LAMIVUDINE and ZIDOVUDINE (Page 4 of 7)

8.5 Geriatric Use


Clinical trials 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, caution should be exercised in the administration of lamivudine and zidovudine tablet 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

Lamivudine and zidovudine tablet is not recommended for patients with creatinine clearance less than 50 mL per min because 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 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

Lamivudine and zidovudine tablet 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 lamivudine and zidovudine tablet. 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

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, 300 mg of zidovudine, and the inactive ingredients microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate and opadry white (hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide).
Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidine-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 C8H11N303S and a molecular weight of 229.26. It has the following structural formula:

http://medlibrary.org/lib/images-rx/lamivudine-and-zidovudine/lamizidofigure1.jpg

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
Zidovudine: The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24. It has the following structural formula:

lamizudofigure2

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

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: 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 Parameters a 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 ratio b 0.12 [0.04 to 0.47] n = 38 c 0.60 [0.04 to 2.62] N = 39 d
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) 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 Lamivudine and Zidovudine Tablet: Lamivudine and Zidovudine tablet may be administered with or without food. The lamivudine and zidovudine AUC following administration of lamivudine and zidovudine tablet with food was similar when compared to fasting healthy subjects (n = 24).

Special Populations

Renal Impairment: Lamivudine and Zidovudine Tablet: 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).

Hepatic Impairment: Lamivudine and Zidovudine Tablet: 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).

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 that 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.

Gender
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.

Race
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 Interactions
No drug interaction trials have been conducted using lamivudine and zidovudine 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 every12 hours).

Other interactions

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 [see Warnings and Precautions ( 5.5)].

Table 4 presents drug interaction information for the individual components of lamivudine and zidovudine tablet. Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUC a

Coadministered Drug and Dose Drug and Dose n Concentration of Lamivudine or Zidovudine Concentration of Coadministered Drug
AUC Variability
Nelfinavir 750mg every 8h 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 8h 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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