[Posted 03/01/2011] ISSUE: FDA updated the public about an ongoing safety review of abacavir and a possible increased risk of heart attack. There has been conflicting information on the potential increased risk of heart attack with abacavir (Ziagen) treatment. An increased risk of heart attack (myocardial infarction or MI) has been seen in several observational studies and one randomized controlled trial (RCT) with abacavir. However, an increased risk of heart attack has not been seen in other RCTs and the safety database maintained by the drug manufacturer.
FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated abacavir. This meta-analysis did not show an increased risk of MI associated with the use of abacavir. FDA will continue to communicate any new safety information to the public as it becomes available.
BACKGROUND: Abacavir is an antiviral medication used in combination with other antiretroviral drugs [abacavir and lamivudine (Epzicom); abacavir, lamivudine, and zidovudine (Trizivir)] for the treatment of HIV-1 infection.
RECOMMENDATION: Healthcare professionals should continue to prescribe abacavir according to the professional label. Patients should not stop taking their abacavir without first talking to their healthcare professional. For more information visit the FDA website at: [Web] and [Web].
Treatment of HIV infection in conjunction with other antiretrovirals.
A preferred or alternative NRTI for use in multiple-drug antiretroviral regimens for initial therapy in adults.
Fixed-combination preparation containing lamivudine and zidovudine (Combivir®) used in conjunction with other antiretrovirals.
Fixed-combination preparation containing lamivudine and abacavir (Epzicom®) used in conjunction with other antiretrovirals.
Fixed-combination preparation containing abacavir, lamivudine, and zidovudine (Trizivir®) used for triple NRTI treatment; can be used alone or in conjunction with other antiretrovirals. If using Trizivir®, consider that data are limited regarding use of the fixed combination in patients with higher viral loads (>100,000 copies/mL) at baseline.
Because of a high rate of virologic failure, a triple NRTI regimen of abacavir, lamivudine (or emtricitabine), and tenofovirnot recommended in treatment-naive or previously treated patients.
Because of inferior antiretroviral activity, a triple NRTI regimen of abacavir, lamivudine, and zidovudine is not recommended for initial therapy.
For patients coinfected with hepatitis B virus (HBV), some experts recommend an NRTI combination of tenofovir and (emtricitabine or lamivudine); avoid use of regimens containing only 1 of these antiretrovirals (may increase risk of HBV resistance).
Maternal-fetal Transmission of HIV
If a single-dose nevirapine regimen (alone or in conjunction with intrapartum/newborn zidovudine) is used for prevention of maternal-fetal transmission of HIV in women in labor who received no prior antiretroviral therapy, some clinicians suggest that consideration be given to adding zidovudine and lamivudine regimen in the mother and lamivudine in the neonate to reduce the development of nevirapine resistance.
Postexposure Prophylaxis of HIV
Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus. Used in conjunction with other antiretrovirals.
Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.
Chronic Hepatitis B Virus (HBV) Infection
Management of chronic HBV infection associated with evidence of HBV replication and active liver inflammation.
Safety and efficacy not established in patients with decompensated liver disease and there are no studies in pregnant women and no data regarding effect on vertical transmission of HBV.
Safety and efficacy for treatment of chronic HBV infection in patients coinfected with both HBV and HIV† have not been established.
Appears to reduce risk of HBV reinfection in orthotopic liver transplant recipients†.
Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.
Dosage and Administration
Administration
Oral Administration
Administer single-entity preparations (Epivir®, Epivir-HBV®) or fixed-combination preparations (Combivir®, Epzicom®, Trizivir®) orally without regard to meals.
For treatment of HIV infection, lamivudine oral solution containing 10 mg/mL and film-coated tablets containing 150 mg of the drug (Epivir®) are used.
For management of chronic HBV infection, lamivudine oral solution containing 5 mg/mL and film-coated tablets containing 100 mg of the drug (Epivir-HBV®) are used.
Because dosage of lamivudine and zidovudine cannot be adjusted individually, the fixed-combination containing lamivudine and zidovudine (Combivir®) should not be used in individuals requiring dosage adjustment, including children <12 years of age, patients with impaired renal function (i.e., Clcr <50 mL/minute), patients with impaired hepatic function, and patients who experience dose-limiting adverse effects.
Since dosage of lamivudine and abacavir cannot be adjusted individually, the fixed-combination containing lamivudine and abacavir (Epzicom®) should not be used in pediatric patients; patients with impaired renal function (i.e., Clcr <50 mL/minute); patients with hepatic impairment; or patients who experience dose-limiting adverse effects.
