ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abacavir

Cardiovascular :

Myocardial infarction.

Skin :

Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see ADVERSE REACTIONS (6.1)].

Abacavir, Lamivudine, and/or Zidovudine

Body as a Whole :

Redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS (5.8)].

Cardiovascular :

Cardiomyopathy.

Digestive :

Stomatitis.

Endocrine and Metabolic :

Gynecomastia.

Gastrointestinal:

Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.

General :

Vasculitis, weakness.

Hemic and Lymphatic :

Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.

Hepatic :

Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS (5.4)] , elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS (5.5)].

Hypersensitivity :

Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal :

Arthralgia, myalgia, muscle weakness, rhabdomyolysis.

Nervous :

Dizziness, paresthesia, peripheral neuropathy, seizures.

Psychiatric :

Insomnia and other sleep disorders.

Respiratory :

Abnormal breath sounds/wheezing.

Skin :

Alopecia, erythema multiforme, Stevens-Johnson syndrome.

7 DRUG INTERACTIONS

7.1 Abacavir

Methadone

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN® twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY (12.3)]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

7.2 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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C:

There are no adequate and well-controlled studies of abacavir, lamivudine and zidovudine tablets in pregnant women. Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below). Abacavir, lamivudine and zidovudine tablets should be used during pregnancy only if the potential benefits outweigh the risks.

Pregnancy Exposure Registry:

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir, lamivudine and zidovudine tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Abacavir:

Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.

Lamivudine:

Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

Zidovudine:

Reproduction studies with orally administered zidovudine in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an additional teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of approximately 3,700 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less. Two rodent carcinogenicity studies were conducted [see NONCLINICAL TOXICOLOGY (13.1)].

8.2 Lactation

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.

8.4 Pediatric Use

Abacavir, lamivudine and zidovudine tablet is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see DOSAGE AND ADMINISTRATION (2.2)].

Therapy-Experienced Pediatric Trial

A randomized, double-blind trial, CNA3006, compared ZIAGEN® plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.

8.5 Geriatric Use

Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of abacavir, lamivudine and zidovudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY (12.3)].

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