Abacavir and Lamivudine (Page 5 of 8)

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. 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) serious 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 are not recommended for patients with creatinine clearance less than 50 mL per min because abacavir and lamivudine tablets are 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 tablets are 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, USP (also known as EPIVIR ® or 3TC) with inhibitory activity against HIV-1.

Abacavir and lamivudine tablets USP are for oral administration. Each yellow, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate, USP and 300 mg of lamivudine, USP, and the inactive ingredients FD&C yellow #6, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Abacavir Sulfate, USP The chemical name of abacavir sulfate, USP is (1 S,cis)-4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate, USP is the enantiomer with 1S , 4R absolute configuration on the cyclopentene ring. It has the following structural formula:

abacavir structure
(click image for full-size original)

(C 14 H 18 N 6 O) 2 •H 2 SO 4 M.W. 670.76

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

In vivo , abacavir sulfate, USP dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.

Lamivudine, USP
The chemical name of lamivudine, USP is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine, USP is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has the following structural formula:

lamivudine structure

C 8 H 11 N 3 O 3 S M.W. 229.3

Lamivudine, USP is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Abacavir and lamivudine tablets are 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 tablets 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 * for Abacavir and Lamivudine in Adults
*
Data presented as mean ± standard deviation except where noted.
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

Effect of Food on Absorption of Abacavir and Lamivudine Tablets

Abacavir and lamivudine tablets may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUC last , AUC , and C max for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC ), but the rate of absorption (C max ) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.

Specific Populations

Renal Impairment: Abacavir and Lamivudine Tablets: The effect of renal impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components).

Hepatic Impairment: Abacavir and Lamivudine Tablets: The effect of hepatic impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components).

Pregnancy: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration of abacavir and lamivudine tablets in pediatric subjects weighing 25 kg and above are limited. 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. Refer to the EPIVIR ® and ZIAGEN ® USPI for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration ( 2.3), Adverse Reactions ( 6.1), Clinical Studies ( 14.2)].

Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.

Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.

Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.

Drug Interactions

The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with abacavir and lamivudine tablets.

Cytochrome P450 Enzymes: In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Abacavir: Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h).

Other Interactions

Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Methadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN ® twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions ( 7)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions ( 5.4)].

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.

Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine
*
The drug-drug interaction was only evaluated in males.

Coadministered Drug and Dose

Drug and Dose

n

Concentrations of Abacavir or Lamivudine

Concentration of Coadministered Drug

AUC

Variability

Ethanol 0.7 g/kg

Abacavir Single 600 mg

24

↑41%

90% CI: 35% to 48%

*

Nelfinavir 750 mg every 8 h x 7 to 10 days

Lamivudine Single 150 mg

11

↑10%

95% CI: 1% to 20%

Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily x 5 days

Lamivudine Single 300 mg

14

↑43%

90% CI: 32% to 55%

↑ = Increase; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.

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