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Lamivudine

Pronunciation
( 3TC )

Pronunciation: la-MIV-ue-deen
Class: Nucleoside reverse transcriptase inhibitor

Trade Names

Epivir
- Tablets, oral 150 mg
- Tablets, oral 300 mg
- Solution, oral 10 mg/mL

Epivir-HBV
- Tablets, oral 100 mg
- Solution, oral 5 mg/mL

Heptovir (Canada)

Pharmacology

Inhibits replication of HIV and hepatitis B virus (HBV).

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Pharmacokinetics

Absorption

C max is approximately 1.5 mcg/mL (HIV, 300 mg daily). T max is 0.5 to 2 h. Absolute bioavailability is approximately 86% (for 150 mg oral tablet).

Distribution

Less than 36% protein bound. Vd is approximately 1.3 L/kg.

Metabolism

Metabolism of lamivudine is a minor route of elimination. The metabolite is trans-sulfoxide metabolite.

Elimination

The majority is eliminated unchanged in the urine. Mean half-life is 5 to 7 h. Cl is approximately 398.5 mL/min.

Special Populations

Renal Function Impairment

AUC, C max , and half-life are increased. It is recommended that the dosage be modified in these patients.

Hepatic Function Impairment

Pharmacokinetics are not altered by hepatic impairment; therefore, dosage adjustment is not required.

Children

The absolute bioavailability is decreased. Systemic Cl is decreased with increasing age.

Indications and Usage

Epivir

In combination with other antiretroviral agents for the treatment of HIV infection.

Epivir-HBV

Treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.

Contraindications

Hypersensitivity to any component of the product.

Dosage and Administration

HIV Infection ( Epivir )
Adults and children older than 16 y

PO 150 mg twice daily or 300 mg once daily in combination with other antiretroviral agents.

Children 3 mo to 16 y of age

PO 4 mg/kg twice daily (max, 150 mg twice daily) in combination with other antiretroviral agents. Dosage adjustment needed in patients with renal impairment.

Chronic Hepatitis B ( Epivir-HBV )
Adults

PO 100 mg once daily. Safety and efficacy of treatment longer than 1 y not established.

Children 2 to 17 y of age

PO 3 mg/kg once daily (max, 100 mg/day). Safety and efficacy of treatment longer than 1 y not established.

Renal Function Impairment
Epivir Adults and adolescents Patients weighing 30 kg or more CrCl 50 mL/min or more

PO 150 mg twice daily or 300 mg once daily.

CrCl 30 to 49 mL/min

PO 150 mg once daily.

CrCl 15 to 29 mL/min

PO 150 mg first dose, then 100 mg once daily.

CrCl 5 to 14 mL/min

PO 150 mg first dose, then 50 mg once daily.

CrCl less than 5 mL/min

PO 50 mg first dose, then 25 mg once daily.

Dialysis

No additional dosing is needed after routine (4-h) hemodialysis or peritoneal dialysis.

Children

There are insufficient data to recommend a specific dose adjustment in children with renal impairment; however, a reduction in dose and/or an increase in the dosing interval should be considered.

Epivir-HBV Adults CrCl at least 50 mL/min

PO 100 mg/day.

CrCl 30 to 49 mL/min

PO 100 mg first dose, then 50 mg/day.

CrCl 15 to 29 mL/min

PO 100 mg first dose, then 25 mg/day.

CrCl 5 to 14 mL/min

PO 35 mg first dose, then 15 mg/day.

CrCl less than 5 mL/min

PO 35 mg first dose, then 10 mg/day.

Dialysis

No additional dosing is needed after routine (4-h) hemodialysis or peritoneal dialysis.

Children

There are insufficient data to recommend a specific dose adjustment in children with renal impairment; however, a reduction in dose and/or an increase in the dosing interval should be considered.

Storage/Stability

Store Epivir oral solution at 77°F and tablets at 59° to 86°F. Store Epivir-HBV tablets between 59° and 86°F and oral solution between 68° and 77°F. Keep containers tightly closed.

