ABACAVIR, LAMIVUDINE AND ZIDOVUDINE (Page 4 of 7)

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and 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 similar to those seen in adults, instruct mothers not to breastfeed if they are receiving abacavir, lamivudine and zidovudine tablets.

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 (2.3)].

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)].

8.6 Patients with Impaired Renal Function

Abacavir, lamivudine and zidovudine tablet is not recommended for patients with creatinine clearance less than 50 mL per min because abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of abacavir, lamivudine and zidovudine tablet is required for patients with renal impairment then the individual components should be used [see DOSAGE AND ADMINISTRATION (2.3), CLINICAL PHARMACOLOGY (12.3)].

8.7 Patients with Impaired Hepatic Function

Abacavir, lamivudine and zidovudine tablet is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of abacavir, lamivudine and zidovudine tablet, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see CLINICAL PHARMACOLOGY (12.3)].

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, abacavir, lamivudine and zidovudine tablets are contraindicated in these patients [see CONTRAINDICATIONS (4)].

Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

10 OVERDOSAGE

There is no known specific treatment for overdose with abacavir, lamivudine and zidovudine tablets. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Abacavir

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine

Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Zidovudine

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, 3′- azido-3′-deoxy-5′-O -β-D -glucopyranuronosylthymidine (GZDV), is enhanced.

11 DESCRIPTION

Abacavir, lamivudine and zidovudine tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN®), lamivudine (also known as EPIVIR® or 3TC), and zidovudine (also known as RETROVIR® , azidothymidine, or ZDV) with inhibitory activity against HIV-1.

Abacavir, lamivudine and zidovudine tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and yellow ferric oxide. The tablets are coated with a film opadry green that is made of FD&C blue no. 2, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow ferric oxide.

Abacavir Sulfate

The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S , 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14 H18 N6 O)2 ·H2 SO4 and a molecular weight of 670.74 g per mol. It has the following structural formula:

Abacavir Sulfate
(click image for full-size original)

Abacavir sulfate is a white to off-white powder and soluble in water. Dosages are expressed in terms of abacavir.

Lamivudine

The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, 0.2 hydrate. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8 H11 N3 O3 S·0.2H2 O and a molecular weight of 232.86 g per mol. It has the following structural formula:

Lamivudine
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Lamivudine is a white to off-white solid and is soluble in water.

Zidovudine

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C10 H13 N5 O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

Zidovudine
(click image for full-size original)

Zidovudine is a white to yellowish powder with a solubility of 20.1 mg/mL in water at 25°C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Abacavir, lamivudine and zidovudine tablet is an antiretroviral agent [see Microbiology (12.4)].

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