Lamivudine

Revision as of 19:49, 6 January 2015 by Stefano Giannoni (talk | contribs)
Jump to navigation Jump to search

Lamivudine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF LAMIVUDINE, DIFFERENT FORMULATIONS OF LAMIVUDINE.
See full prescribing information for complete Boxed Warning.
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Exacerbations of Hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Important Differences Among Lamivudine-Containing Products: Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV® tablets and oral solution (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1.

Overview

Lamivudine is a nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Human immunodeficiency virus (HIV-1) infection

  • Dosage: 300 mg daily or 150 mg q12h
  • In combination with other antiretroviral agents.

Chronic Hepatitis B (HBV) infection

  • Dosage: 100 mg daily

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Lamivudine in adult patients.

Non–Guideline-Supported Use

Posttransplant Prophylaxis for Hepatitis B

  • Dosage: 100mg daily [1]
  • In combination with HBIG.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Human immunodeficiency virus (HIV-1) infection

Chronic Hepatitis B (HBV) infection

  • Dosage: patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg.
  • The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Lamivudine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Lamivudine in pediatric patients.

Contraindications

  • Hypersensitivity to lamivudine or to any component of the tablets or oral solution.

Warnings

WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF LAMIVUDINE, DIFFERENT FORMULATIONS OF LAMIVUDINE.
See full prescribing information for complete Boxed Warning.
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Exacerbations of Hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Important Differences Among Lamivudine-Containing Products: Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV® tablets and oral solution (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1.

Lactic Acidosis and Severe Hepatomegaly With Steatosis

  • Obesity and prolonged nucleoside exposure may be risk factors.
  • Particular caution should be exercised when administering EPIVIR 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 EPIVIR 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).

Patients With HIV-1 and Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

  • In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, 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.
  • There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

Important Differences Among Lamivudine-Containing Products

  • EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution.
  • EPIVIR-HBV was developed for patients with chronic hepatitis B.
  • The formulation and dosage of lamivudine in EPIVIR-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 EPIVIR-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, EPIVIR Tablets, EPIVIR Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine) Tablets, or abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen.

Emergence of Lamivudine-Resistant HBV

  • In non–HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response.
  • Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Use With Other Lamivudine- and Emtricitabine-Containing Products

Use With Interferon- and Ribavirin-Based Regimens

Pancreatitis

  • 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, EPIVIR should be used with caution.
  • Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Immune Reconstitution Syndrome

Fat Redistribution

Adverse Reactions

Clinical Trials Experience

Because 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 practice.

Adults Population

Clinical Trials in HIV-1

The safety profile of EPIVIR 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 ≥5% of subjects during therapy with EPIVIR 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3.

Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007.

EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving EPIVIR 300 mg once daily or EPIVIR 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.

The frequencies of selected laboratory abnormalities reported subjects receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

Pediatric Population

Clinical Trials in HIV-1

EPIVIR 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 ≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus zidovudine 160 mg/m2 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside‑experienced pediatric subjects receiving EPIVIR 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 EPIVIR. 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 EPIVIR plus zidovudine. Pancreatitis was observed in 1 subject in this trial who received open‑label EPIVIR in combination with zidovudin and ritonavir following discontinuation of didanosine monotherapy.

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 (<1%) in Trial ACTG300.

Selected laboratory abnormalities experienced by therapy‑naive (56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

Neonatal Population
Clinical Trials in HIV-1

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. 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 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 reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of EPIVIR. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Body as a Whole

  • Redistribution/accumulation of body fat.

General

Endocrine and Metabolic

Hemic and Lymphatic

Hepatic and Pancreatic

Hypersensitivity

Musculoskeletal

Skin

Drug 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).
  • No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Interferon- and Ribavirin-Based Regimens
Zalcitabine
Trimethoprim/Sulfamethoxazole (TMP/SMX)
  • No change in dose of either drug is recommended.
  • There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.
Drugs with No Observed Interactions With EPIVIR
  • A drug interaction trial showed no clinically significant interaction between EPIVIR and zidovudine.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C There are no adequate and well-controlled trials of EPIVIR in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. EPIVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial 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, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients.

Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamivudine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Lamivudine during labor and delivery.

Nursing Mothers

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 serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.

Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

Pediatric Use

The safety and effectiveness of twice-daily EPIVIR in combination with other antiretroviral agents have been established in pediatric patients 3 months and older.

Geriatic Use

Clinical trials of EPIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly.

Gender

There is no FDA guidance on the use of Lamivudine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Lamivudine with respect to specific racial populations.

Renal Impairment

Dosing of EPIVIR is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2.

No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis.

