LAMIVUDINE HBV (Generic for EPIVIR HBV)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered with or without food. Food decreases the rate, but not the extent, of oral absorption.
-The scored tablet is the preferred dosage formulation in pediatric patients able to take a solid dosage form due to lower virologic suppression rates and increased risk of viral resistance with the oral solution as a result of an interaction with sorbitol-containing medicines. Consider increased monitoring of viral load when using the oral solution.
Oral Liquid Formulations
-Administer using a calibrated oral syringe to give an accurate dosage.
-Avoid chronic coadministration of lamivudine oral solution with sorbitol-containing medicines as decreased lamivudine concentrations may occur.

In trials of pediatric patients with HBV infection, the commonly observed side effects were similar to those of adult patients.

The safety profile of once-daily lamivudine dosing for HIV infection has been shown to be comparable to that of twice-daily dosing. In a randomized multicenter trial (ARROW), the frequency of Grade 3 and 4 adverse events was similar in patients who received once-daily dosing compared with patients who received twice-daily dosing.

During lamivudine clinical trials, ear pain (otalgia), discharge, redness, and swelling were reported in 7% of pediatric HIV patients and nasal discharge (rhinorrhea) or nasal congestion was noted in 8% of pediatric HIV patients. Cough (15%) and wheezing (7%) were also noted in pediatric HIV patients. Respiratory infection and sepsis have been reported in neonates as well. During lamivudine therapy for hepatitis B infection, ear, nose and throat infections were reported in 25% of adults, while sore throat was reported in 13% of adult patients. Nasal signs and symptoms occurred in 20% of adult HIV patients receiving lamivudine.

Elevated hepatic enzymes were reported in 1% to 2% of pediatric HIV patients, including neonates, during lamivudine clinical trials. Jaundice has also been reported in neonates in clinical trials. Hyperbilirubinemia (bilirubin greater than 2.5-times the upper limit of normal) has been reported in 0.8% of adult HIV patients treated with lamivudine plus zidovudine. There have been reports of severe acute hepatitis B exacerbation in patients with HBV and HIV coinfection after the discontinuation of lamivudine; close monitoring of clinical signs and symptoms (i.e., jaundice), including laboratory monitoring, are recommended for several months following discontinuation. Typically, this is associated with a return of HBV DNA and increases in ALT concentrations towards pre-treatment values, and with mild ALT flares (2-times or more of the patient's baseline ALT). Patients receiving lamivudine for HBV only had fewer clinically notable post-treatment recurrences of hepatitis (i.e., peak ALT greater than 500 International Units/mL or elevation of serum bilirubin) than patients receiving lamivudine for both HBV and HIV. Recurrence was usually noted within 3 months after discontinuation and is usually self-limited, although some fatalities have been reported. The casual relationship of discontinuation of lamivudine to the recurrence of HBV infection is not known. There is insufficient evidence to determine whether re-initiation of therapy alters the course of posttreatment exacerbations of hepatitis.

Fever was reported in 25% of pediatric patients during lamivudine trials. In adult patients, headache is the most common adverse event reported in patients receiving the combination of lamivudine plus zidovudine (35%) for HIV infection. Other generalized reactions in HIV and/or HBV adult patients included depression (9%), dizziness (10%), insomnia and other sleep disorders (11%), malaise and fatigue (27%), fever or chills (10%), and weakness (post-marketing).

In pediatric patients receiving lamivudine in clinical trials, GI effects included nausea/vomiting (8%), diarrhea (8%), and stomatitis (6%). One neonate died from gastroenteritis with acidosis and convulsions, while 2 other non fatal cases of gastroenteritis and diarrhea were reported. Other GI effects reported in adult trials include abdominal pain and discomfort (9%), anorexia/decreased appetite (10%), abdominal cramps (6%), and dyspepsia (5%). Hyperglycemia was noted in post-marketing reports.

Lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors, including lamivudine. Many of these cases have occurred in women. Hepatomegaly has also been reported in pediatric (11%) and neonatal HIV patients. There have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. If a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity while receiving lamivudine, the drug should be discontinued.

In one patient receiving zalcitabine/zidovudine therapy, mild paresthesia developed after zalcitabine was discontinued and lamivudine was added to the regimen. Within 3 weeks, painful burning paresthesias developed, increasing in intensity as therapy with lamivudine continued. Following discontinuation of lamivudine, the patient's condition improved. In pediatric HIV trials, paresthesias and peripheral neuropathy were reported in up to 15% of patients.

