For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

 

Qualitative and Quantitative Composition

Each tablet contains:

Lamivudine IP … 100 mg

Colour: Titanium Dioxide, Red Oxide of Iron & Yellow Oxide of Iron

Dosage Form and Strength

Tablets: 100 mg for oral use.

Clinical Particulars

Therapeutic Indications

LAMIVIR- HBV Tablets are indicated for the treatment of chronic hepatitis B virus infection in adults.

Posology and Method of Administration

HIV Counseling and Testing

HIV counseling and testing should be offered to all patients before beginning treatment with LAMIVIR-HBV Tablets and periodically during treatment because of the risk of emergence of resistant-HIV-1 and limitation of treatment options if LAMIVIR-HBV Tablets are prescribed to treat chronic hepatitis B infection in a patient who has unrecognized HIV-1 infection or acquires HIV-1 infection during treatment (see Special Warnings and Precautions for Use).

Adults

The recommended oral dose of LAMIVIR-HBV Tablets for the treatment of chronic hepatitis B in adults is 100 mg once daily.

The formulation and dosage of lamivudine in LAMIVIR-HBV Tablets are not appropriate for patients dually infected with hepatitis B virus (HBV) and HIV. If lamivudine is administered to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the appropriate prescribing information should be consulted.

Special Populations

Pediatric

LAMIVIR-HBV Tablets has not been evaluated in pediatric patients.

Renal Impairment

It is recommended that doses of lamivudine be adjusted in accordance with renal function (Table 1) (see Pharmacology, Pharmacokinetics, Special Populations).

Creatinine Clearance (mL/min)	Recommended Dosage of Lamivudine
≥50	100 mg once daily
30 to 49	100 mg first dose, then 50 mg once daily
15 to 29	100 mg first dose, then 25 mg once daily
5 to 14	35 mg first dose, then 15 mg once daily
<5	35 mg first dose, then 10 mg once daily

Following correction of the dosage for renal impairment, no additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis.

There are insufficient data to recommend a specific dosage of lamivudine in pediatric patients with renal impairment.

LAMIVIR-HBV Tablets should not be used with other medications that contain lamivudine or medications that contain emtricitabine.

Contraindications

LAMIVIR-HBV Tablets are contraindicated in patients with a previous hypersensitivity to lamivudine.

Special Warnings and Precautions for Use

General

Patients should be assessed before beginning treatment with LAMIVIR-HBV Tablets by a physician experienced in the management of chronic hepatitis B.

Lactic Acidosis/SevereHepatomegaly with Steatosis 

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals, including lamivudine. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Most of these reports have described patients receiving nucleoside analogs for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Treatment with LAMIVIR- HBV Tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

Exacerbation of Hepatitis after Discontinuation of Treatment

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine (these have been primarily detected by serum ALT elevations, in addition to the re-emergence of HBV DNA commonly observed after stopping treatment). Although most events appear to have been self-limited, fatalities have been reported in some cases. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with lamivudine. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of post-treatment exacerbations of hepatitis.

Risk of HIV-1 Resistance if Lamivudine Is Used in Patients with Unrecognized or Untreated HIV-1 Infection

LAMIVIR-HBVTablets contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection, including lamivudine tablets or in lamivudine-containing antiretroviral fixed-dose combination products.

LAMIVIR-HBV Tablets are not appropriate for patients co-infected with HBV and HIV-1. If a patient with unrecognized or untreated HIV-1 infection is prescribed LAMIVIR-HBV Tablets for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment. HIV counseling and testing should be offered to all patients before beginning treatment with LAMIVIR-HBV Tablets and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and limitation of treatment options if LAMIVIR-HBV Tablets are prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment.

Emergence of Resistance-associated HBV Substitutions

In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on–lamivudine re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit. Subjects treated with lamivudine (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their own previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In order to reduce the risk of resistance in patients receiving monotherapy with  lamivudine tablets, a switch to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of treatment. Optimal therapy should be guided by resistance testing.

Drug Interactions 

Drugs Inhibiting Organic Cation Transporters

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.

