Lamivudine and zidovudine
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B Zidovudine, a component of COMBIVIR (lamivudine and zidovudine) tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV ‑ 1) disease [see Warnings and Precautions ( 5.1 )] . Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions ( 5.2 )] .
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of COMBIVIR). Discontinue COMBIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions ( 5.3 )] . Severe acute exacerbations of hepatitis B have been reported in patients who are co ‑ infected with hepatitis B virus (HBV) and HIV ‑ 1 and have discontinued lamivudine, which is one component of COMBIVIR.
Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue COMBIVIR and are co ‑ infected with HIV ‑ 1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions ( 5.4 )] . WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning • Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of COMBIVIR.
( 5.1 ) • Symptomatic myopathy associated with prolonged use of zidovudine. ( 5.2 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including lamivudine and zidovudine (components of COMBIVIR). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. ( 5.3 ) • 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, a component of COMBIVIR.
Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.4 )
Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor, Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor
Dosing in kidney impairment
patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations] .
Preparation and administration
Before prescribing COMBIVIR tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a COMBIVIR tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because COMBIVIR is a fixed‑dose tablet and cannot be dose adjusted, COMBIVIR is not recommended for:
Drug interactions
Check lamivudine and zidovudine against a medication listLabel text (3 paragraphs)
7 DRUG INTERACTIONS • Agents antagonistic with zidovudine: Concomitant use should be avoided. ( 7.1 ) • Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.1 ) • Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. ( 7.2 )
7.1 Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro: • Stavudine • Doxorubicine • Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: • Ganciclovir • Interferon alfa • Ribavirin • Other bone marrow suppressive or cytotoxic agents
7.2 Lamivudine Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology ( 12.3 )] .
Contraindications
4 CONTRAINDICATIONS COMBIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine. COMBIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COMBIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The APR uses the MACDP as the U.S. reference population for birth defects in the general population.
The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases.
There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data) . In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose.
Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that…
Lactation
8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV‑1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV‑1 infection. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving COMBIVIR.
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
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