Lamivudine (3TC) is a synthetic nucleoside analog, classified as a nucleoside reverse transcriptase inhibitor (NRTI). Lamivudine 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 lamivudine 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 HBV DNA below the level of detection; however, after an initial response, approximately one-third of patients had reappearance of HBV DNA during lamivudine treatment. Due to high rates of resistance development in treated patients, initiation of lamivudine 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 as the lower dose formulation (Epivir-HBV) in patients without HIV.
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 hepatitis B, the commonly observed side effects were similar to adult patients.
During lamivudine therapy for hepatitis B some the most common adverse reactions included infection of the ear, nose and throat (25%), while sore throat was reported in 13% of patients. Nasal signs and symptoms occurred in 20% of adult HIV patients receiving lamivudine. 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. Cough was reported in 18% of adult HIV patients. Respiratory infection and sepsis have been reported in neonates as well.
Elevated hepatic enzymes were recorded in adult HIV patients taking combined therapy with lamivudine and zidovudine at a rate of 1.7% to 3.7% and in up to 27% of adult hepatitis B patients. Elevated transaminases were reported in 1% to 2% of pediatric HIV patients, including neonates. 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 following 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.
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 patients included depression (9%), dizziness (10%), insomnia and other sleep disorders (11%), malaise and fatigue (27%), fever or chills (10% adults; fever 25% pediatrics), and weakness (post-marketing).
Diarrhea was reported by 14% of patients receiving lamivudine for hepatitis B. Gastrointestinal effects were reported in patients receiving combination HIV therapy include nausea and vomiting (33%/13% adults; 8% pediatrics), diarrhea (18% adults; 8% pediatrics), anorexia/decreased appetite (10%), abdominal pain (9%), abdominal cramps (6%), and dyspepsia (5%). Other GI-related adverse reactions reported during clinical practice include hyperglycemia (post-marketing) and stomatitis (6% pediatrics). One neonate died from gastroenteritis with acidosis and convulsions, while 2 other non fatal cases of gastroenteritis and diarrhea were reported.
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. Neuropathy was also noted in 12% of adults with HIV.
Arthralgia (5%), myalgia (8%), and musculoskeletal pain (12%) have been reported in HIV patients treated with lamivudine/zidovudine combination therapy. Rhabdomyolysis, CPK elevation, and muscle cramps have been reported with lamivudine during post-marketing reports.
Alopecia has been reported as an adverse reaction lamivudine 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. Skin rash (unspecified) has been reported in 9% of adult HIV patients and 12% of pediatric HIV patients. Other reactions reported during post-marketing reports include anaphylactoid reactions, pruritus, and urticaria.
Pancreatitis has been reported with the use of lamivudine. In adult HIV patients, pancreatitis has been reported in 0.3% of patients. 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 4.2% of adult HIV patients and 3% of pediatric HIV patients. Elevated lipase has been noted in 3% of pediatric HIV patients and in 10% of hepatitis B patients.
Lipodystrophy syndrome consisting of redistribution or accumulation of body fat has been reported during postmarketing use of lamivudine. The mechanism by which nucleoside analogues, such as lamivudine, may cause body fat changes is not known. It has been suggested that nucleoside analogs may damage the mitochondria of adipocytes.
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 infections (Epivir-HBV).
Limited short-term safety information is available from 2 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 patients with HIV who are 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 was noted in 4% of pediatric HIV patients and in 2.9% of adult HIV patients. Neutropenia was reported in 7.2% of adult HIV patients and 8% of pediatric HIV patients. Thrombocytopenia was noted in 0.4% of adult HIV patients and 1% of pediatric HIV patients. Thrombocytopenia also occurred in 4% of patients treated for hepatitis B.
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.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a 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; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. 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 two formulations, Epivir and Epivir-HBV. Epivir is indicated for use as part of a fully suppressive antiretroviral regimen to treat patients with HIV, whereas Epivir-HBV is approved to treat patients with the hepatitis B virus (HBV). Prior to and during the 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 antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine (Epivir). If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) due to the risk of developing HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. 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. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Safety and efficacy of Epivir-HBV have not been established in patients with decompensated hepatic disease, organ transplant, hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection, or in patients with hepatitis delta. Nucleoside analogs, including lamivudine, have been associated with fatal cases of hepatotoxicity or lactic acidosis. Female sex and obesity may be risk factors for developing these adverse events in patients receiving a nucleoside analog. A majority of these cases occurred in females; it is unknown if pregnant women are at increased risk. Clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. 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 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. Treatment 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 transaminases. Following discontinuation of lamivudine in patients with HBV 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, patients should be closely monitored for several months after stopping lamivudine therapy for hepatitis B.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. 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 HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Geriatric patients are more likely to have decreased renal function and may require dose reduction and special monitoring. Clinical studies of Epivir-HBV did not contain significant numbers of elderly patients to determine if they would respond differently from younger patients.