Arthralgia (5%), myalgia (8%), and musculoskeletal pain (12%) have been reported in adult HIV patients treated with lamivudine/zidovudine combination therapy. Rhabdomyolysis, CPK elevation, and muscle cramps have been reported with lamivudine during post-marketing reports.

Skin rash (unspecified) has been reported in 12% of pediatric HIV patients during lamivudine trials. Alopecia has been reported as an adverse reaction during post-marketing reports. One study, which investigated lamivudine use in patients previously intolerant of other antiretroviral agents, found that 5 of 16 patients voluntarily reported unusual hair loss. Hair loss can be associated with HIV infection. Other reactions reported during post-marketing reports include anaphylactoid reactions, pruritus, and urticaria.

Pancreatitis has been reported with the use of lamivudine. Children with a history of pancreatitis or other significant risk factors are most vulnerable and fatalities have been reported. In clinical trials, pancreatitis has been reported in 0.4-18% of pediatric HIV patients. Lamivudine therapy should be terminated if any clinical signs or symptoms of pancreatitis develop, or if laboratory abnormalities suggest pancreatitis. Hyperamylasemia has been reported in 3% of pediatric HIV patients, while elevated lipase has been noted in 3% of pediatric HIV patients.

While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome consisting of redistribution/accumulation of body fat has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes lamivudine.

Splenomegaly (5%) and lymphadenopathy (9%) were observed in pediatric HIV patients receiving lamivudine during clinical trials, and have been reported during postmarketing use for the treatment of hepatitis B infection (Epivir-HBV).

Limited short-term safety information is available from two small, uncontrolled studies in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at week 38 or 36 of gestation. Electrolyte disturbances and hypoglycemia were reported. One infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse events comparable to those reported in pediatric and adult HIV-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.

Severe anemia associated with pure red cell aplasia has been observed during post-marketing reports with lamivudine. Decreased hemoglobin (< 7 g/dL) was noted in 4% of pediatric HIV patients while neutropenia (ANC < 400/mm3) was reported in 8% of pediatric HIV patients. Thrombocytopenia (platelets < 50,000/mm3) was noted in 1% of pediatric HIV patients.

Avoid chronic coadministration of lamivudine oral solution and sorbitol-containing medications if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine, respectively.

Unplanned lamivudine therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake, or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Lamivudine is available in 2 formulations, Epivir and Epivir-HBV. Epivir is indicated for use as part of a fully suppressive antiretroviral (ARV) regimen to treat HIV-infected patients, whereas Epivir-HBV is approved to treat patients infected with the hepatitis B virus (HBV). Prior to and during use of the Epivir-HBV formulation, all patients should be offered HIV counseling and have their HIV serum status determined. If Epivir-HBV is administered to patients who have unrecognized or untreated HIV infection, or who acquire HIV infection during treatment, the virus may rapidly develop resistance to lamivudine, thereby limiting potential treatment options. Similarly, HBV screening is recommended for any patient who presents with HIV infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive ARV regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. Patients with hepatitis B and HIV coinfection have been reported to experience clinical or laboratory evidence of hepatitis B exacerbation upon discontinuation of lamivudine.

The scored tablet is the preferred dosage formulation in children and adolescents able to take a solid dosage form due to lower virologic suppression rates and increased risk of viral resistance with the oral solution. Additionally, the tablet formulation is preferred when possible to avoid an interaction between lamivudine oral solution and sorbitol-containing medications. Consider increased monitoring of viral load when using the oral solution in all pediatric patients, including infants and neonates.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

The safety and efficacy of Epivir-HBV have not been established in patients with decompensated hepatic disease or organ transplant, and patients dually infected with hepatitis B virus (HBV) and hepatitis C virus, or hepatitis delta. Hepatotoxicity or lactic acidosis, including fatal cases, has been reported with the use of nucleoside analogs, including lamivudine. Adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk also applies to pediatric females. In addition, obesity may also be a risk factor for nucleoside analog-induced lactic acidosis and hepatotoxicity. Most of these reports describe patients receiving lamivudine for HIV treatment, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Lamivudine should be used with caution in patients with hepatic disease or in those with known risk factors for liver disease (e.g., alcoholism); however, cases of lactic acidosis or liver problems have been reported in patients with no risk factors. Discontinue treatment 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 transaminases. After discontinuation of lamivudine in patients with HBV and/or HIV infection, some patients experienced clinical or laboratory evidence of recurrent hepatitis, which has been fatal in some cases. This reaction may be more severe in patients with decompensated hepatic disease. Thus, closely monitor patients for several months after stopping lamivudine therapy for hepatitis B.