Drug Interactions

Antiretroviral therapy

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. Inflammatory response to indolent or residual opportunistic infection (eg, Mycobacterium avium ) may occur. Additional evaluation of treatment may be needed.

Drugs with active renal secretion via the organic cationic transport system (eg, trimethoprim)

Lamivudine Cl may be reduced, increasing plasma concentrations. Dosage adjustments are not needed.

Interferon- and ribavirin-based regimens

Risk of hepatic decompensation may be increased. Monitor closely for treatment-associated toxicities, especially hepatic decompensation. It may be necessary to discontinue lamivudine or reduce the dose or discontinue interferon alfa, ribavirin, or both if worsening clinical toxicities are observed.

Methadone

Methadone may delay the absorption of lamivudine, resulting in a decrease in lamivudine bioavailability. Close clinical and laboratory monitoring, including changes in HIV RNA viral load, are warranted. Larger doses of lamivudine may be needed.

Trimethoprim/Sulfamethoxazole

Trimethoprim 160 mg and sulfamethoxazole 800 mg have been shown to increase lamivudine AUC 43%. Dosage adjustments are not needed.

Zalcitabine

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Use in combination is not recommended.

Adverse Reactions

Unless otherwise stated, the following adverse reactions were reported in patients receiving lamivudine in combination with zidovudine for HIV infection or during postmarketing.

CNS

Headache (35%); fatigue and malaise (27%); neuropathy (12%); insomnia and other sleep disorders (11%); dizziness (10%); depression (9%); paresthesia, peripheral neuropathy, weakness (postmarketing).

Children

Paresthesia and peripheral neuropathy (15%).

Dermatologic

Skin rash (9%); alopecia, pruritus (postmarketing).

Children

Skin rashes (12%).

EENT

Ear, nose, throat infection (for HBV treatment) (25%); nasal signs and symptoms (20%); sore throat (for HBV treatment) (13%).

Children

Nasal discharge or congestion (8%); ear signs or symptoms including discharge, erythema, pain, swelling (7%).

GI

Nausea (33%); diarrhea (18%); abdominal pain and discomfort (16%); nausea and vomiting (13%); anorexia and/or decreased appetite (10%); abdominal pain (9%); abdominal cramps (6%); dyspepsia (5%); pancreatitis, stomatitis (postmarketing).

Children

Pancreatitis (14%); diarrhea, nausea and vomiting (8%); stomatitis (6%); splenomegaly (5%).

Hematologic-Lymphatic

Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy (postmarketing).

Children

Lymphadenopathy (9%).

Hepatic

Hepatic steatosis, lactic acidosis, posttreatment exacerbation of hepatitis B (postmarketing).

Children

Hepatomegaly (11%).

Hypersensitivity

Anaphylaxis, urticaria (postmarketing).

Lab Tests

Increased lipase (10%); increased CPK (9%); decreased absolute neutrophil count (ANC) (7%); increased ALT (4%; for HBV treatment, 27%), increased amylase (4%); decreased Hgb (3%); increased AST (2%); increased bilirubin (1%).

Children

Decreased ANC (8%); decreased Hgb (4%); increased lipase, increased total amylase (3%); increased AST (2%); decreased platelets, increased ALT (1%).

Metabolic-Nutritional

Hyperglycemia, redistribution/accumulation of body fat (postmarketing).

Musculoskeletal

Musculoskeletal pain (12%); myalgia (8%); arthralgia (5%; for HBV treatment, 7%); muscle weakness, rhabdomyolysis (postmarketing).

Respiratory

Cough (18%); abnormal breath sounds/wheezing (postmarketing).

Children

Cough (15%); abnormal breath sounds/wheezing (7%).

Miscellaneous

Fever and chills (10%); weakness (postmarketing).

Children

Fever (25%).

Precautions

Warnings

Lactic acidosis with severe hepatomegaly and steatosis (including fatal cases) has been reported with the use of lamivudine alone or in combination.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued lamivudine.