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 pediatric patients 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. 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.
There have been no studies of Epivir-HBV in pregnant patients with hepatitis B virus (HBV), and there are no data regarding the effects on vertical transmission; appropriate infant immunizations should be used to prevent neonatal acquisition of HBV. For HIV, antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend lamivudine as part of a preferred 2-NRTI backbone in patients who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes 5,613 first trimester exposures to lamivudine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, prevalence of defects was 3.1% (95% CI: 2.6% to 3.6%). Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy, and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to lamivudine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding mothers with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mg/L (range less than 0.5 to 6.09 mg/L) and 0.9 mg/L (range less than 0.5 to 8.2 mg/L). Use of lamivudine in HIV-negative breast-feeding mothers being treated for hepatitis B infection has not been studied; a consensus among health-care providers regarding the use of lamivudine in this population has not been established. Other antiretroviral mediations whose passage into human breast milk have been evaluated include tenofovir, nevirapine, zidovudine, and nelfinavir.
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. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. 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 result kept in the patient's medical record until it becomes 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, antimicrobial resistance can develop when lamivudine is used either alone or in combination with other agents. Monotherapy with lamivudine is not recommended. In patients without HIV who are receiving lamivudine for the treatment of chronic hepatitis B virus (HBV), the emergence of lamivudine-resistant HBV has been detected and has been associated with a diminished response. In order to reduce the risk of resistance, consider switching to an alternative HBV regimen if HBV DNA remains detectable after 24 weeks of treatment. The emergence of HBV variants associated with resistance to lamivudine has also been reported in patients with HIV who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV. Prior to beginning lamivudine for the treatment of chronic HBV, patients should be tested for HIV infection to avoid inappropriate therapy and development of resistant HIV.
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 progressive multifocal leukoencephalopathy (PML), 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.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-For pregnant and non-pregnant patients, lamivudine plus tenofovir alafenamide, tenofovir disoproxil fumarate, or abacavir (HLA-B*5701 negative patients only) are preferred 2-NRTI backbones.
-In non-pregnant patients unable to take abacavir or tenofovir, lamivudine may be given with dolutegravir (if pre-treatment HIV RNA less than 500,000 copies/mL and without HBV coinfection) or darunavir boosted with ritonavir (if without HBV coinfection).
-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).
-Pediatric guidelines are also available.
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 (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.
Adults: 300 mg PO once daily or 150 mg PO twice daily.
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.
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 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.
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.
Adults: 300 mg PO once daily or 150 mg PO twice daily.
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).
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.
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.
Infants 1 to 2 months*: 4 mg/kg/dose PO twice daily.
Neonates*: 2 mg/kg/dose PO twice daily.
For human immunodeficiency virus (HIV) prophylaxis*:
-for human immunodeficiency virus (HIV) prophylaxis* after occupational exposure to HIV:
Oral dosage:
Adults: 300 mg PO once daily plus tenofovir 300 mg PO once daily, in combination with a third antiretroviral agent, is a preferred regimen for HIV post-exposure prophylaxis (PEP). Alternative lamivudine dosing is 150 mg PO twice daily. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however, if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. The recommended third antiretroviral agent to be administered in combination with lamivudine and tenofovir varies among published guidelines and includes one of the following: raltegravir, dolutegravir, lopinavir; ritonavir, or atazanavir boosted with ritonavir. Additionally, lamivudine plus tenofovir may be used as part of alternative regimens in combination with other antiretroviral agents. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).
-for human immunodeficiency virus (HIV) prophylaxis* after non-occupational HIV exposure, including sexual assault:
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 (tablets):
Adults: 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 adults 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.
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.
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.
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 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.
Oral dosage (oral solution):
Adults: 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 adults 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.
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.
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.
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.
-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:
Infants older than 4 weeks: 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.
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.
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 (lamivudine HBV):
Adults: 100 mg PO once daily. The optimum duration of treatment is not known. 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.
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 Epivir HBV or lamivudine HBV formulations or dosing recommendations.
Oral dosage (lamivudine solution):
Adults: 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.
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.
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.
Oral dosage (lamivudine tablets):
Adults: 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.
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.
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.
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 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.
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:
Infants older than 4 weeks: 4 mg/kg/dose PO twice daily in combination with zidovudine and either nevirapine or raltegravir. 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.
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.
