RETROVIR (zidovudine) Capsules, Syrup, & Tablets
[March 4, 1998: Glaxo Wellcome]

PRECAUTIONS:
Information for Patients: Fifth paragraph, second sentence revised (new text in italics) -

"The long-term consequences of in utero and infant exposure to Retrovir are unknown, including the possible risk of cancer.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Fourth paragraph, first sentence -

"It is not known how predictive the results of rodent carcinogenicity studies may be for humans."

moved (see below)

The four paragraphs beginning "No evidence of mutagenicity...", "In two in vivo micronucleus studies...", "In a study involving 11 AIDS patients ..." and "No effect on male or female fertility..." deleted and replaced with -

"Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine employed in this study produced zidovudine exposures approximately three times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

"It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

"Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus test after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

"Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates."

Pregnancy: Pregnancy Category C: Text added as new second paragraph -

"Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, Impairment of Fertility)."

Source: FDA MedWatch