Zidovudine (Page 3 of 6)

6.2 Postmarketing Experience


In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zidovudine.

Body as a Whole:

Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat

[see Warnings and Precautions (5.6)]

.


Cardiovascular:

Cardiomyopathy

,

syncope.

Endocrine:

Gynecomastia.

Eye:

Macular edema.

Gastrointestinal:

Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

General:

Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hemic and Lymphatic:

Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary Tract and Pancreas:

Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Musculoskeletal:

Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.

Nervous:

Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Respiratory:

Dyspnea, rhinitis, sinusitis.

Skin:

Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweat, urticaria.

Special Senses:

Amblyopia, hearing loss, photophobia, taste perversion.

Urogenital:

Urinary frequency, urinary hesitancy.

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents


Stavudine:

Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship 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


Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated

in vitro

.

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents


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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


Teratogenic Effects

Pregnancy Category C.

In humans, treatment with zidovudine 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

[see Clinical Studies (14.3)]

. There were no differences in pregnancy-related adverse events between the treatment groups. Animal

r

eproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.

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

[see Clinical Studies (14.3)]

. 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.

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 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)]

.

Antiretroviral Pregnancy Registry:

To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers


Zidovudine is excreted in human milk

[see Clinical Pharmacology (12.3)]

.

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 both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving zidovudine.

8.4 Pediatric Use


Zidovudine has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Zidovudine has also been studied in neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].

8.5 Geriatric Use


Clinical studies of zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment


In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is recommended

[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment


Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function which may increase the risk of hematologic toxicity

[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

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