Patients with peripheral neuropathy can experience exacerbations during lamivudine therapy.

Lamivudine is primarily excreted unchanged in the urine. Patients with renal impairment have an increased lamivudine half-life. Lamivudine should be used with caution in patients with impaired renal function, including renal failure, and dosage adjustments are required.

There appears to be a significant risk of pancreatitis in pediatric patients treated with lamivudine. In children with a history of pancreatitis or other significant risk factors for pancreatitis, lamivudine should be used with extreme caution and only if there is no satisfactory alternative. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Patients with diabetes mellitus should be warned that the Epivir formulation of lamivudine oral solution contains 3 grams of sucrose in each 15-ml dose and the Epivir-HBV formulation of lamivudine oral solution contains 4 grams of sucrose in each 20-ml dose.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop in the setting of immune reconstitution; the time to onset is variable and may occur months after treatment initiation.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when lamivudine is used either alone or in combination with other agents. Monotherapy with lamivudine is not recommended. Prior to beginning lamivudine therapy for HBV, patients should be tested for HIV infection to avoid inappropriate therapy and development of resistant HIV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with a diminished response. Emergence of HBV variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV.

Description: Lamivudine (3TC) is a synthetic nucleoside analog, classified as a nucleoside reverse transcriptase inhibitor (NRTI). It is used as an antiviral agent in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Lamivudine is similar in structure to other nucleoside analogs such as zidovudine, zalcitabine, and didanosine. Although it is initially effective as monotherapy for HIV infection, resistance develops within 12 weeks; therefore the optimal use of lamivudine is as part of a 3-drug regimen. Most lamivudine-treated patients showed a decrease of hepatitis B virus (HBV) DNA below the level of detection; however, after an initial response, approximately one-third of patients had reappearance of HBV DNA during treatment. Due to high rates of resistance development in treated patients, initiation of treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate. Lamivudine may be used as part of a combination regimen for HBV. Lamivudine is FDA-approved in patients as young as 3 months when used for HIV and for patients as young as 2 years when used for HBV.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Lamivudine is used as part of a 3-drug combination antiretroviral regimen with zidovudine and either nevirapine or raltegravir for the prevention of perinatal HIV transmission in neonates with presumed HIV exposure or those at high risk for perinatal HIV transmission (i.e., mother has not received antepartum antiretroviral therapy).
-For treatment-naive pediatric patients, lamivudine is one of the preferred nucleoside reverse transcriptase inhibitors (NRTIs) to be included as part of a 2-NRTI backbone regimen. The 2-NRTI backbone should be used in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), or integrase strand transfer inhibitor (INSTI). Specific recommendations vary depending on age.
-Lamivudine in combination with dolutegravir (if pre-treatment HIV RNA less than 500,000 copies/mL and without HBV coinfection) or darunavir/ritonavir (if without HBV coinfection) is also a regimen that may be used as initial therapy in treatment-naive adolescents unable to take abacavir or tenofovir.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: hepatitis B virus, human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (solution):
NOTE: The scored tablet is the preferred dosage formulation in pediatric patients able to take a solid dosage form due to lower virologic suppression rates and increased risk of viral resistance with the oral solution. Additionally, the tablet formulation is preferred when possible to avoid an interaction between lamivudine oral solution and sorbitol-containing medicines. Consider increased monitoring of viral load when using the oral solution.
Neonates*: 2 mg/kg/dose PO twice daily.
Infants 1 to 2 months*: 4 mg/kg/dose PO twice daily.
Infants and Children 3 months to 2 years: 5 mg/kg/dose PO twice daily. The FDA-approved dose is 5 mg/kg/dose PO twice daily or 10 mg/kg/dose PO once daily with data regarding efficacy of once-daily dosing limited to patients who transitioned from twice-daily dosing after 36 weeks of treatment. Guidelines do not recommend once-daily dosing in infants and young children.
Children 3 to 12 years: 5 mg/kg/dose PO twice daily. May transition to 10 mg/kg/dose PO once daily for children 3 years or older who have been clinically stable for 36 weeks with undetectable viral loads and stable CD4 counts. Max: 300 mg/day.
Adolescents: 5 mg/kg/dose PO twice daily. May transition to 10 mg/kg/dose PO once daily for children 3 years or older who have been clinically stable for 36 weeks with undetectable viral loads and stable CD4 counts. Max: 300 mg/day. Guidelines recommend that adolescents in early puberty (i.e., Sexual Maturity Rating (SMR) Stages 1 to 3) be administered doses based on pediatric schedules, whereas those in late puberty (i.e., SMR Stage 4 or 5) use adult dosing schedules (i.e., 300 mg PO once daily or 150 mg PO twice daily).
Oral dosage (tablets):
NOTE: The scored tablet is the preferred dosage formulation in pediatric patients able to take a solid dosage form due to lower virologic suppression rates and increased risk of viral resistance with the oral solution.
Children weighing 14 to 19 kg: 75 mg PO twice daily. May transition to 150 mg PO once daily for children 3 years or older who have been clinically stable for 36 weeks with undetectable viral loads and stable CD4 counts.
Children weighing 20 to 24 kg: 75 mg PO once daily in the morning and 150 mg PO once daily in the evening. May transition to 225 mg PO once daily for children 3 years or older who have been clinically stable for 36 weeks with undetectable viral loads and stable CD4 counts.
Children and Adolescents weighing 25 kg or more: 150 mg PO twice daily. May transition to 300 mg PO once daily for children 3 years or older who have been clinically stable for 36 weeks with undetectable viral loads and stable CD4 counts.

