Zidovudine (Page 5 of 9)

8.2 Lactation

Risk Summary

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. Zidovudine is present in human milk. There is no information on the effects of zidovudine on the breastfed infant or the effects of the drug 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, instruct mothers not to breastfeed if they are receiving zidovudine.

8.4 Pediatric Use

Zidovudine has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks 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 (2.2), 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

Unchanged zidovudine and its glucuronide metabolite (formed in the liver) are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of zidovudine in patients with impaired hepatic function or liver cirrhosis [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)] .

10 OVERDOSAGE

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3ʹ‑azido-3ʹ-deoxy-5ʹ- O -β- D -glucopyranuronosylthymidine (GZDV), is enhanced. If overdose occurs, the patient should be monitored for evidence of toxicity and given standard supportive treatment as required.

11 DESCRIPTION

Zidovudine (formerly called azidothymidine [AZT]), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3ʹ-Azido-3ʹ-deoxythymidine; it has the following structural formula:

Zidovudine Structural Formula

Zidovudine is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C 10 H 13 N 5 O 4 .

Zidovudine tablets are for oral administration. Each film-coated tablet contains 300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, polyethylene glycol, titanium dioxide, polyvinyl alcohol-part hydrolyzed, talc and lecithin soya.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zidovudine is an antiretroviral agent [see Microbiology (12.4)] .

12.3 Pharmacokinetics

Absorption and Bioavailability

Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per kg. The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every 4 hours were 1.1 and 0.1 mcg per mL, respectively.

In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are summarized in Table 7.

Table 7. Zidovudine Pharmacokinetic Parameters in Adult Subjects
*
Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with zidovudine.
Approximate range.

Parameter

Mean ± SD

(except where noted)

Oral bioavailability (%)

64 ± 10

(n = 5)

Apparent volume of distribution (L/kg)

1.6 ± 0.6

(n = 8)

Cerebrospinal fluid (CSF):plasma ratio *

0.6 [0.04 to 2.62]

(n = 39)

Systemic clearance (L/h/kg)

1.6 ± 0.6

(n = 6)

Renal clearance (L/h/kg)

0.34 ± 0.05

(n = 9)

Elimination half-life (h)

0.5 to 3

(n = 19)

Distribution

The apparent volume of distribution of zidovudine is 1.6 ± 0.6 L per kg (Table 7); and binding to plasma protein is low (less than 38%).

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