Since dosage of the drugs cannot be adjusted individually, the fixed-combination containing lamivudine, abacavir, and zidovudine (Trizivir®) should not be used in pediatric patients; adolescents or adults with low body weight (i.e., <40 kg); patients with impaired renal function (i.e., Clcr <50 mL/minute); patients with impaired hepatic function; or patients who experience dose-limiting adverse effects.
Dosage
Dosage of Combivir®, Epzicom®, and Trizivir® expressed as number of tablets.
Epivir®, Epzicom®, and Combivir® must be used in conjunction with other antiretrovirals; Trizivir® may be used alone or in conjunction with other antiretrovirals.
Pediatric Patients
Treatment of HIV Infection
Oral
Infants <30 days of age†: 2 mg/kg twice daily (Epivir®) suggested by some experts.
Children 3 months to 16 years of age: 4 mg/kg (maximum 150 mg) twice daily (Epivir®).
Adolescents ≥16 years of age weighing ≥50 kg: 150 mg twice daily or 300 mg once daily (Epivir®).
Adolescents ≥16 years of age weighing <50 kg: 4 mg/kg (maximum 150 mg) twice daily (Epivir®).
Combivir®: 1 tablet twice daily in adolescents ≥12 years of age.
Trizivir®: 1 tablet twice daily in adolescents weighing ≥40 kg.
Maternal-fetal Transmission of HIV
Zidovudine and Lamivudine Regimen
Oral
Neonates born to women who received no antiretroviral therapy prior to labor: 2 mg/kg every 12 hours (Epivir®) given for 7 days in conjunction with a 6 week regimen of oral or IV zidovudine.
Used in conjunction with intrapartum regimen of IV and oral zidovudine and oral lamivudine in the mother.
Chronic Hepatitis B Virus (HBV) Infection
Oral
Children 2–17 years of age: 3 mg/kg once daily (maximum 100 mg) (Epivir-HBV®).
Optimal duration of treatment unknown; safety and efficacy >1 year not established.
Adults
Treatment of HIV Infection
Oral
150 mg twice daily or 300 mg once daily (Epivir®).
Combivir®: 1 tablet twice daily.
Epzicom®: 1 tablet once daily.
Trizivir®: 1 tablet twice daily in adults weighing ≥40 kg.
Maternal-fetal Transmission of HIV
Zidovudine and Lamivudine Regimen
Oral
Women in labor who have received no prior antiretroviral therapy: 150 mg at onset of labor, then 150 mg every 12 hours during labor. Given with IV zidovudine during labor, then lamivudine 150 mg twice daily and oral zidovudine 300 mg twice daily for 1 week.
Usually used in conjunction with a 7-day regimen of oral zidovudine and lamivudine in the neonate.
Postexposure Prophylaxis of HIV
Occupational Exposure
Oral
300 mg once daily or 150 mg twice daily (Epivir®).†
Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.†
Nonoccupational Exposure
Oral
300 mg once daily or 150 mg twice daily (Epivir®).†
Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.†
Chronic Hepatitis B Virus (HBV) Infection
Oral
100 mg once daily (Epivir-HBV®).
Optimal duration of treatment unknown; safety and efficacy >1 year not established.
Prescribing Limits
Pediatric Patients
Treatment of HIV Infection
Oral
Children 3 months to 16 years of age: Maximum 150 mg twice daily (Epivir®).
Chronic Hepatitis B Virus (HBV) Infection
Oral
Children 2–17 years of age: Maximum 100 mg daily (Epivir-HBV®).
Special Populations
Hepatic Impairment
Treatment of HIV Infection
Oral
Dosage adjustment not needed.
Chronic Hepatitis B Virus (HBV) Infection
Oral
Dosage adjustment not needed.
Renal Impairment
Treatment of HIV Infection
Oral
Consider reducing dose and/or increasing dosing interval in pediatric patients with renal impairment; data insufficient to make a specific recommendation.
Dosage in Adults and Adolescents with Renal Impairment (Epivir®).
Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving lamivudine. Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors. Has been reported in patients with no known risk factors.
Use with caution in patients with known risk factors for liver disease.
Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).
Considerations in Patients with Chronic Hepatitis B Virus (HBV) Infection
Posttreatment exacerbations of HBV infection and emergence of resistant strains of HBV reported following discontinuance of lamivudine therapy for HBV (non-HIV-infected patients). Exacerbations of HBV infection also reported following discontinuance of a lamivudine-containing antiretroviral regimen in patients coinfected with HBV and HIV.
