Lamivudine (Page 3 of 6)

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine tablets (HBV). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.

Blood and Lympatic System Disorders: Thrombocytopenia.

Digestive: Stomatitis.

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Blood and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic: Lactic acidosis and steatosis, posttreatment exacerbation of hepatitis [see Boxed Warning], pancreatitis.

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Cramps, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, pruritus, rash.

7 DRUG INTERACTIONS

Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects:

Pregnancy Category C.
There are no adequate and well-controlled trials of lamivudine tablets (HBV) in pregnant women. Because animal reproduction studies are not always predictive of human response, lamivudine tablets (HBV) should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.
Antiretroviral Pregnancy Registry:
To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Animal Data: Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 60 times that for the adult HBV dose. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 60 times those in humans.
Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

8.3 Nursing Mothers

Lamivudine is excreted in human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily, 6 times the recommended dosage for hepatitis B infection) or combination therapy (150 mg lamivudine twice daily [3 times the recommended dosage for hepatitis B infection] and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. Because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue lamivudine tablets (HBV) taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.

8.4 Pediatric Use

Lamivudine tablets (HBV) is indicated for the treatment of chronic hepatitis B virus infection in pediatric patients aged 2 to 17 years [see Indications and Usage ( 1), Clinical Pharmacology ( 12.3), Clinical Studies ( 14.2)] . The safety and efficacy of lamivudine tablets (HBV) in pediatric patients younger than 2 years have not been established.

8.5 Geriatric Use

Clinical trials of lamivudine tablets (HBV) 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. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration ( 2.4), Clinical Pharmacology ( 12.3)] .

8.6 Patients With Impaired Renal Function

Reduction of the dosage of lamivudine tablets (HBV) is recommended for patients with impaired renal function [see Dosage and Administration ( 2.4), Clinical Pharmacology ( 12.3)] .

8.7 Patients With Impaired Liver Function

No dose adjustment for lamivudine is required for patients with impaired hepatic function.

10 OVERDOSAGE

There is no known antidote for lamivudine tablets (HBV). If overdose occurs, the patient should be monitored, and standard supportive treatment utilized, as required.
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.

11 DESCRIPTION

Lamivudine tablet (HBV) is a synthetic nucleoside analogue with activity against 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 (HBV) are for oral administration. Each tablet contains 100 mg of lamivudine, USP and the inactive ingredients crospovidone, isomalt, isopropyl alcohol, magnesium stearate and methylene chloride. The tablets are coated with Opadry Pink containing hypromellose, iron oxide red, polyethylene glycol, polysorbate 80, titanium dioxide and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects.
Absorption and Bioavailability: Following single oral doses of 100 mg, the peak serum lamivudine concentration (C max ) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC [0 to 24h] ) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (C max ), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably.
After oral administration of lamivudine once daily to HBV-infected adults, the AUC and C max increased in proportion to dose over the range from 5 mg to 600 mg once daily.
Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg per mL oral solution.
Effects of Food on Oral Absorption: The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states.
Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 asymptomatic HIV-1-infected subjects was 1.3 ± 0.4 L per 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 less than 36% and independent of dose. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per 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 humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. In 9 healthy subjects receiving 300 mg of lamivudine as single oral doses, a total of 4.2% (range: 1.5% to 7.5%) of the dose was excreted as the trans-sulfoxide metabolite in the urine, the majority of which was excreted in the first 12 hours. Serum concentrations of the trans-sulfoxide 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 per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.
In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, 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 subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg.
Special Populations:Adults With Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy subjects and in subjects with impaired renal function, with and without hemodialysis (Table 5). Table 5. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Oral Dose of Lamivudine in Subjects With Varying Degrees of Renal Function

Parameter Creatinine Clearance Criterion (Number of Subjects)
≥80 mL/min (n = 9) 20-59 mL/min (n = 8) <20 mL/min (n = 6)
Creatinine Clerance (mL/min) 97 (range 82-117) 39 (range 25-49) 15 (range 13-19)
C max (mcg/mL) 1.31 ± 0.35 1.85 ± 0.40 1.55 ± 0.31
AUC (mcg.h/mL) 5.28 ± 1.01 14.67 ± 3.74 27.33 ± 6.56
Cl/F (mL/min) 326.4 ± 63.8 120.1 ± 29.5 64.5 ± 18.3

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. T max 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 ( 2.4)] .
Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL per 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.
Pediatric Patients With Renal Impairment: The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.
Adults With Hepatic Impairment: The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6). Subjects were stratified by severity of hepatic impairment. Table 6. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Dose of Lamivudine in Subjects With Normal or Impaired Hepatic Function a Hepatic impairment assessed by aminopyrine breath test.

Parameter Normal (n = 8) Impairment a
Moderate (n = 8) Severe (n = 8)
C max (mcg/mL) 0.92 ± 0.31 1.06 ± 0.58 1.08 ± 0.27
AUC (mcg.h/mL) 3.96 ± 0.58 3.97± 1.36 4.30 ± 0.63
T max (h) 1.3 ± 0.8 1.4 ± 0.8 1.4 ± 1.2
Cl/F (mL/min) 424.7 ± 61.9 456.9 ± 129.8 395.2 ± 51.8
Clr (mL/min) 279.2 ± 79.2 323.5 ± 100.9 216.1 ± 58.0

Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease [see Indications and Usage ( 1)] .
Adults Post-Hepatic Transplant: Fourteen HBV-infected subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population [see Indications and Usage ( 1)] .
Pediatric Subjects: Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine T max was 0.5 to 1 hour. In general, both C max and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults.
Gender: There are no significant gender differences in lamivudine pharmacokinetics.
Race: There are no significant racial differences in lamivudine pharmacokinetics.
Drug Interactions:Interferon Alfa: Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics trial. Results indicated a 10% reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the 2 drugs were given in combination. All other pharmacokinetic parameters (C max , T max , and t1/2) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this trial.
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.
Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 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 44% ± 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.
Zidovudine: Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult subjects in a single-center, open-label, randomized, crossover trial. No significant differences were observed in AUC or total clearance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in C max of zidovudine.

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