Sorbitol

Co-administration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine Consider more frequent monitoring of HBV viral load when chronic co-administration cannot be avoided.

Use in Special Population

Patients with Renal Impairment

Reduction of the dosage of LAMIVIR- HBV Tablets is recommended for patients with impaired renal function (see CLINICAL PARTICULARS).

Patients with Hepatic Impairment

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

Pregnancy 

Risk Summary

Available data from the Antiretroviral Pregnancy Registry (APR) show no substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as a U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occur at less than 20 weeks’ gestation. Of over 11,000 women exposed to lamivudine in the APR, less than 1% were treated for HBV. The majority of women exposed to lamivudine in the APR were HIV-1-infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition to lamivudine, HIV-1-infected women were also treated with other concomitant medications for HIV-1 infection (see Human Data). The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C_max) 60 times the recommended clinical dose (see Human Data).

Human Data

Based on prospective reports from the APR of over 11,000 exposures to lamivudine (including over 4,600 exposed in the first trimester) during pregnancy resulting in live births, less than 1% of which were patients with HBV, there was no substantial difference in birth defects with lamivudine compared with the birth defect rate of 2.7% observed in the comparator population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine containing regimens.

The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers are similar at similar doses. Lamivudine pharmacokinetics were studied in pregnant women with HIV-1 infection during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily (3 times the recommended daily dosage for HBV) with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily (6 times the recommended daily dosage for HBV) without other antiretrovirals. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9- (1.2- to 12.8-) fold greater compared with paired maternal serum concentrations (n = 8).

Lactating Women

Risk Summary

Lamivudine is present in human milk. There is no information available regarding lamivudine concentrations in milk from lactating women receiving lamivudine for treatment of HBV infection. However, in lactating women with HIV-1 infection being treated with lamivudine at 3 or 6 times the recommended daily dose for HBV, lamivudine concentrations in milk were similar to those observed in serum (see Human Data). The lamivudine dose received by a breastfed infant of a mother being treated for HIV-1 infection was estimated to be approximately 6% of the recommended daily lamivudine dose for HBV in children over 2 years of age. There is no information available regarding the effects of the drug on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lamivudine and any potential adverse effects on the breastfed infant from lamivudine or from the underlying maternal condition.

Human Data

In mothers with HIV receiving lamivudine monotherapy (300 mg twice daily [6 times the recommended daily dosage for HBV]) or combination therapy (150 mg lamivudine twice daily [3 times the recommended daily dosage for HBV] with 300 mg zidovudine twice daily), the median breast milk to plasma lamivudine concentration ratio was 0.6 to 3.3, and the estimated infant daily dose was approximately 6% of the recommended 3-mg-per-kg daily lamivudine dose for treatment of HBV in children over 2 years of age. In breastfed infants of mothers with HIV-1 infection receiving lamivudine therapy, the blood concentrations of lamivudine decreased after delivery and were undetectable at 6 months despite constant milk concentrations. This is consistent with increased lamivudine renal clearance in the first 6 months of life.

Pediatric Use

Safety and efficacy of LAMIVIR-HBV Tablets in pediatric patients have not been established.

Geriatric Use

Clinical studies of lamivudine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of LAMIVIR-HBV Tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Effects on Ability to Drive and Use Machines

Not applicable

Undesirable Effects

The following adverse reactions are discussed in other sections of the labeling:

• Exacerbations of hepatitis B after discontinuation of treatment [see Special Warnings and Precautions for Use].
• Risk of emergence of resistant HIV-1 infection [see Special Warnings and Precautions for Use].
• Risk of emergence of resistant HBV infection [see Special Warnings and Precautions for Use].
• Lactic acidosis and severe hepatomegaly with steatosis [see Special Warnings and Precautions for Use].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience in Adult Subjects with Chronic HBV InfectionClinical adverse reactions (regardless of the investigator’s causality assessment) reported in greater or equal to 10% of subjects who received lamivudine and reported at a rate greater than in subjects who received placebo are listed in Table 2.

