay, and an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses up to 2 g/kg that produced plasma concentrations 35-45 times higher than those attained in humans receiving dosages recommended for treatment of 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

Lamivudine crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.

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.

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Registry data include over 11,000 prospective reports of lamivudine exposures during pregnancy resulting in live births, including over 4300 first-trimester exposures to the drug.

Reproduction studies in rats or rabbits using oral lamivudine dosages that resulted in plasma concentrations up to approximately 35 times higher than plasma concentrations attained with the recommended human dosage used for the treatment of HIV infection in adults have not revealed evidence of teratogenicity. Although there was evidence of early embryolethality in rabbits at exposure levels similar to those observed in humans, this effect was not seen in rats at exposure levels up to 35 times higher than those in humans.

The US Department of Health and Human Services (HHS) Panel on Treatment of Pregnant Women with HIV Infection 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 abacavir and lamivudine (should be used only in those negative for HLA-B*5701) or tenofovir DF and emtricitabine (or lamivudine). Tenofovir DF and emtricitabine (or lamivudine) is the preferred dual NRTI option for treatment of HIV-1 infection in pregnant women coinfected with HBV. These experts state that zidovudine and lamivudine is an alternative dual NRTI option for initial regimens used for treatment of HIV infection in antiretroviral-naive pregnant women.

The American Association for the Study of Liver Diseases (AASLD) and other experts state that recommendations regarding use of antiviral therapy for the management of HBV infection in pregnant women generally are the same as those for other adults. AASLD suggests that hepatitis B surface antigen (HBsAg)-positive pregnant women with HBV DNA levels exceeding 200,000 IU/mL receive antiviral therapy since this may reduce the risk of perinatal transmission of HBV; however, preferred antiviral agents, exact viral load threshold, and optimal gestational week during the third trimester to initiate such therapy have not been clearly identified. Routine screening for HBV infection is recommended for all pregnant women. For prevention of perinatal transmission of HBV, US Public Health Service Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), and other experts state that infants born to HBsAg-positive women should receive their first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth.

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 47-70 times higher than those seen in humans receiving the recommended dosage for treatment of HIV infection or 70-104 times higher than those reported in humans receiving the usually recommended dosage for treatment of chronic HBV infection.

Lactation

Lamivudine is distributed into milk in humans. It is not known whether the drug affects human milk production or affects the breast-fed infant.

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the HHS Panel and the US Centers for Disease Control and Prevention (CDC) recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from lamivudine in nursing infants, women should be instructed not to breast-feed while they are receiving lamivudine, lamivudine/zidovudine, abacavir/lamivudine, abacavir/lamivudine/zidovudine, or abacavir/dolutegravir/lamivudine.

If lamivudine is being used for treatment of chronic HBV infection, the benefits of breast-feeding and the importance of lamivudine to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Drug Interactions

The following drug interactions are based on studies using lamivudine. When the fixed combination containing lamivudine and zidovudine (lamivudine/zidovudine), fixed combination containing abacavir and lamivudine (abacavir/lamivudine), fixed combination containing abacavir, lamivudine, and zidovudine (abacavir/lamivudine/zidovudine), or fixed combination containing abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine) is used, interactions associated with each drug in the fixed combination should be considered.

Drugs Affecting or Affected by Membrane Transporters

Based on in vitro studies, lamivudine at clinically important concentrations is not expected to affect the pharmacokinetics of drugs that are substrates of organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE) 1 or MATE2-K, organic cation transporter (OCT) 1, OCT2, or OCT3.

Lamivudine is a substrate of P-gp and BCRP; however, it is unlikely that these transporters play a clinically important role in absorption of lamivudine. Therefore, concomitant use of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro.

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 does not have a clinically important 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.

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

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

In vitro studies indicate that the antiretroviral effects of lamivudine and delavirdine or efavirenz may be additive or synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between lamivudine and etravirine, nevirapine, 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

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. emtricitabine, stavudine, tenofovir) are additive to synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between lamivudine and abacavir.

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 if lamivudine is used concomitantly with zidovudine.

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.

Atazanavir

Concomitant use of atazanavir and lamivudine does not result in clinically important interactions.

No clinically important pharmacokinetic interactions were reported when unboosted atazanavir (400 mg once daily) was used concomitantly with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily).

Darunavir

Concomitant use of ritonavir-boosted darunavir and lamivudine does not result in clinically important interactions.

Dosage adjustments are not needed if ritonavir-boosted darunavir is used concomitantly with lamivudine.

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.