For human immunodeficiency virus (HIV) prophylaxis*:
-for human immunodeficiency virus (HIV) prophylaxis to prevent mother-to-child transmission (MTCT) during breastfeeding:
NOTE: Lamivudine is an alternative option for infants who cannot tolerate zidovudine or nevirapine or for breastfeeding parents with viral resistance to nevirapine. For high-risk infants, treatment should start after completion of 6 weeks of presumptive HIV therapy.
Oral dosage:
Neonates 32 weeks gestation and older and 0 to 4 weeks: 2 mg/kg/dose PO twice daily. Optimal treatment duration has not been established. For low-risk infants, some recommend 2 to 6 weeks of treatment while others recommend continuing treatment throughout breastfeeding and 1 to 4 weeks after weaning. For high-risk infants, treatment is recommended throughout breastfeeding and for 1 to 4 weeks after weaning.
Infants older than 4 weeks of age: 4 mg/kg/dose PO twice daily. Optimal treatment duration has not been established. For low-risk infants, some recommend 2 to 6 weeks of treatment while others recommend continuing treatment throughout breastfeeding and 1 to 4 weeks after weaning. For high-risk infants, treatment is recommended throughout breastfeeding and for 1 to 4 weeks after weaning.
-for human immunodeficiency virus (HIV) prophylaxis* after non-occupational HIV exposure:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
Oral dosage (oral solution):
Infants and Children 4 weeks to 1 year: 4 mg/kg/dose PO twice daily in combination with zidovudine and raltegravir or lopinavir/ritonavir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in infants and children younger than 2 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years: 4 mg/kg/dose (Max: 150 mg/dose) PO twice daily in combination with zidovudine and raltegravir or lopinavir/ritonavir for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents: 150 mg PO twice daily or 300 mg PO once daily in combination with zidovudine and raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents with renal dysfunction (CrCl 59 mL/minute or less). Lamivudine and zidovudine doses should be adjusted to degree of renal impairment. Lamivudine in combination with zidovudine and darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Oral dosage (tablets):
Children weighing 14 to 19 kg: One-half tablet (75 mg) PO twice daily or 1 tablet (150 mg) PO once daily in combination with zidovudine and raltegravir or lopinavir/ritonavir for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 20 to 24 kg: One-half tablet (75 mg) PO in the morning and 1 tablet (150 mg) PO in the evening or one and one-half tablets (225 mg) PO once daily in combination with zidovudine and raltegravir or lopinavir/ritonavir for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 25 kg or more: 150 mg PO twice daily or 300 mg PO once daily in combination with zidovudine and raltegravir or lopinavir/ritonavir for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents: 150 mg PO twice daily or 300 mg PO once daily in combination with zidovudine and raltegravir or dolutegravir for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adolescents with renal dysfunction (CrCl 59 mL/minute or less). Lamivudine and zidovudine doses should be adjusted to degree of renal impairment. Lamivudine in combination with zidovudine and darunavir/ritonavir is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