Clinical and laboratory evidence of exacerbations of hepatitis (increases in serum ALT concentrations, increases in serum HBV DNA levels) reported following discontinuance of lamivudine. Most events appear to have been self-limited; some fatalities reported.
Closely monitor patients with both clinical and laboratory follow-up for at least several months after stopping lamivudine treatment. Insufficient evidence to determine whether reinitiation of therapy alters the course of posttreatment exacerbations of hepatitis.
HIV counseling and testing should be offered to all patients prior to and during Epivir-HBV® therapy.
Epivir-HBV® is not appropriate for patients coinfected with HBV and HIV since it contains a lower dose of lamivudine than Epivir®. If a decision is made to use lamivudine in such patients, Epivir® should be used in dosages appropriate for treatment of HIV infection. Use of Epivir-HBV® in patients with unrecognized or untreated HIV infection may result in rapid emergence of resistant HIV because the dose is subtherapeutic and monotherapy is inappropriate.
Interactions
Concomitant use with ribavirin and interferon alfa associated with increased risk of fatal hepatic decompensation in patients coinfected with HBV and HIV. (See Specific Drugs under Interactions.)
General Precautions
Do not use multiple lamivudine-containing preparations concomitantly.
Lamivudine should not be administered with emtricitabine (Emtriva®) or fixed-combination preparations containing emtricitabine (Truvada®, Atripla®).
Use of Fixed Combinations
When used in fixed combination with abacavir (Epzicom®), consider the cautions, precautions, and contraindications associated with abacavir.
When used in fixed combination with zidovudine (Combivir®), consider the cautions, precautions, and contraindications associated with zidovudine.
When used in fixed combination with abacavir and zidovudine (Trizivir®), consider the cautions, precautions, and contraindications associated with the concomitant agents.
HBV Resistance
Lamivudine-resistant HBV detected in patients receiving the drug for treatment of HBV; diminished treatment response reported. Lamivudine-resistant HBV also detected in HIV-infected patients coinfected with HBV who received a lamivudine-containing antiretroviral regimen.
Monitoring ALT concentrations and HBV DNA levels may assist in treatment decisions if emergence of resistant HBV is suspected.
Adipogenic Effects
Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.
Immune Reconstitution Syndrome
During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.
Diabetes Mellitus
Epivir® oral solution contains 3 g of sucrose per 15 mL of solution.
Epivir-HBV® oral solution contains 4 g of sucrose per 20 mL of solution.
Possible Prescribing and Dispensing Errors
Ensure accuracy of the prescription; similarity of spelling lamotrigine (Lamictal®) and lamivudine may result in errors.
Specific Populations
Pregnancy
Category C.
Antiretroviral Pregnancy Registry at 800-258-4263.
A preferred NRTI for use in multiple-drug antiretroviral regimens in pregnant women.
Lamivudine has not been shown to affect transmission of HBV from mother to infant; immunize the infant to prevent neonatal acquisition of HBV.
Lactation
Distributed into human milk.
Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.
Instruct HBV-infected women not to breast-feed because of the risks of adverse effects in the infant.
Pediatric Use
Safety and efficacy established for treatment of HIV infection in pediatric patients >3 months of age.
Limited pharmacokinetic and safety data available in infants ≤1 week of age who received lamivudine for prevention of perinatal transmission of HIV.
Pancreatitis, sometimes fatal, reported in antiretroviral nucleoside-experienced HIV-infected pediatric patients. Caution in pediatric patients with prior antiretroviral nucleoside exposure, history of pancreatitis, or other risk factors for pancreatitis. Discontinue lamivudine if sign, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.
Safety and efficacy established for management of chronic HBV infection in pediatric patients 2–17 years of age. Safety and efficacy for this indication not established in children <2 years of age.
Geriatric Use
Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.
Hepatic Impairment
Safety and efficacy not established in the presence of decompensated liver disease.
Use with caution in patients with known risk factors for liver disease.
Renal Impairment
Dosage adjustment needed based on degree of renal impairment. (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Nausea, dizziness, fatigue and/or malaise, headache, dreams, insomnia and other sleep disorders, rash.
Interactions
Eliminated in the urine by active organic cationic secretion; possibility of interactions with other drugs eliminated by active renal secretion via the organic cationic transport system.
Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HBV and HIV who are receiving interferon alfa, ribavirin, and antiretroviral agents
If lamivudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing lamivudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin
In vitro evidence of additive or synergistic antiretroviral effects
Ribavirin
Ribavirin can reduce phosphorylation of lamivudine; no evidence of pharmacokinetic or pharmacodynamic interaction in patients coinfected with HBV and HIV
Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HBV and HIV who are receiving interferon alfa or peginterferon alfa, ribavirin, and antiretroviral agents
If lamivudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing lamivudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Childs Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin
In vitro evidence of additive or synergistic antiretroviral effects
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed from GI tract; peak plasma concentrations achieved within 0.5–2 hours. Absolute bioavailability is 86–87% in HIV-infected individuals.
Fixed-combination tablet containing lamivudine 150 mg and zidovudine 300 (Combivir®) is bioequivalent to one 150-mg tablet of lamivudine and one 300-mg tablet of zidovudine given simultaneously.
Fixed-combination tablet containing abacavir 600 mg and lamivudine 300 (Epzicom®) is bioequivalent to two 300-mg tablets of abacavir and two 150-mg tablets of lamivudine given simultaneously.
Fixed-combination tablet containing abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg (Trizivir®) is bioequivalent to a 300-mg abacavir tablet, a 150-mg lamivudine tablet, and a 300-mg zidovudine tablet given simultaneously.
Food
Food does not appear to affect absorption.
Special Populations
Peak plasma concentrations and AUCs in patients with hepatic impairment are similar to those in patients with normal hepatic function.
Peak plasma concentrations and AUCs increased in patients with renal impairment.
Absolute bioavailability is 66% in HIV-infected pediatric patients (4.8 months to 16 years of age).
Distribution
Extent
Not well characterized; distributes into extravascular spaces.
Distributed into CSF; concentrations in CSF may be 5.6–30.9% of concurrent plasma concentrations in HIV-infected children.
Crosses the placenta and is distributed into milk.
Plasma Protein Binding
<36%.
Elimination
Metabolism
Metabolism is a minor route of elimination.
Intracellularly, lamivudine is phosphorylated and converted by cellular enzymes to the active 5′-triphosphate metabolite.
Elimination Route
Eliminated unchanged in urine by active organic cationic secretion.
Half-life
5–7 hours.
Half-life of 2 hours reported in children 4 months to 14 years of age.
Special Populations
Pharmacokinetics not altered in patients with hepatic impairment.
Half-life increased with diminishing renal function. Hemodialysis increases clearance; length of time of hemodialysis (4 hours) insufficient to substantially alter mean lamivudine exposure after single-dose administration. Not known whether lamivudine is removed by peritoneal dialysis or continuous (24 hour) hemodialysis.
Stability
Storage
Oral
Solution
Epivir®: 25°C in tightly closed bottles.
Epivir-HBV®: 20–25°C in tightly closed bottles.
Tablets
Epivir® and Epivir-HBV®: 25°C (may be exposed to 15–30°C).
Combivir®: 2–30°C.
Epzicom®: 25°C (may be exposed to 15–30°C).
Trizivir®: 25°C (may be exposed to 15–30°C).
Actions
Dideoxy analogue of cytidine.
Pharmacologically related to other NRTIs (e.g., abacavir, didanosine, emtricitabine, stavudine, zidovudine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.
Active in vitro against HIV-1 and HIV-2. Also active against HBV.
Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
Inhibits replication of HBV by interfering with HBV polymerase.
Strains of HIV-1 with reduced susceptibility to lamivudine have been produced in vitro and have emerged during therapy with the drug.
HBV with reduced susceptibility to lamivudine have emerged during therapy. YMDD-mutant HBV detected in adults and children receiving the drug; mutant viruses associated with diminished treatment response.
Strains of HIV resistant to lamivudine may be cross-resistant to some other NRTIs.
Cross-resistance between lamivudine and PIs is highly unlikely since the drugs have different target enzymes. Cross-resistance between lamivudine and NNRTIs is considered to be low since the drugs bind at different sites on reverse transcriptase and have different mechanisms of action.
Advice to Patients
Critical nature of compliance with HIV therapy. Importance of using lamivudine in conjunction with other antiretrovirals—not for monotherapy.
Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur. HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.
Lamivudine is not a cure for HBV infection; long-term benefits unknown; worsening of disease possible. Advise patients to report new symptoms to their clinician. Patients should be advised that deterioration of liver disease has occurred when treatment is discontinued and that any change in treatment should be discussed with the clinician.
Importance of testing for HIV in patients receiving Epivir-HBV® for management of chronic HBV infection.
Importance of reading the patient package insert for Epivir-HBV® provided by the manufacturer.
Importance of using Epivir®, not Epivir-HBV®, for treatment of HIV infection.
Possibility of pancreatitis in pediatric patients; parents or guardians advised to monitor pediatric patients for signs and symptoms.
Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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