Lamivudine and Zidovudine (Page 3 of 7)

6.2 Postmarketing Experience


In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of lamivudine, zidovudine, and/or lamivudine and zidovudine tablet. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine, zidovudine, and/or lamivudine and zidovudine tablet.
Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.9)].
Cardiovascular: Cardiomyopathy.
Endocrine and Metabolic: Gynecomastia, hyperglycemia.
Gastrointestinal: Oral mucosal pigmentation, stomatitis.
General: Vasculitis, weakness.
Hemic and Lymphatic: Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.
Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.7)].
Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.
Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.
Nervous: Paresthesia, peripheral neuropathy, seizures.
Respiratory: Abnormal breath sounds/wheezing.
Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

7 DRUG INTERACTIONS


No drug interaction studies have been conducted using lamivudine and zidovudine tablets [see Clinical Pharmacology (12.3)].

7.1 Antiretroviral Agents


Lamivudine: Zalcitabine: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine and zidovudine tablet in combination with zalcitabine is not recommended.
Zidovudine: Stavudine: Concomitant use of lamivudine and zidovudine tablet with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided.

7.2 Doxorubicin


Zidovudine: Concomitant use of lamivudine and zidovudine tablet with doxorubicin should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro.

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents


Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

7.4 Interferon- and Ribavirin-Based Regimens

Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-l/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

7.5 Trimethoprim/Sulfamethoxazole (TMP/SMX)


Lamivudine: 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects:
Pregnancy Category C.
Fetal Risk Summary: There are no adequate and well-controlled studies of lamivudine and zidovudine tablet in pregnant women. Clinical trial data demonstrate that maternal zidovudine treatment during pregnancy reduces vertical transmission of HIV-1 infection to the fetus. Animal reproduction studies performed with lamivudine and zidovudine showed increased embryotoxicity fetal malformations (zidovudine), and increased embryolethality (lamivudine). Lamivudine and Zidovudine Tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations: Treatment of HIV during pregnancy optimizes the health of both mother and fetus. Clinical trial data reviewed by FDA demonstrate that maternal zidovudine treatment significantly reduces vertical transmission of HIV-1 infection to the fetus [see Clinical Studies (14.2)]. Published data suggest that combination antiretroviral regimens may reduce the rate of vertical transmission even further.
Pharmacokinetics of lamivudine and zidovudine in pregnant women are similar to the pharmacokinetics in nonpregnant women. No dose adjustments are needed during pregnancy.
In a clinical trial, adverse events among HIV-1-infected women were not different among untreated women and women treated with zidovudine. It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients (see Human data below).
Data:Human Data: Lamivudine: Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa. The study 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. Lamivudine pharmacokinetics in pregnant women were similar to those seen in nonpregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.
Zidovudine: A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug [see Clinical Studies (14.2)].
Zidovudine pharmacokinetics were studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.
Animal Data: Lamivudine: 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 [see Nonclinical Toxicology (13.2)].
Zidovudine: Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose [see Nonclinical Toxicology (13.2)].

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