For the treatment of chronic hepatitis B infection, including in persons coinfected with HIV:
-for the treatment of chronic hepatitis B infection in persons without HIV coinfection:
Oral dosage (lamuvidine HBV):
Children and Adolescents 2 to 17 years: 3 mg/kg/dose PO once daily (Max: 100 mg/dose). The optimum duration of treatment is not known. Use of the oral solution is recommended for a required dose less than 100 mg or if unable to swallow tablets. For HBeAg-positive chronic hepatitis, continue treatment until have achieved HBeAg seroconversion and undetectable serum HBV DNA and completed at least 6 months of additional treatment after the appearance of anti-HBe. For HBeAg-negative chronic hepatitis, continue treatment until have achieved HBsAg clearance. Persons not achieving a primary response (less than 2 log decrease in serum HBV DNA after at least 6 months of therapy) should be switched to alternative therapy or receive additional treatment. Some experts suggest caution when initiating therapy and recommend considering treatment in children that are HBeAg-positive and immune active, that have reactivation, and that are HBeAg-negative and immune active if there is moderate or severe hepatic inflammation or fibrosis or a family history of hepatocellular carcinoma.
-for the treatment of chronic hepatitis B infection in persons coinfected with HIV:
NOTE: Do not use the Epivir-HBV or Lamivudine-HBV formulations and dosing recommendations.
Oral dosage (lamivudine solution):
Infants and Children: 4 mg/kg/dose (Max: 150 mg/dose) PO twice daily as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV in children 2 years and older, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Most persons on HAART should receive HBV therapy indefinitely.
Adolescents: 150 mg PO twice daily or 300 mg PO once daily as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. Most persons on HAART should receive HBV therapy indefinitely.
Oral dosage (lamivudine tablets):
Children weighing 14 to 19 kg: 75 mg PO twice daily or 150 PO as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV in children 2 years and older, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Most persons on HAART should receive HBV therapy indefinitely.
Children weighing 20 to 24 kg: 75 mg PO in the morning and 150 mg PO in the evening or 225 mg PO once daily as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV in children 2 years and older, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Most persons on HAART should receive HBV therapy indefinitely.
Children weighing 25 kg or more: 150 mg PO twice daily or 300 mg PO once daily as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV in children 2 years and older, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Most persons on HAART should receive HBV therapy indefinitely.
Adolescents: 150 mg PO twice daily or 300 mg PO once daily as part of a fully suppressive antiretroviral regimen. When treating both HIV and HBV, tenofovir and lamivudine or tenofovir and emtricitabine (at appropriate HIV treatment doses and in combination with other antiretroviral agents) are appropriate first-line treatment options. Most persons on HAART should receive HBV therapy indefinitely.

