Lamivudine (Page 4 of 7)

10 OVERDOSAGE

There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Study ACTG300. One case involved a single dose of 7 mg/kg of lamivudine; the second case involved use of 5 mg/kg of lamivudine twice daily for 30 days. There were no clinical signs or symptoms noted in either case. 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. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

11 DESCRIPTION

Lamivudine USP (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine USP is 2(1H) — Pyrimidinone, 4-amino-1- [2- (hydroxymethyl)-1,3-oxathio-lan-5-yl], (2R-cis)-. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.26. It has the following structural formula:

structure.jpg

Lamivudine USP is a white to an off white solid and soluble in water. Lamivudine tablets are for oral administration. Each film-coated tablet contains 150 mg or 300 mg of lamivudine USP and the following inactive ingredients: crospovidone, isomalt, isopropyl alcohol, magnesium stearate and methylene chloride. The tablets are coated with opadry white containing hypromellose, polyethylene glycol, polysorbate 80 and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-l-infected adult patients after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.
The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected patients.
The steady-state pharmacokinetics properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice daily with respect to plasma AUC 24,.ss ; however, C max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC 24,ss and C max24,ss ; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-1-infected patients. Absolute bioavailability in 12 adult patients was 86%±16% (mean ± SD) for the 150-mg tablet and 87%±13% for the oral solution. After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (C max ) was 1.5 ±0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.
The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.
Effects of Food on Oral Absorption: An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected patients on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ±1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); C max in the fed state was 40%±23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC¥) in the fed and fasted states;therefore, lamivudine tablets may be administered with or without food.
Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.
Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
Metabolism: Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within
12 hours after a single oral dose of lamivudine in 6 HIV-l-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). In 20 HIV-l-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ±SD) of total clearance of lamivudine.
In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t1/2) ranged from 5 to 7 hours. In HIV-1-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half- life were independent of dose and body weight over an oral dosing range of 0.25 to10 mg/kg.
Special Populations: Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7). Table 7. Pharmacokinetic Parameters (Mean ± SD) After a Single 300-mg Oral Dose of Lamivudine in 3 Groups of Adults With Varying Degrees of Renal Function

ParameterCreatitine Clearance Criterion (Number of Subjects)
>60 mL/min10-30 mL/min<10 mL/min
Creatitine clearance111± 1428 ± 86 ± 2
C max (mcg/mL) 2.6 ± 0.53.6 ± 0.85.8 ± 1.2
AUC∞ (mcg.hr/mL)11.0 ± 1.748.0 ± 19157± 74
Cl/F (mL/min)464 ± 76114 ± 3436 ± 11

Exposure (AUC∞), C max , and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration (2.3)].
Based on a study in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.
It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.
The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
Hepatic Impairment: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensate liver disease.
Pediatric Patients: In Study NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric patients (age range:
4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2,4, 8, 12, and 20 mg/kg/day. The mechanism for the diminished absolute bioavailabilty of lamivudine in infants and children is unknown.
Systemic clearance decreased with increasing age in pediatric patients, as shown in Figure 1. Figure 1. Systemic Clearance (L/hr•kg) of Lamivudine in Relation to Age

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After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric patients ranging from 4 months to 14 years of age, C max was 1.1 ± 0.6 mcg/mL and half- life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half-life was 3.7 ± 1 hours.) Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric patients receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.
Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric patients after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 patients ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.
Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants up to 1 week of age in 2 studies in South Africa. In these studies, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric patients (>3 months of age) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old [see Adverse Reactions (6.1)].
Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years of age have not been studied [see Use in Specific Populations (8.5)].
Gender: There are no significant gender differences in lamivudine pharmacokinetics.
Race: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions: Interferon Alfa : There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a study of 19 healthy male subjects [see Warnings and Precautions (5.4)].
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-l/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-l/HCV co-infected patients [see Warnings and Precautions (5.4)].
Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were co administered to 14 HIV-1-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC¥, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine [see Drug Interactions (7.3)]. Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-l-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr) [see Drug Interactions (7.4)].

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