Abacavir and Lamivudine (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 and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine 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 abacavir and lamivudine tablets.

8.4 Pediatric Use

The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or abacavir and lamivudine tablets [see DOSAGE AND ADMINISTRATION ( 2.3), ADVERSE REACTIONS ( 6.2), CLINICAL STUDIES ( 14.2)] .

In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.

8.5 Geriatric Use

Clinical trials of abacavir and lamivudine 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 and lamivudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see DOSAGE AND ADMINISTRATION ( 2.4), USE IN SPECIFIC POPULATIONS ( 8.6, 8.7)].

8.6 Patients with Impaired Renal Function

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

8.7 Patients with Impaired Hepatic Function

Abacavir and lamivudine 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 and lamivudine tablets, 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 and lamivudine tablets are contraindicated in these patients [see CONTRAINDICATIONS ( 4)].

10 OVERDOSAGE

There is no known specific treatment for overdose with abacavir and lamivudine 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.

11 DESCRIPTION

Abacavir and Lamivudine Tablets USP

Abacavir and lamivudine tablets USP contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR ®) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1.

Abacavir and lamivudine tablets USP are for oral administration. Each orange colored, oval shaped, biconvex, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients crospovidone, magnesium stearate, microcrystalline cellulose, and povidone. The tablets are coated with a film that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol, polysorbate, and titanium dioxide.

Abacavir Sulfate

The chemical name of abacavir sulfate is (1S,4R)- 4-[2-Amino-6-(cyclopropylamino) -9H- purin-9-yl]-2-cyclopentene-1-methanol sulfate (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C 14 H 18 N 6 O) 2 . H 2 SO 4 and a molecular weight of 670.74 g per mol. It has the following structural formula:

Image-02
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Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg per mL in distilled water at 25°C.

In vivo, abacavir sulfate dissociates to its free base, abacavir. 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. 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 C 8 H 11 N 3 O 3 S and a molecular weight of 229.26 g per mol. It has the following structural formula:

image-03
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Lamivudine is a white to off-white solid with a solubility of approximately 68 mg per mL in water at 20°C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Abacavir and lamivudine tablet is an antiretroviral agent [see MICROBIOLOGY ( 12.4)].

12.3 Pharmacokinetics

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 abacavir and lamivudine tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (C max ), of each component.

Abacavir:

Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C max was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC was 11.95 ± 2.51 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.

Lamivudine:

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state C max (C max , ss ) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC 24 , ss ) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.

Table 2. Pharmacokinetic Parameters a for Abacavir and Lamivudine in Adults

a Data presented as mean ± standard deviation except where noted.

b Approximate range.

Parameter Abacavir Lamivudine
Oral bioavailability (%) 86 ± 25 n = 6 86 ± 16 n = 12
Apparent volume of distribution (L/kg) 0.86 ± 0.15 n = 6 1.3 ± 0.4 n = 20
Systemic clearance (L/h/kg) 0.80 ± 0.24 n = 6 0.33 ± 0.06 n = 20
Renal clearance (L/h/kg) 0.007 ± 0.008 n = 6 0.22 ± 0.06 n = 20
Elimination half-life (h) 1.45 ± 0.32 n = 20 5 to 7 b

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