COMBIVIR (Page 4 of 6)

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. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs 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 COMBIVIR.

8.4 Pediatric Use

COMBIVIR is not recommended for use in pediatric patients who weigh less than 30 kg because it is a fixed‑dose combination tablet that cannot be adjusted for this patient population [see Dosage and Administration (2.2)].

8.5 Geriatric Use

Clinical trials of COMBIVIR 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 COMBIVIR 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

COMBIVIR is not recommended for patients with creatinine clearance less than 50 mL per min because COMBIVIR 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 COMBIVIR 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

COMBIVIR is a fixed‑dose combination and the dosage of the individual components cannot be adjusted. 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 COMBIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

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

COMBIVIR tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV‑1.

COMBIVIR tablets are for oral administration. Each film‑coated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

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 C8 H11 N3 O3 S and a molecular weight of 229.3 g per mol. It has the following structural formula:

lamivudine chemical structure

Lamivudine is a white to off‑white crystalline 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 chemical structure

Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Pharmacokinetics in Adults

One COMBIVIR tablet was bioequivalent to 1 EPIVIR tablet (150 mg) plus 1 RETROVIR tablet (300 mg) following single‑dose administration to fasting healthy subjects (n = 24).

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 (approximately 5% of an oral dose after 12 hours). 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 area under the curve (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, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

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

Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults

Parameter

Lamivudine

Zidovudine

Oral bioavailability (%)

86 ± 16

n = 12

64 ± 10

n = 5

Apparent volume of distribution (L/kg)

1.3 ± 0.4

n = 20

1.6 ± 0.6

n = 8

Plasma protein binding (%)

<36

<38

CSF:plasma ratiob

0.12
[0.04 to 0.47]

n = 38c

0.60
[0.04 to 2.62]

n = 39d

Systemic clearance (L/h/kg)

0.33 ± 0.06

n = 20

1.6 ± 0.6

n = 6

Renal clearance (L/h/kg)

0.22 ± 0.06

n = 20

0.34 ± 0.05

n = 9

Elimination half-life (h)e

5 to 7

0.5 to 3

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

b Median [range].

c Children.

d Adults.

e Approximate range.

Effect of Food on Absorption of COMBIVIR: COMBIVIR may be administered with or without food. The lamivudine and zidovudine AUC following administration of COMBIVIR with food was similar when compared with fasting healthy subjects (n = 24).

Specific Populations

Patients with Renal Impairment: COMBIVIR: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Patients with Hepatic Impairment: COMBIVIR: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Pregnant Women: 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 non-pregnant 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 lamivudine and zidovudine have not been studied in subjects over 65 years of age.

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

Racial Groups: Lamivudine: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.

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

Drug Interaction Studies

No drug interaction trials have been conducted using COMBIVIR tablets.

Lamivudine and 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 hours).

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

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.

Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24) ; 14%, 32%, and 36% in the AUC(∞) ; and 28%, 52%, and 55% in the Cmax : of lamivudine, respectively.

Table 4 presents drug interaction information for the individual components of COMBIVIR.

Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa

Coadministered Drug and Dose

Drug and Dose

n

Concentrations of Lamivudine or Zidovudine

Concentration of Coadministered Drug

AUC

Variability

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%

Atovaquone

750 mg every 12 h

with food

Zidovudine

200 mg every 8 h

14

↑31%

Range:

23% to 78%b

Clarithromycin

500 mg twice daily

Zidovudine 100 mg every 4 h x 7 days

4

↓12%

Range:

↓34% to ↑14%

Not Reported

Fluconazole

400 mg daily

Zidovudine 200 mg every 8 h

12

↑74%

95% CI:

54% to 98%

Not Reported

Methadone

30 to 90 mg daily

Zidovudine 200 mg every 4 h

9

↑43%

Range:

16% to 64%b

Nelfinavir

750 mg every 8 h x 7 to 10 days

Zidovudine single 200 mg

11

↓35%

Range:

28% to 41%

Probenecid

500 mg every 6 h x 2 days

Zidovudine 2 mg/kg every 8 h x 3 days

3

↑106%

Range:

100% to 170%b

Not Assessed

Rifampin

600 mg daily x

14 days

Zidovudine 200 mg every 8 h x 14 days

8

↓47%

90% CI:

41% to 53%

Not Assessed

Ritonavir

300 mg every 6 h x 4 days

Zidovudine 200 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

Zidovudine 100 mg every 8 h x 4 days

6

↑80%

Range:

64% to 130%b

Not Assessed

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

a This table is not all inclusive.

b Estimated range of percent difference.

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