Lamivudine and Zidovudine (Page 4 of 7)

8.3 Nursing Mothers


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. Because of both the potential for HIV-1 transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine and zidovudine.
Although no studies of lamivudine and zidovudine excretion in breast milk have been performed, lactation studies performed with lamivudine and zidovudine show that both drugs are excreted in human breast milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. In another study, after administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.

8.4 Pediatric Use


Lamivudine and Zidovudine should not be administered to pediatric patients weighing less than 30 kg, because it is a fixed-dose combination that cannot be adjusted for this patient population.

8.5 Geriatric Use


Clinical studies of lamivudine and zidovudine tablet did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Lamivudine and Zidovudine is not recommended for patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) because it is a fixed-dose combination that cannot be adjusted.

8.6 Renal Impairment


Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance less than 50 mL/min should not receive lamivudine and zidovudine because it is a fixed-dose combination that cannot be adjusted.

8.7 Hepatic Impairment


A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Lamivudine and Zidovudine is not recommended for patients with impaired hepatic function because it is a fixed-dose combination that cannot be adjusted.

10 OVERDOSAGE


Lamivudine and Zidovudine Tablet: There is no known antidote for lamivudine and zidovudine tablet.
Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. 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. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1 report of a grand mal seizure. Hematologic changes were transient. All patients recovered. 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


Lamivudine and Zidovudine Tablets, USP: Lamivudine and Zidovudine Tablets, USP are combination tablets containing lamivudine and zidovudine. Lamivudine and zidovudine (azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV-1.
Lamivudine and Zidovudine Tablets, USP are for oral administration. Each film-coated tablet contains 150 mg of lamivudine USP, 300 mg of zidovudine USP, and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.
Lamivudine: The chemical name of lamivudine is 2(1H) — Pyrimidinone, 4-amino-1- [2- (hydroxymethyl)-1,3-oxathio-lan-5-yl], (2R-cis)-. It has a molecular formula of C8 H11 N3 O3 S and a molecular weight of 229.26. It has the following structural formula:

Lamivudine Chemical Structure


Lamivudine is white to an off-white solid. Soluble in water.
Zidovudine: The chemical name of zidovudine is Thymidine, 3’-azido-3’-deoxy-. It has a molecular formula of C10 H13 N5 O4 and a molecular weight of 267.24. It has the following structural formula:

Zidovudine Chemical Structure


Zidovudine is a white to yellowish powder. Sparingly soluble in water and soluble in alcohol.
This product meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


Lamivudine and Zidovudine Tablet is an antiviral agent [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics


Pharmacokinetics in Adults:Lamivudine and Zidovudine Tablet: One lamivudine and zidovudine tablet was bioequivalent to 1 lamivudine tablet (150 mg) plus 1 zidovudine tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).
Lamivudine: The pharmacokinetic properties of lamivudine in fasting patients are summarized in Table 3. 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: The pharmacokinetic properties of zidovudine in fasting patients are summarized in Table 3. 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.

Table 3. Pharmacokinetic Parameters* for Lamivudine and Zidovudine in Adults
Parameter Lamivudine Zidovudine
* Data presented as mean ± standard deviation except where noted. Median [range]. Children. § Adults. Approximate range.

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 ratio

0.12 [0.04 to 0.47]

n = 38

0.60 [0.04 to 2.62]

N = 39 §

Systemic clearance (L/hr/kg)

0.33 ± 0.06

N = 20

1.6 ± 0.6

n = 6

Renal clearance (L/hr/kg)

0.22 ± 0.06

N = 20

0.34 ± 0.05

n = 9

Elimination half-life (hr)

5 to 7

0.5 to 3


Effect of Food on Absorption of Lamivudine and Zidovudine: Lamivudine and Zidovudine may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine with food was similar when compared to fasting healthy subjects (n = 24).
Special Populations:
Pregnancy: See Use in Specific Populations (8.1).
Lamivudine and Zidovudine: No data are available.
Zidovudine: Zidovudine pharmacokinetics has been studied in a Phase 1 study of 8 women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The pharmacokinetics of zidovudine was similar to that 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. In a nonpregnant adult population, a potential for interaction has been identified.
Nursing Mothers: See Use in Specific Populations (8.3).
Pediatric Patients: Lamivudine and Zidovudine Tablet should not be administered to pediatric patients weighing less than 30 kg.
Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in patients over 65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in zidovudine AUC or lamivudine AUC normalized for body weight.
Race:Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.
Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.
Drug Interactions:See Drug Interactions (7).
No drug interaction studies have been conducted using lamivudine and zidovudine tablets. However, Table 4 presents drug interaction information for the individual components of lamivudine and zidovudine tablet.
Lamivudine Plus Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q l2 hr).

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

Note: ROUTINE DOSE MODIFICATION OF LAMIVUDINE AND ZIDOVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Drugs That May Alter Lamivudine Blood Concentrations
Coadministered Drug and Dose Lamivudine Dose n Lamivudine Concentrations Concentration of Coadministered Drug
AUC Variability

↑ = 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.

Nelfinavir750 mg q 8 hr x 7 to10 days single 150 mg 11 ↑AUC 10% 95% CI:1% to 20%
Trimethoprim 160 mg/Sulfamethoxazole800 mg daily x 5 days single 300 mg 14 ↑AUC 43% 90% CI:32% to 55%
Drugs That May Alter Zidovudine Blood Concentrations
Coadministered Drug and Dose Zidovudine Dose n Zidovudine Concentrations Concentration of Coadministered Drug
AUC Variability
Atovaquone750 mg q 12 hrwith food 200 mg q 8 hr 14 ↑AUC 31% Range23% to 78%b
Clarithromycin500 mg twice daily 100 mg q 4 hr x 7 days 4 ↓AUC 12% Range↓34% to ↑14% Not Reported
Fluconazole400 mg daily 200 mg q 8 hr 12 ↑AUC 74% 95% CI:54% to 98% Not Reported
Methadone30 to 90 mg daily 200 mg q 4 hr 9 ↑AUC 43% Range16% to 64%b
Nelfinavir750 mg q 8 hr x 7 to 10 days single 200 mg 11 ↓AUC 35% Range28% to 41%
Probenecid500 mg q 6 hr x2 days 2 mg/kg q8 hr x 3 days 3 ↑AUC106% Range100% to170%b Not Assessed
Rifampin600 mg daily x 14 days 200 mg q 8 hr x 14 days 8 ↓AUC 47% 90% CI: 41% to 53% Not Assessed
Ritonavir300 mg q 6 hr x4 days 200 mg q 8 hr x 4 days 9 ↓AUC 25% 95% CI:15% to 34%
Valproic acid250 mg or 500 mg q8 hr x 4 days 100 mg q 8 hr x 4 days 6 ↑AUC 80% Range64% to 130%b Not Assessed

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 patients [see Warnings and Precautions (5.5)].

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