For perinatal human immunodeficiency virus (HIV) prophylaxis* in neonates at high risk for HIV acquisition:
NOTE: Presumptive therapy with a 3-drug combination antiretroviral (ARV) regimen, consisting of zidovudine, lamivudine, and either nevirapine or raltegravir at treatment doses, is recommended for neonates with presumed HIV exposure (mothers with unknown HIV status who test HIV positive at delivery or postpartum or whose newborns have a positive HIV antibody test) and neonates born to HIV-infected mothers who have not received antepartum ARV treatment, who have received only intrapartum ARV treatment, who have suboptimal viral suppression (defined as at least 2 consecutive tests with HIV RNA less than 50 copies/mL obtained at least 4 weeks apart within 4 weeks of delivery), or who have acute or primary HIV infection during pregnancy or breastfeeding. Consider raltegravir use in the 3-drug combination ARV prophylaxis regimen if the mother has HIV-1 and HIV-2 infection, since HIV-2 is not susceptible to nevirapine.
NOTE: The ARV regimen for newborns born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery or through consultation via the National Perinatal HIV hotline (1-888-448-8765). Additionally, no evidence exists that shows that neonatal prophylaxis regimens customized based on presence of maternal drug resistance are more effective than standard neonatal prophylaxis regimens.
Oral dosage:
Neonates 32 weeks gestation and older and 0 to 4 weeks: 2 mg/kg/dose PO twice daily in combination with zidovudine and either nevirapine or raltegravir. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For lamivudine, nevirapine, and raltegravir, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Infants older than 4 weeks: 4 mg/kg/dose PO twice daily in combination with zidovudine and either nevirapine or raltegravir. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For lamivudine, nevirapine, and raltegravir, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; doses up to 4 mg/kg/day PO have been used off-label for HIV.
-Infants
1 to 2 months: Safety and efficacy have not been established; doses up to 8 mg/kg/day PO have been used off-label for HIV and HIV/HBV coinfection.
3 to 11 months: 10 mg/kg/day PO for HIV; doses up to 8 mg/kg/day PO have been recommended for HIV/HBV coinfection.
-Children
1 year: 10 mg/kg/day PO for HIV; doses up to 8 mg/kg/day PO have been recommended for HIV/HBV coinfection.
2 to 12 years: 10 mg/kg/day PO (Max: 300 mg/day) for HIV; doses up to 8 mg/kg/day PO (Max: 300 mg/day) have been recommended for HIV/HBV coinfection; 3 mg/kg/day PO (Max: 100 mg/day) for HBV alone.
-Adolescents
300 mg/day PO for HIV and HIV/HBV coinfection; 3 mg/kg/day PO (Max: 100 mg/day) for HBV alone.

Patients with Hepatic Impairment Dosing
Pharmacokinetic parameters of lamivudine are not altered by diminishing hepatic function; therefore, no dosage adjustment is required with impaired hepatic function. Safety and efficacy have not been established in patients with decompensated hepatic disease. Treatment should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Patients with Renal Impairment Dosing
The following off-label pediatric dosage adjustments based on a twice daily dosage regimen in patients with normal renal function have been recommended when treating HIV :
GFR more than 50 mL/minute/1.73 m2: No dosage adjustment needed.
GFR 30 to 50 mL/minute/1.73 m2: Extend the dosing interval to every 24 hours.
GFR 10 to 29 mL/minute/1.73 m2: Reduce dose to 50% of the normal dose and extend the dosing interval to every 24 hours.
GFR less than 10 mL/minute/1.73 m2: Reduce dose to 25% of the normal dose and extend the dosing interval to every 24 hours.

FDA-labeled dosage adjustments in adolescents weighing 25 kg or more when treating HIV (Epivir) :
CrCl 50 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 49 mL/minute: 150 mg PO once daily.
CrCl 15 to 29 mL/minute: 150 mg PO first dose, then 100 mg PO once daily.
CrCl 5 to 14 mL/minute: 150 mg PO first dose, then 50 mg PO once daily.
CrCl less than 5 mL/minute: 50 mg PO first dose, then 25 mg PO once daily.

Dosage adjustments are recommended in adult patients being treated for hepatitis B (Epivir HBV); however, specific pediatric dosage adjustments are not available. A dose reduction should be considered. The adult dosage adjustments are as follows :
CrCl 50 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 49 mL/minute: 100 mg PO once, then 50 mg PO once daily.
CrCl 15 to 29 mL/minute: 100 mg PO once, then 25 mg PO once daily.
CrCl 5 to 14 mL/minute: 35 mg PO once, then 15 mg PO once daily.
CrCl less than 5 mL/minute: 35 mg PO once, then 10 mg PO once daily.

Intermittent hemodialysis
Reducing the dose to 25% of the normal dose and extending the dosing interval to every 24 hours has been recommended based on a twice daily dosage regimen in patients with normal renal function being treated for HIV (Epivir). The hemodialysis extraction ratio is approximately 53% to 65%. Dose after hemodialysis on dialysis days. No additional dosing of lamivudine is required after routine (4-hour) hemodialysis.

Peritoneal dialysis
Reducing the dose to 25% of the normal dose and extending the dosing interval to every 24 hours has been recommended based on a twice daily dosage regimen in patients with normal renal function being treated for HIV (Epivir).

Continuous renal replacement therapy (CRRT)
Extending the dosing interval to every 24 hours has been recommended based on a twice daily dosage regimen in patients with normal renal function being treated for HIV (Epivir).