Maximum Dosage Limits:
-Adults
300 mg/day PO for HIV and HIV/HBV coinfection; 100 mg/day PO for HBV alone.
-Geriatric
300 mg/day PO for HIV and HIV/HBV coinfection; 100 mg/day PO 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.
-Children
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.
1 year: 10 mg/kg/day PO for HIV; doses up to 8 mg/kg/day PO have been recommended for HIV/HBV coinfection.
-Infants
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.
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.
-Neonates
Safety and efficacy have not been established; doses up to 4 mg/kg/day PO have been used off-label for HIV.
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
FDA-labeled dosage adjustments in adults and 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.
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 adults being treated for hepatitis B (Epivir HBV) :
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
The hemodialysis extraction ratio is approximately 53% to 65%. Dose after hemodialysis on dialysis days. After corrections for renal impairment, no additional dose modifications are required after routine (4-hour) hemodialysis. For pediatric patients, 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).
Peritoneal dialysis
After corrections for renal impairment, no additional dose modifications are required after routine (4-hour) peritoneal dialysis (CAPD). Alternatively in adult patients, a dose of 50 mg PO once then 25 to 50 mg PO every 24 hours has been suggested. For pediatric patients, 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)
For adult patients, dose with 100 mg PO on day 1, then 50 mg PO every 24 hours. For pediatric patients, 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
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Dofetilide: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
Donepezil; Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Empagliflozin; Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Ertugliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Interferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Alfa-n3: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Beta-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Gamma-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferons: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Peginterferon Alfa-2a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Peginterferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Peginterferon beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Pioglitazone; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Procainamide: (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
Ribavirin: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Ropeginterferon alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol 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.
Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway.
Lamivudine is a potent reverse-transcriptase inhibitor. It has been shown to inhibit both type 1 and type 2 HIV reverse transcriptase. Lamivudine 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. In vitro activity has been assessed in some 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. In combination with zidovudine, lamivudine has been shown to increase CD4 cell counts and reduce HIV-1 RNA levels.
Treatment-emergent lamivudine resistance in HIV is believed to be caused by a single mutation at codon 184 of the HIV reverse transcriptase gene (M184V or M184I). However, this mutation inhibits the appearance of the mutation at codon 215 that is associated with resistance to zidovudine. Apart from the benefits of combination therapy in antiretroviral-naive patients, it has been found that lamivudine can restore zidovudine sensitivity for patients already carrying HIV by reversing an existing mutation at codon 215. For HBV, resistance to lamivudine develops with rtM204V/I substitutions in the YMDD motif of the catalytic domain of HBV reverse transcriptase. Other substitutions reported in lamivudine-resistant HBV isolates include rtV173L, rtL180M, rtH55R, rtL80I/V, rtV173M, rtA181T/V, rtT184S, rtF219Y, rtL229F/M/V/W, and rtQ267H. In clinical trials, the prevalence of YMDD substitutions in recipients of lamivudine (100 mg daily) was 10% and 24% at treatment weeks 24 and 52, respectively. A long-term follow up of patients with HBV receiving 100 mg of lamivudine daily found the prevalence of treatment-emergent YMDD substitutions to be 23% at year 1, 46% at year 2, 55% at year 3, 71% at year 4, and 65% at year 5.
Lamivudine is administered orally. It distributes into extravascular spaces. When administered to pregnant women, drug concentrations in cord blood are similar to those observed in maternal blood at delivery. The volume of distribution is independent of dose and does not correlate with body weight. Plasma 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 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. The bioavailability in children is about 66%. 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
Hepatic Impairment
Lamivudine pharmacokinetics are not altered by hepatic dysfunction. Dose adjustments are not required in patients with hepatic dysfunction; however, safety and efficacy in decompensated liver disease has not been established.
Renal Impairment
Total clearance of lamivudine decreases as creatinine clearance decreases. Lamivudine exposure (AUC), Cmax, and half-life increase with diminishing renal function; doses should be modified in patients with renal impairment. Hemodialysis increases clearance; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine 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 lamivudine 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. The effect of renal impairment on pharmacokinetic parameters in pediatric patients is not known.
Pediatrics
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 that of the tablets in pediatric patients, despite no differences in adults. Pediatric patients receiving the oral solution at the recommended dosage 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.
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.
Other
Pregnancy
According to population pharmacokinetic modeling, the oral clearance of lamivudine is increased by 22% during pregnancy; however, the overall drug exposure appears to be similar between pregnant, non-pregnant, and postpartum women. No change in dose is indicated during pregnancy. There is high placental transfer to the fetus, with drug concentrations in neonatal and umbilical cord serum samples being similar to those observed in the mother.