Epivir and Epivir-HBV contain different doses of lamivudine. Patients with HIV should only receive dosage forms appropriate for treatment of HIV. If Epivir-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely. Because Epivir-HBV contains a lower dose of lamivudine, offer HIV counseling and testing to all patients before beginning treatment and periodically during treatment.


Monitor

Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after stopping lamivudine. Monitor patients being treated for chronic hepatitis B for loss of therapeutic response, which may affect advisability of continuing therapy.


Pregnancy

Category C . Antiretroviral agents, with the exception of efavirenz, should be continued during pregnancy.

Lactation

Excreted in breast milk. HIV-infected mothers should not breast-feed.

Children

Epivir

Safety and efficacy in children younger than 3 mo is not established.

Epivir-HBV

Safety and efficacy in children younger than 2 y is not established.

Elderly

Select dose with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Renal Function

Dosage adjustment is recommended.

Special Risk Patients

Safety and efficacy of Epivir-HBV have not been established in patients with decompensated liver disease or organ transplants or patients dually infected with HBV and HCV, hepatitis delta, or HIV. Appropriate infant immunizations should be used to prevent neonatal acquisition of HBV.

Emtricitabine- or lamivudine-containing products

Lamivudine should not be used in combination with other emtricitabine- or lamivudine-containing products.

Fat distribution

Accumulation/redistribution of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” has occurred in patients receiving antiretroviral therapy. A causal relationship has not been established.

Immune reconstitution syndrome

Has occurred.

Pancreatitis

Reported in patients receiving lamivudine, particularly in HIV-infected children with prior nucleoside exposure.

Resistant HBV

In non–HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response.

Overdosage

Symptoms

Data are limited. No signs or symptoms have been noted in the few cases of overdosage reported.

Patient Information

  • Instruct patients that the lamivudine tablets and oral solution are for oral ingestion only and to take only as prescribed. Inform patients that discontinuation of lamivudine has been associated with deterioration of liver disease in patients with HBV with or without HIV. Instruct patients to discuss any changes in regimen with their health care provider.
  • Instruct patients that lamivudine is not a cure for HIV or HBV infections and that opportunistic infections and other complications of HIV and HBV infections may continue to develop.
  • Caution patients or guardians that long-term effects of lamivudine and results from controlled clinical trials evaluating therapeutic effects and adverse reactions are unknown.
  • Inform patients of potential adverse reactions.
  • Instruct patients to notify their health care provider if signs of infection, such as a sore throat, fever, cough, or respiratory congestion, occur.
  • Instruct families to notify their health care provider of changes in neurological status, such as memory loss or confusion.
  • Warn patients that the risk of transmission of HIV or HBV to others through sexual contact or exposure to the patients' blood is still present. Instruct patients in methods and precautions to prevent transmission of HIV or HBV.
  • Instruct patients, parents, or guardians to monitor patients, especially children, for signs and symptoms of pancreatitis.
  • Caution women to discontinue breast-feeding if receiving lamivudine because of the potential for adverse reactions from lamivudine in breast-feeding infants, as well as for transmission of the HIV virus.
  • Advise women to notify their health care provider if they are pregnant or planning to become pregnant, because lamivudine is transferred to the fetus through the placenta.
  • Stress the importance of regular exams and laboratory work. Encourage patients to comply with the treatment regimen.
  • Advise patients that Epivir-HBV tablets and oral solution contain a lower dose of the same active ingredient as Epivir oral solution and tablets. Advise patients not to take Epivir-HBV concurrently with Epivir or other lamivudine- or emtricitabine-containing products.
  • Advise patients of the importance of taking lamivudine with combination therapy for HIV on a regular dosing schedule and to avoid missing doses.
  • Inform patients that redistribution or accumulation of body fat may occur during treatment with antiretroviral therapy.
  • Advise diabetic patients that lamivudine oral solutions contain sucrose.

Copyright © 2009 Wolters Kluwer Health.

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