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Lamivudine is a potent reverse-transcriptase inhibitor. It has been shown to inhibit both type 1 and type 2 HIV reverse transcriptase. It can also inhibit replication of hepatitis B virus (HBV) because this replication depends on reverse transcription of an intermediate RNA to a minus-stranded DNA, which then serves as the template for synthesis of the plus-stranded DNA. The in vitro activity has been assessed in a number of cell lines where lamivudine showed anti-HIV activity in all virus-cell infections tested. Intracellular phosphorylation produces the 5'-triphosphate metabolite (L-TP) in vitro. This active metabolite inhibits reverse transcriptase and viral DNA synthesis. L-TP also inhibits cellular DNA polymerase. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains.

Pharmacokinetics: Lamivudine is administered orally. It distributes into extravascular spaces. The volume of distribution is independent of dose and does not correlate with body weight. Protein binding is less than 36%. Hepatic metabolism is a minor route of elimination; most of an oral dose (71%) is excreted unchanged in the urine by active organic cationic secretion. The only known metabolite in humans is the trans-sulfoxide metabolite, which accounts for approximately 5% of a dose appearing in the urine. The mean elimination half-life in adults after a single dose ranged from 13 to 19 hours with plasma sampling for up to 48 or 72 hours after dosing.

Affected cytochrome P450 isoenzymes: none
Based on in vitro study results, lamivudine at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3.

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim, an inhibitor of these transporters, has been shown to increase lamivudine plasma concentrations; however, the interaction is not considered clinically significant as no dose adjustments are necessary. Lamivudine is also a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine and coadministration of drugs that affect these transporters is unlikely to affect the disposition and elimination of lamivudine.


-Route-Specific Pharmacokinetics
Oral Route
Lamivudine absorption is rapid, with a mean absolute bioavailability of 86% for the tablet and 87% for the oral solution in adults. Food has no significant effect on systemic exposure. Food decreases Cmax and increases time to Cmax, but does not affect the bioavailability. AUC and Cmax increase in proportion to oral dose over the range from 0.25 to 10 mg/kg.


-Special Populations
Pediatrics
Neonates
Clearance is delayed in neonates, likely due to immature renal function. The half-life at birth is approximately 14 hours, decreasing to 6 hours after 1 week.

Infants, Children, and Adolescents
In pediatric patients, the bioavailability of both lamivudine tablets and oral solution is lower than that for adults. The relative bioavailability of the oral solution is approximately 40% lower than the tablets in pediatric patients, despite no differences in adults. Pediatric patients receiving the oral solution at the recommended dose achieved approximately 25% lower plasma concentrations compared with adults; concentrations achieved with the tablets were comparable or slightly higher than those observed in adults. Lower lamivudine exposure in pediatric patients receiving the oral solution is likely due to an interaction between lamivudine and concomitant solutions containing sorbitol. Both Cmax and AUC show dose proportionality in the dosing range studied. Lamivudine was found to penetrate into the cerebrospinal fluid (CSF) in children; CSF concentrations ranged from 5.6% to 30.9% of the concentration in a simultaneous serum sample. Weight-corrected oral clearance was higher at age 2 and declined from 2 to 12 years, where values were then similar to adults. The half-life is approximately 2 hours, which is shorter than in adults. Studies in pediatric patients with clinically stable HIV have shown that once-daily dosing provides comparable exposure as twice-daily dosing for both the oral solution and tablet formulations. The mean Cmax was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing.

Hepatic Impairment
Lamivudine pharmacokinetics are not altered by hepatic dysfunction. Dose adjustments are not required in patients with hepatic dysfunction; however, the safety and efficacy in decompensated liver disease has not been established.

Renal Impairment
The effect of renal impairment on pharmacokinetic parameters in pediatric patients is not known. In adult patients, total clearance decreases as creatinine clearance decreases. Lamivudine exposure (AUC), Cmax, and half-life increase with diminishing renal function. Hemodialysis increases clearance; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean exposure after a single dose. The hemodialysis extraction ratio is approximately 53% to 65%. Continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis have negligible effects on clearance. After correction of dose for creatinine clearance, no additional dose modifications are necessary after routine hemodialysis or peritoneal dialysis. It is not known if continuous (24-hour) hemodialysis can remove lamivudine.