LAMIVUDINE is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use: The dosage of this product is for HIV-1 and not for HBV. LAMIVUDINE is a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Limitation of Use: The dosage of this product is for HIV-1 and not for HBV.
(1)
Contraindications
LAMIVUDINE is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. LAMIVUDINE is contraindicated in patients with previous hypersensitivity reaction to lamivudine. (4)
Warnings and precautions
Co-infected HIV-1/HBV Patients: Emergence of lamivudineresistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. (5.2) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue LAMIVUDINE as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both.
(5.3) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. (5.4) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.5, 5.7) Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets.
(5.6)
5.1Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors.
Treatment with LAMIVUDINE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.2Patients with and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical
and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV.
The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Important Differences among Lamivudine-containing Products LAMIVUDINE tablets contain a higher dose of the same active ingredient (lamivudine) than LAMIVUDINE-HBV tablets. LAMIVUDINE-HBV was developed for patients with chronic hepatitis B.
The formulation and dosage of lamivudine in LAMIVUDINE-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with LAMIVUDINE-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment.
If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, LAMIVUDINE tablets, or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for LAMIVUDINE-HBV).
Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.
5.3Use with Interferon- and Ribavirin-based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3) ] , hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.
Patients receiving interferon alfa with or without ribavirin and LAMIVUDINE should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of LAMIVUDINE should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
See the full prescribing information for interferon and ribavirin.
5.4Pancreatitis
In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, LAMIVUDINE should be used with caution. Treatment with LAMIVUDINE should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1) ] .
5.5Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LAMIVUDINE. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.6Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution
Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets [see Clinical Pharmacology (12.3) , Microbiology (12.4) , Clinical Studies (14.2) ]. LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate.
Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution.
5.7Fat Redistribution Redistribution/accumulation
of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
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Interactions
Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) [see Pharmacokinetics (12.3) ]. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LAMIVUDINE during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. Data Human Data: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP.
The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals.
These trials were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans.
Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose.
No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.
8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.
Adverse reactions
The following adverse reactions are discussed in other sections of the labeling: Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning , Warnings and Precautions (5.1) ]. Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2) ]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.3) ]. Pancreatitis [see Warnings and Precautions (5.4) ].
Immune reconstitution syndrome [see Warnings and Precautions (5.5) ]. Fat redistribution [see Warnings and Precautions (5.7) ]. The most common reported adverse reactions (incidence greater than equal to 15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough. (6.1) The most common reported adverse reactions (incidence greater than equal to 15%) in pediatric patients subjects were fever and cough.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Clinical Trials Experience in Adult
SubjectsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety profile of LAMIVUDINE in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials.The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea, and cough.Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with LAMIVUDINE 150 mg twice daily plus RETROVIR® 200 mg 3 times daily for up to 24 weeks are listed in Table 3.
Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)Adverse ReactionLAMIVUDINE 150 mgTwice Dailyplus RETROVIR(n = 251)RETROVIRaEither zidovudine monotherapy or zidovudine in combination with zalcitabine.(n = 230)Body as a WholeHeadache35%27%Malaise & fatigue27%23%Fever or chills10%12%DigestiveNausea33%29%Diarrhea18%22%Nausea & vomiting13%12%Anorexia and/or decreased appetite10%7%Abdominal pain9%11%Abdominal cramps6%3%Dyspepsia5%5%Nervous SystemNeuropathy12%10%Insomnia & other sleep disorders11%7%Dizziness10%4%Depressive disorders9%4%RespiratoryNasal signs & symptoms20%11%Cough18%13%SkinSkin rashes9%6%MusculoskeletalMusculoskeletal pain12%10%Myalgia8%6%Arthralgia5%5%Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received LAMIVUDINE in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].LAMIVUDINE 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving LAMIVUDINE 300 mg once daily or LAMIVUDINE 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar.
Selected laboratory abnormalities observed during therapy are summarized in Table 4.Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007)ULN = Upper limit of normal.ND = Not done.Test (Threshold Level)24-Week Surrogate EndpointClinical Endpoint TrialThe median duration on study was 12 months.LAMIVUDINE plus RETROVIREither zidovudine monotherapy or zidovudine in combination with zalcitabine.LAMIVUDINE plus Current TherapyCurrent therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.Placebo plus Current TherapyAbsolute neutrophil count(<750/mm3)7.2%5.415%13%Hemoglobin (<8.0 g/dL)2.9%1.82.2%3.4%Platelets (<50,000/mm3)0.4%1.32.8%3.8%ALT (>5.0 x ULN)3.7%3.63.8%1.9%AST (>5.0 x ULN)1.7%1.84.0%2.1%Bilirubin (>2.5 x ULN)0.8%0.4NDNDAmylase (>2.0 x ULN)4.2%1.52.2%1.1%The frequencies of selected laboratory abnormalities reported in subjects receiving LAMIVUDINE 300 mg once daily or LAMIVUDINE 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Clinical Trials Experience in Pediatric Subjects LAMIVUDINE oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials.Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with LAMIVUDINE 4 mg per kg twice daily plus RETROVIR 160 mg per m2 3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.
Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300Adverse ReactionLAMIVUDINEplus RETROVIRDidanosine(n = 235)Body as a WholeFever25%32%DigestiveHepatomegaly11%11%Nausea & vomiting8%7%Diarrhea8%6%Stomatitis6%12%Splenomegaly5%8%RespiratoryCough15%18%Abnormal breath sounds/wheezing7%9%Ear, Nose and ThroatSigns or symptoms of earsaIncludes pain, discharge, erythema, or swelling of an ear.7%6%Nasal discharge or congestion8%11%OtherSkin rashes12%14%Lymphadenopathy9%11%Pancreatitis Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving LAMIVUDINE alone or in combination with other antiretroviral agents.
In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with LAMIVUDINE. Three of these subjects died of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to LAMIVUDINE plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open-label LAMIVUDINE in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.4)].Paresthesias and Peripheral Neuropathies Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (less than1%) in Trial ACTG300.
Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300ULN = Upper limit of normal.Test(Threshold Level)LAMIVUDINE plus RETROVIRDidanosineAbsolute neutrophil count (<400/mm3)8%3%Hemoglobin (<7.0 g/dL)4%2%Platelets (<50,000/mm3)1%3%ALT (>10 x ULN)1%3%AST (>10 x ULN)2%4%Lipase (>2.5 x ULN)3%3%Total Amylase (>2.5 x ULN)3%3%Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution.
However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.Neonates Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa 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 [see Clinical Pharmacology (12.3)].
Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal ins
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Composition
Active ingredients
LAMIVUDINE 300MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Lamivudine
Pharmacologic class
Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor, Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor
