Lamivudine

Pronunciation

(la MI vyoo deen)

U.S. Brand Names

Epivir®; Epivir-HBV®

Synonyms

3TC

Generic Available

No

Canadian Brand Names

Heptovir®; 3TC®

Use

Epivir®: Treatment of HIV infection when antiretroviral therapy is warranted; should always be used as part of a multidrug regimen (at least three antiretroviral agents)

Epivir-HBV®: Treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation

Use - Unlabeled/Investigational

Prevention of HIV following needlesticks (with or without protease inhibitor)

Pregnancy Risk Factor

C

Pregnancy Implications

Lamivudine crosses the placenta. The pharmacokinetics of lamivudine during pregnancy are not significantly altered and dosage adjustment is not required. The Perinatal HIV Guidelines Working Group recommends lamivudine for use during pregnancy; the combination of lamivudine with zidovudine is the recommended dual combination NRTI in pregnancy. It may also be used in combination with zidovudine in HIV-infected women who are in labor, but have had no prior antiretroviral therapy, in order to reduce the maternal-fetal transmission of HIV. Cases of lactic acidosis/hepatic steatosis syndrome have been reported in pregnant women receiving nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy in women receiving nucleoside analogues. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to lamivudine or any component of the formulation

Warnings/Precautions

A decreased dosage is recommended in patients with renal dysfunction since AUC, Cmax, and half-life increased with diminishing renal function; use with extreme caution in children with history of pancreatitis or risk factors for development of pancreatitis. Do not use as monotherapy in treatment of HIV. Treatment of HBV in patients with unrecognized/untreated HIV may lead to rapid HIV resistance. In addition, treatment of HIV in patients with unrecognized/untreated HBV may lead to rapid HBV resistance. Patients with HIV infection should receive only dosage forms appropriate for treatment of HIV.

Lactic acidosis and severe hepatomegaly with steatosis have been reported, including fatal cases. Use caution in hepatic impairment. Pregnancy, obesity, and/or prolonged therapy may increase the risk of lactic acidosis and liver damage.

Monitor patients closely for several months following discontinuation of therapy for chronic hepatitis B; clinical exacerbations may occur.

Adverse Reactions

(As reported in adults treated for HIV infection)

>10%:

Central nervous system: Headache, fatigue

Gastrointestinal: Nausea, diarrhea, vomiting, pancreatitis (range: 0.5% to 18%; higher percentage in pediatric patients)

Neuromuscular & skeletal: Peripheral neuropathy, paresthesia, musculoskeletal pain

1% to 10%:

Central nervous system: Dizziness, depression, fever, chills, insomnia

Dermatologic: Rash

Gastrointestinal: Anorexia, abdominal pain, heartburn, elevated amylase

Hematologic: Neutropenia

Hepatic: Elevated AST, ALT

Neuromuscular & skeletal: Myalgia, arthralgia

Respiratory: Nasal signs and symptoms, cough

<1%, postmarketing, and/or case reports: Alopecia, anaphylaxis, anemia, hepatomegaly, hyperbilirubinemia, hyperglycemia, increased CPK, lactic acidosis, lymphadenopathy, peripheral neuropathy, pruritus, red cell aplasia, rhabdomyolysis, splenomegaly, steatosis, stomatitis, thrombocytopenia, urticaria, weakness

Overdosage/Toxicology

Limited information is available, although there have been no clinical signs or symptoms noted, and hematologic tests remained normal in overdose. No antidote is available. Limited (negligible) removal following 4-hour hemodialysis. It is not known if continuous 24-hour hemodialysis would be effective.

Drug Interactions

Ribavirin: Concomitant use of ribavirin and nucleoside analogues may increase the risk of developing lactic acidosis (includes adefovir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine).

Sulfamethoxazole/trimethoprim: Increased AUC and decreased clearance of lamivudine with concomitant use

Trimethoprim (and other drugs excreted by organic cation transport): May increase serum levels/effects of lamivudine.

Zalcitabine: Intracellular phosphorylation of lamivudine and zalcitabine may be inhibited if used together; concomitant use should be avoided.

Zidovudine: Plasma levels of zidovudine are increased by ~39% with concomitant use.

Ethanol/Nutrition/Herb Interactions

Food: Food decreases the rate of absorption and Cmax; however, there is no change in the systemic AUC. Therefore, may be taken with or without food.

Stability

Store at 2°C to 25°C (68°F to 77°F) tightly closed.

Mechanism of Action

Lamivudine is a cytosine analog. After lamivudine is triphosphorylated, the principle mode of action is inhibition of HIV reverse transcription via viral DNA chain termination; inhibits RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase. The monophosphate form of lamivudine is incorporated into the viral DNA by hepatitis B virus polymerase, resulting in DNA chain termination.

Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: Vd: 1.3 L/kg

Protein binding, plasma: <36%

Metabolism: 5.6% to trans-sulfoxide metabolite

Bioavailability: Absolute; Cpmax decreased with food although AUC not significantly affected

Children: 66%

Adults: 87%

Half-life elimination: Children: 2 hours; Adults: 5-7 hours

Excretion: Primarily urine (as unchanged drug)

Dosage

Note: The formulation and dosage of Epivir-HBV® are not appropriate for patients infected with both HBV and HIV. Use with at least two other antiretroviral agents when treating HIV

Oral:

Children 3 months to 16 years: HIV: 4 mg/kg twice daily (maximum: 150 mg twice daily)

Children 2-17 years: Treatment of hepatitis B (Epivir-HBV®): 3 mg/kg once daily (maximum: 100 mg/day)

Adolescents and Adults: Prevention of HIV following needlesticks (unlabeled use): 150 mg twice daily (with zidovudine with or without a protease inhibitor, depending on risk)

Adults:

HIV: 150 mg twice daily or 300 mg once daily; <50 kg: 2 mg/kg twice daily

Treatment of hepatitis B (Epivir-HBV®): 100 mg/day

Dosing interval in renal impairment in pediatric patients: Insufficient data; however, dose reduction should be considered.

Dosing interval in renal impairment in patients >16 years for HIV:

Clcr 30-49 mL/minute: Administer 150 mg once daily

Clcr 15-29 mL/minute: Administer 150 mg first dose, then 100 mg once daily

Clcr 5-14 mL/minute: Administer 150 mg first dose, then 50 mg once daily

Clcr<5 mL/minute: Administer 50 mg first dose, then 25 mg once daily

Dosing interval in renal impairment in adult patients with hepatitis B:

Clcr 30-49: Administer 100 mg first dose then 50 mg once daily

Clcr 15-29: Administer 100 mg first dose then 25 mg once daily

Clcr 5-14: Administer 35 mg first dose then 15 mg once daily

Clcr<5: Administer 35 mg first dose then 10 mg once daily

Dialysis: Negligible amounts are removed by 4-hour hemodialysis or peritoneal dialysis. Supplemental dosing is not required.

Administration

May be taken with or without food. Adjust dosage in renal failure.

Monitoring Parameters

Amylase, bilirubin, liver enzymes, hematologic parameters, viral load, and CD4 count; signs and symptoms of pancreatitis

Dietary Considerations

May be taken with or without food. Each 5 mL of oral solution contains 1 g of sucrose.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Lamivudine is not a cure for HIV or hepatitis B, nor has it been found to reduce transmission. Long-term effects are unknown. You will need frequent blood tests to adjust dosage for maximum therapeutic effect. Take as directed for full course of therapy; do not discontinue (even if feeling better). Take with or without food. Do not take antacids within 1 hour of lamivudine. Mix four tablets in 3-5 oz water, allow to stand a few minutes, stir, and drink immediately. You may experience loss of appetite or change in taste (sucking on lozenges, chewing gum, or small, frequent meals may help); dizziness or numbness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or headache, fever, or muscle pain (an analgesic may be recommended). Report persistent lethargy, acute headache, severe nausea or vomiting, respiratory difficulty, loss of sensation, or rash. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information

Lamivudine has been well studied in the treatment of chronic hepatitis B infection. Potential compliance problems, frequency of administration, and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

A high rate of early virologic nonresponse was observed when abacavir, lamivudine and tenofovir were used as the initial regimen in treatment-naive patients. A high rate of early virologic nonresponse was also observed when didanosine, lamivudine, and tenofovir were used as the initial regimen in treatment-naive patients. Use of either of these combinations is not recommended; patients currently on either of these regimens should be closely monitored for modification of therapy.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Fatigue and insomnia are common; may cause dizziness or depression

Mental Health: Effects on Psychiatric Treatment

May rarely cause neutropenia; use caution with clozapine and carbamazepine

Dosage Forms

Solution, oral:

Epivir®: 10 mg/mL (240 mL) [strawberry-banana flavor]

Epivir-HBV®: 5 mg/mL (240 mL) [strawberry-banana flavor]

Tablet:

Epivir®: 150 mg, 300 mg

Epivir-HBV®: 100 mg

References

CDC and the National Foundation for Infectious Disease, "Update: Provisional Public Health Service Recommendations for Chemoprophylaxis After Occupational Exposure to HIV,"MMWR Morb Mortal Wkly Rep, 1996, 45(22):468-80.

Dienstag JL, Perrillo, RP, Schiff, ER, et al, "A Preliminary Trial of Lamivudine for Chronic Hepatitis B Infection,"N Engl J Med, 1995, 333(25):1657-61.

Eron JJ, Benoit SL, Jemsek J, et al, "Treatment With Lamivudine, Zidovudine, or Both in HIV-Positive Patients With 200 to 500 CD4⁺ Cells Per Cubic Millimeter,"N Engl J Med, 1995, 333(25):1662-9.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Panel on Clinical Practices for Treatment of HIV Infection," March 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed June 1, 2004.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction,"Am J Health Syst Pharm, 1998, 55:2528-33.

Johnson MA, Verpooten GA, Daniel MJ, et al, "Single Dose Pharmacokinetics of Lamivudine in Subjects With Impaired Renal Function and the Effect of Haemodialysis,"Br J Clin Pharmacol, 1998, 46(1):21-7.

Lai CL, Chien RN, Leung NW, et al, "A One-Year Trial of Lamivudine for Chronic Hepatitis B,"N Engl J Med, 1998, 339(2):61-8.

Lewis LL, Mueller B, Schock R, et al, "A Phase I/II Study to Evaluate the Safety, Toxicity, and Preliminary Efficacy of Combinations of Lamivudine (3TC), Zidovudine (AZT) and Didanosine (ddI) in Children With HIV Infection,"Natl Conf Hum Retroviruses Relat Infect (2nd), 1995, Jan 29-Feb 2:103.

Lewis LL, Venzon D, Church J, et al, "Lamivudine in Children With Human Immunodeficiency Virus Infection: A Phase I/II Study,"J Infect Dis, 1996, 174(1):16-25.

Perry CM and Faulds D, "Lamivudine. A Review of Its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in the Management of HIV Infection,"Drugs, 1997, 53(4):657-80.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," March 1, 1999. Available at: http://www.aidsinfo.nih.gov.

International Brand Names

Birvac® (AR); Cipla-Lamivudine® (ZA); Epirex Pour-on® (AT); Epivir 3TC® (CL, EC, RU); Epivir® (AT, BE, BG, CZ, DE, DK, ES, FI, FR, GB, HR, IE, IL, IT, KW, LU, NL, NO, PT, RO, SE, SG, SI, TH, TR, YU); Heptodine® (AR); Heptovir® (CA); Imunoxa® (AR); Inhavir® (CO); Kess® (AR); Ladiwin® (IN); Lamibergen® (AR); Lamidac® (IN); Lamilea® (AR); Lamivudina Biocrom® (AR); Lamivudina Delta® (AR); Lamivudina Dosa® (AR); Oralmuv® (AR); 3TC® (AR, AU, CA, CH, CR, DO, GT, HN, ID, MX, NZ, PA); 3 TC® (PL); 3TC® (SV, ZA); Vuclodir® (AR); Zeffix® (AT, AU, BE, BG, BR, CH, DE, DK, ES, FI, FR, GB, HR, HU, IE, IL, IT, NL, NZ, PL, PT, RO, RU, SE, SG, SI, TH, YU)