Adverse Event	Lamivudine 100 mg (n=332)	Placebo (n=200)
Ear, Nose and Throat
Ear, nose and throat infections	25%	21%
Sore throat	13%	8%
Gastrointestinal
Diarrhea	14%	12%

^aIncludes adverse events regardless of severity and causality assessment.

Specified laboratory abnormalities reported in subjects who received lamivudine and reported at a rate greater than in subjects who received placebo are listed in Table 3.

Test (Abnormal Level)	Subjects with Abnormality/Subjects with Observations
	Lamivudine 100 mg	Placebo
Serum lipase ≥2.5 x ULNb	10%	7%
CPK ≥7 x baseline	9%	5%
Platelets <50,000/mm3	4%	3%

^aIncludes subjects treated for 52 to 68 weeks

^‡Includes observations during and after treatment in the two placebo-controlled trials that collected this information.

ULN = Upper limit of normal.

In subjects followed for up to 16 weeks after discontinuation of treatment, post-treatment ALT elevations were observed more frequently in subjects who had received lamivudine than in subjects who had received placebo. A comparison of ALT elevations between weeks 52 and 68 in subjects who discontinued lamivudine at week 52 and subjects in the same studies who received placebo throughout the treatment course is shown in Table 4.

Abnormal Value	Subjects with ALT Elevation/ Subjects with Observationsa
	Lamivudine 100 mgb	Placebob
ALT ≥2 x baseline value	27%	19%
ALT ≥3 x baseline valuec	21%	8%
ALT ≥2 x baseline value and absolute ALT >500 IU/L	15%	7%
ALT ≥2 x baseline value; and bilirubin >2 x ULN and ≥2 x baseline value	0.7%	0.9%

^aEach subject may be represented in one or more category.

^bDuring treatment phase

^cComparable with Grade 3 toxicity in accordance with modified WHO criteria.

ULN = Upper limit of normal.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of lamivudine 100 mg tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their 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 Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.

Digestive: Stomatitis.

Ear and Labyrinth Disorders:Hearing loss

Endocrine and Metabolic: Hyperglycemia. General Weakness.

Hepatic and Pancreatic: Lactic acidosis and steatosis [see Special Warnings and Precautions for Use], posttreatment exacerbations of hepatitis [see Special Warnings and Precautions for Use], pancreatitis.

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Cramps, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, pruritus, rash.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

There is no known antidote for an overdose of lamivudine. If overdose occurs, the patient should be monitored and standard supportive treatment applied, as required. In studies, a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis and automated peritoneal dialysis; hence, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Pharmacological Properties

Mechanism of Action

Lamivudine is an antiviral agent with activity against HBV.

Pharmacodynamic Properties

Lamivudine is a synthetic nucleoside analog. Intracellularly, lamivudine is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate, (3TC-TP). The principal mode of action of 3TC-TP is inhibition of the RNA- and DNA-dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue.

Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.

In assays relating to potential substance effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.

Pharmacokinetics Properties

The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 to 600 mg per day administered to HBV-infected subjects.

Absorption and Bioavailability:

Lamivudine was rapidly absorbed after oral administration in HBV-infected patients and in healthy subjects. 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/mL and 1.05 ± 0.32 mcg/mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC _{[0-24 hr]}) 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•hr/mL, respectively.

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 patients was 86% ± 16% (mean ± SD) for the 150 mg tablet.

Effects of Food on Oral Absorption

LAMIVIR-HBVTablets may be administered with or without food.

The 100 mg tablet was administered orally to 24 healthy subjects on two 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 intravenous (IV) administration of lamivudine to 20 HIV-1-infected 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 less than 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 humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). 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. Lamivudine is not significantly metabolized by cytochrome (CY) P450 enzymes.

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-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 subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, 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 from 0.25 to 10 mg/kg.

Special Populations

Patients with Renal Impairment

The pharmacokinetic properties of lamivudine have been determined in healthy subjects and in adults with impaired renal function, with and without hemodialysis.