HCV Antivirals

HCV Polymerase Inhibitors

Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir

Concomitant use of lamivudine and the fixed combination of dasabuvir sodium, ombitasvir, paritaprevir, and ritonavir (dasabuvir/ombitasvir/paritaprevir/ritonavir) or fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir sodium does not result in clinically important interactions.

Dosage adjustments are not needed if lamivudine is used concomitantly with dasabuvir/ombitasvir/paritaprevir/ritonavir (fixed combination) or ombitasvir/paritaprevir/ritonavir with dasabuvir (copackaged).

HCV Protease Inhibitors

Glecaprevir and Pibrentasvir

Concomitant use of lamivudine and the fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) does not result in clinically important interactions.

Dosage adjustments are not needed if lamivudine is used concomitantly with glecaprevir/pibrentasvir.

Simeprevir

Clinically important pharmacokinetic interactions are not expected if simeprevir is used concomitantly with lamivudine.

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

Clinically important interactions are not expected if lamivudine is used concomitantly with the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir).

Ledipasvir and Sofosbuvir

Clinically important pharmacokinetic interactions are not expected if lamivudine is used concomitantly with the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir).

Interferon Alfa and Peginterferon Alfa

Concomitant use of interferon alfa and lamivudine does not result in clinically important pharmacokinetic interactions. 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 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 immediately 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.

Ribavirin

In vitro studies indicate that ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs, including lamivudine. Ribavirin has decreased the in vitro antiretroviral activity of 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 with or without ribavirin.(See Drug Interactions: Interferon Alfa and Peginterferon Alfa.)

Sorbitol

Concomitant use of sorbitol and lamivudine results in a sorbitol dose-dependent decrease in lamivudine exposures. When healthy adults received a single 300-mg dose of lamivudine oral solution alone or in conjunction with a single 3.2-, 10.2-, or 13.4-g dose of sorbitol in solution, peak plasma concentrations of lamivudine were decreased 28, 52, or 55%, respectively, and the AUC of lamivudine was decreased 20, 39, or 44%, respectively.

Concomitant use of lamivudine and sorbitol-containing preparations should be avoided whenever possible. If chronic concomitant use of sorbitol cannot be avoided in patients receiving lamivudine for the treatment of chronic HBV infection, more frequent monitoring of HBV viral load should be considered.

Trimethoprim

Trimethoprim has been shown to increase lamivudine plasma concentrations. However, this interaction is not considered clinically important and lamivudine dosage adjustments are not needed.

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 150-mg scored tablets and oral solution in adults is similar (86 and 87%, respectively). 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.

The absolute bioavailability of lamivudine tablets and lamivudine oral solution is lower in children than in adults. In addition, the relative bioavailability of the oral solution is approximately 40% lower than that of the tablets in children, despite no difference between the preparations in adults. It has been suggested that lower lamivudine exposures reported in pediatric patients receiving lamivudine oral solution are likely due to an interaction between lamivudine and concomitant solutions containing sorbitol (e.g., abacavir oral solution).(See Drug Interactions: Sorbitol.) Data from pharmacokinetic studies evaluating once- and twice-daily lamivudine regimens in HIV-1-infected pediatric patients 3 months through 12 years of age indicate that AUCs attained with once-daily regimens were similar to those attained with twice-daily regimens when comparing the dosage regimens within the same formulation (i.e., either tablets or the oral solution). However, mean peak plasma concentrations were approximately 80-90% higher with once-daily lamivudine regimens compared with twice-daily lamivudine regimens.

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 (lamivudine/zidovudine) is bioequivalent to one 150-mg lamivudine tablet and one 300-mg zidovudine tablet given simultaneously.

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

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 (abacavir/lamivudine/zidovudine) is bioequivalent to one 300-mg tablet of abacavir, one 150-mg tablet of lamivudine, and one 300-mg tablet of zidovudine administered simultaneously.

Results of a study in healthy, fasting individuals indicate that the commercially available fixed-combination tablet containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine (abacavir/dolutegravir/lamivudine) is bioequivalent to one 50-mg tablet of dolutegravir administered simultaneously with one fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine (abacavir/lamivudine).

Pharmacokinetics of lamivudine in pregnant women are similar to that reported in nonpregnant adults and postpartum women.

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 cord blood and amniotic fluid. Lamivudine concentrations in amniotic fluid are typically twofold higher than maternal serum concentrations and have ranged from 1.2-2.5 mcg/mL or 2.1-5.2 mcg/mL when lamivudine dosage in the mother was 150 or 300 mg twice daily, respectively.

Lamivudine is distributed into milk.

Lamivudine is less than 36% bound to plasma proteins.

Elimination

Lamivudine is not substantially metabolized by cytochrome P-450 (CYP) isoenzymes. 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.

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