ABACAVIR SULFATE, LAMIVUDINE AND ZIDOVUDINE (Page 4 of 7)

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 (-)-1-(2R -Cis)-4-amino-1-[(2-hydroxymethyl)-1,3-oxathiolan-5-yl]-2(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
(click image for full-size original)

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)].

12.3 Pharmacokinetics

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 abacavir, lamivudine and zidovudine tablet versus 1 ZIAGEN® tablet (300 mg), 1 EPIVIR® tablet (150 mg), plus 1 RETROVIR® tablet (300 mg) administered simultaneously in healthy subjects (n = 24), 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 (Cmax), of all 3 components. One abacavir, lamivudine and zidovudine tablet was bioequivalent to 1 ZIAGEN® tablet (300 mg), 1 EPIVIR® tablet (150 mg), plus 1 RETROVIR® tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Abacavir:

Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0 to 12 h) was 6.02 ± 1.73 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. 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).

Zidovudine:

Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3′-amino-3′ deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

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

The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.

Table 3. Pharmacokinetic Parameters * for Abacavir, Lamivudine, and Zidovudine in Adults
Parameter Abacavir Lamivudine Zidovudine
*
Data presented as mean ± standard deviation except where noted.
Approximate range.
Oral bioavailability (%) 86 ± 25 n = 6 86 ± 16 n = 12 64 ± 10 n = 5
Apparent volume of distribution (L/kg) 0.86 ± 0.15 n = 6 1.3 ± 0.4 n = 20 1.6 ± 0.6 n = 8
Systemic clearance (L/h/kg) 0.80 ± 0.24 n = 6 0.33 ± 0.06 n = 20 1.6 ± 0.6 n = 6
Renal clearance (L/h/kg) 0.007 ± 0.008 n = 6 0.22 ± 0.06 n = 20 0.34 ± 0.05 n = 9
Elimination half-life (h) 1.45 ± 0.32 n = 20 5 to 7 0.5 to 3

Effect of Food on Absorption of Abacavir, Lamivudine and Zidovudine tablets

Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of abacavir, lamivudine and zidovudine tablets with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see DOSAGE AND ADMINISTRATION (2.1)].

Special Populations

Renal Impairment:

Abacavir, Lamivudine And Zidovudine Tablets

The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).

Hepatic Impairment:

Abacavir, Lamivudine and Zidovudine Tablets

The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).

Pregnancy:

Abacavir

No data are available on the pharmacokinetics of abacavir during pregnancy.

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.

Zidovudine:

Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients:

The pharmacokinetics of abacavir, lamivudine, and zidovudine 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, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.

Race:

Abacavir and Lamivudine

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

Zidovudine:

The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interactions

The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using abacavir, lamivudine and zidovudine tablets. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine.

Cytochrome P450 Enzymes:

Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Glucuronyl Transferase :

Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover 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.

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.

Interferon Alfa :

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

Methadone :

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see DRUG INTERACTIONS (7.1)]. 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 (5.6)].

The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.

Table 4. Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUC *

↑= Increase; ↓= Decrease; ↔= no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.

*
See DRUG INTERACTIONS (7) for additional information on drug interactions.
The drug-drug interaction was only evaluated in males.
Estimated range of percent difference.
Coadministered Drug and Dose Drug and Dose n Cncentrations of Abacavir , Lamivudine , or Zidovudine Concentration of Coadministered Drug
AUC Variability
Ethanol0.7 g/kg Abacavir single600 mg 24 ↑41% 90% CI:35% to 48%
Nelfinavir750 mg every 8 h x 7 to 10 days Lamivudine Single150 mg 11 ↑10% 95% CI:1% to 20%
Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single300 mg 14 ↑43% 90% CI:32% to 55%
Atovaquone750 mg every 12 h with food Zidovudine200 mg every8 h 14 ↑31% Range: 23% to 78%
Clarithromycin 500 mg twice daily Zidovudine100 mg every4 h x 7 days 4 ↓12% Range:↓34% to ↑14% Not Reported
Fluconazole 400 mg daily Zidovudine200 mg every8 h 12 ↑74% 95% CI:54% to 98% Not Reported
Methadone 30 to 90 mg daily Zidovudine200 mg every4 h 9 ↑43% Range:16% to 64%
Nelfinavir 750 mg every 8 h x 7 to 10 days ZidovudineSingle200 mg 11 ↓35% Range:28% to 41%
Probenecid 500 mg every 6 h x2 days Zidovudine2 mg/kg every8 h x 3 days 3 ↑106% Range:100% to 170% c Not Assessed
Rifampin 600 mg daily x 14 days Zidovudine200 mg every8 h x 14 days 8 ↓47% 90% CI:41% to 53% Not Assessed
Ritonavir 300 mg every 6 h x 4 days Zidovudine200 mg every 8 h x 4 days 9 ↓25% 95% CI:15% to 34%
Valproic acid 250 mg or 500 mg every 8 h x 4 days Zidovudine100 mg every 8 h x4 days 6 ↑80% Range:64% to 130% Not Assesed

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