Although there are insufficient data to recommend a specific dose adjustment of EPIVIR in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

Hepatic Impairment

There is no FDA guidance on the use of Lamivudine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Lamivudine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Lamivudine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral

Monitoring

  • Patients with HIV-1 and Hepatitis B Virus Co-infection should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

IV Compatibility

There is limited information regarding the compatibility of Lamivudine and IV administrations.

Overdosage

There is no known antidote for EPIVIR. One case of an adult ingesting 6 g of EPIVIR was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Trial ACTG300. One case involved a single dose of 7 mg/kg of EPIVIR; the second case involved use of 5 mg/kg of EPIVIR twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

Pharmacology

Template:Px
Lamivudine
Systematic (IUPAC) name
4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one
Identifiers
CAS number 134678-17-4
ATC code J05AF05
PubChem 73339
DrugBank DB00709
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 229.26 g/mol
SMILES eMolecules & PubChem
Synonyms L-2′,3′-dideoxy-3′-thiacytidine
Pharmacokinetic data
Bioavailability 86%
Protein binding Less than 36%
Metabolism ?
Half life 5 to 7 hours
Excretion Renal (circa 70%)
Therapeutic considerations
Pregnancy cat.

B3(AU) C(US)

Legal status

POM(UK) [[Prescription drug|Template:Unicode-only]](US)

Routes Oral

Mechanism of Action

  • Lamivudine is an antiviral agent.
  • Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP).
  • The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA.
  • 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ.

Structure

  • Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and HBV.
  • The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.
  • Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. *Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine.
  • It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3.
  • Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

Pharmacodynamics

There is limited information regarding Lamivudine Pharmacodynamics in the drug label.

Pharmacokinetics

Pharmacokinetics in Adults

  • The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.
  • The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected subjects.
  • The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects.
  • EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen.
  • Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. *Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations.
  • The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
Absorption and Bioavailability
  • Lamivudine was rapidly absorbed after oral administration in HIV-1-infected subjects.
  • Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution.
  • After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD).
  • The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.
  • The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.
Effects of Food on Oral Absorption
  • An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, EPIVIR Tablets and Oral Solution may be administered with or without food.
Distribution
  • The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces.
  • Volume of distribution was independent of dose and did not correlate with body weight.
  • Binding of lamivudine to human plasma proteins is low (<36%).
  • In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism
  • Metabolism of lamivudine is a minor route of elimination.
  • In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
Elimination
  • The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion.
  • In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD).
  • In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.
  • In most single-dose trials in HIV-1-infected subjects, HBV‑infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours.
  • In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).
  • Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg.

Special Populations

Renal Impairment
  • The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7).
  • Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance).
  • Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. *Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment.
  • Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration.
  • Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.
  • It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.
  • The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
Hepatic Impairment
  • The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function.
  • Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function.
  • Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pharmacokinetics in Pediatric Patients

  • In Trial NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric subjects (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day.
  • In the 9 infants and children (age range: 5 months to 12 years) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults.
  • The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.

Systemic clearance decreased with increasing age in pediatric subjects, as shown in Figure 1.

  • After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric subjects ranging in age from 4 months to 14 years, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half‑life was 3.7 ± 1 hours.)
  • Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric subjects receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.
  • Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine.
  • CSF samples were collected between 2 and 4 hours postdose.
  • At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.
  • Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged >3 months) studied previously.
  • There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old.

Pharmacokinetics in Geriatric Patients

  • The pharmacokinetics of lamivudine after administration of EPIVIR to patients over 65 years have not been studied.

Drug Interactions

Interferon Alfa
  • There was no significant pharmacokineti interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.
Ribavirin
  • In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
Trimethoprim/Sulfamethoxazole
  • Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design.
  • Coadministration of TMP-SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. *The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.
Zidovudine
  • No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the 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. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

Clinical Studies

There is limited information regarding Lamivudine Clinical Studies in the drug label.

How Supplied

There is limited information regarding Lamivudine How Supplied in the drug label.

Storage

There is limited information regarding Lamivudine Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Lamivudine |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Lamivudine |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Lamivudine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Lamivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Epivir[2]
  • Epivir HBV
  • Epivir A/F

Look-Alike Drug Names

There is limited information regarding Lamivudine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ Jiang L, Yan L, Li B, Wen T, Zhao J, Jiang L; et al. (2010). "Prophylaxis against hepatitis B recurrence posttransplantation using lamivudine and individualized low-dose hepatitis B immunoglobulin". Am J Transplant. 10 (8): 1861–9. doi:10.1111/j.1600-6143.2010.03208.x. PMID 20659092.
  2. ↑ "EPIVIR- lamivudine tablet, film coated. EPIVIR- lamivudine solution".
Retrieved from "https://www.wikidoc.org/index.php?title=Lamivudine&oldid=1052076"