	Creatinine Clearance Criterion (Number of Subjects)
Parameter	≥80 mL/min (n=9)	20-59 mL/min (n=8)	<20 mL/min (n=6)
Creatinine clearance (mL/min)	97 (range: 82 to117)	39 (range: 25 to 49)	15 (range: 13 to 19)
Cmax (mcg/mL)	1.31 ± 0.35	1.85 ± 0.40	1.55 ± 0.31
AUC (mcg•hr/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

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 CLINICAL PARTICULARS).

Hemodialysis increases 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.

The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B are not known.

Patients with Hepatic Impairment

The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic impairment (Table 6). Subjects were stratified by severity of hepatic impairment.

Parameter	Normal (n=8)	Impairment*
		Moderate (n=8)	Severe (n=8)
Cmax (mcg/mL)	0.92 ± 0.31	1.06 ± 0.58	1.08 ± 0.27
AUCinfinity (mcg•hr/mL)	3.96 ± 0.58	3.97 ± 1.36	4.30 ± 0.63
Tmax (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

*Hepatic impairment assessed by aminopyrinebreath test.

Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of LAMIVIR-HBV Tablets have not been established in the presence of decompensated liver disease (see Special Warnings and Precautions for Use). 

Patients after Hepatic Transplant

In 14 HBV-infected patients who 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 have not been established in this population (Special Warnings and Precautions for Use).

Pregnant Women

The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers was similar at similar doses. Lamivudine pharmacokinetics was studied in 36 pregnant women with HIV during two clinical trials (three to six times the recommended daily dosage for HBV). Lamivudine pharmacokinetics in pregnant women was 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.

Pediatric Patients

LAMIVIR-HBV Tablets pharmacokinetics has not been evaluated in pediatric patients.

Geriatric Patients

The pharmacokinetics of lamivudine after administration of LAMIVIR-HBV Tablets to subjects over 65 years of age has not been studied.

Gender

There are no significant or clinically relevant gender differences in lamivudine pharmacokinetics.

Race 

There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics.

Drug Interaction Studies

Effect of Lamivudine on the Pharmacokinetics of Other Agents:

Based on in vitro study results, lamivudine at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3.

Effect of Other Agents on the Pharmacokinetics of Lamivudine:

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant, and no dose adjustment of lamivudine is needed.

Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

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 C_max of lamivudine.

Trimethoprim/Sulfamethoxazole:

Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-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 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.

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).

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice), and 113 and 187 times (male and female rats, respectively) those observed in humans at the recommended therapeutic dose for chronic hepatitis B.

Mutagenesis

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Impairment of Fertility

Lamivudine did not affect male or female fertility in rats at oral doses up to 4,000 mg per kg per day, associated with concentrations approximately 70 times (male) or 104 times (females) higher than the concentrations (C_max) in humans at the dose of 100 mg

Description

LAMIVIR-HBV is a synthetic nucleoside analogue with activity against HBV. 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 C₈H₁₁N₃O₃S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg per mL in water at 20°C. LAMIVIR-HBV tablets are for oral administration. Each tablet contains 100 mg of lamivudine.

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

As on the pack.

Packaging Information

LAMIVIR-HBV Tablets: Blister pack of 10 tablets.    

Storage and Handling Instructions

Store at 25°C; excursions permitted up to 15° to 30°C.

Patient Counselling Information

A. What are the ingredients in LAMIVIR-HBV?

LAMIVIR HBV contains a medicine called lamivudine.

B. What is the most important information I should know about LAMIVIR-HBV?

LAMIVIR-HBV can cause serious side effects, including:

• Worsening liver disease.Your hepatitis B infection may become worse after stopping treatment with LAMIVIR-HBV. Worsening liver disease can be serious and may lead to death. If you stop treatment with LAMIVIR-HBV, your healthcare provider will need to check your health and do blood tests to check your liver for at least several months after you stop taking LAMIVIR-HBV.
• Risk of HIV-1 resistance in people with unknown HIV-1 infection or in people with untreated HIV-1 infection. If you have or get HIV-1 (Human Immunodeficiency Virus type 1) that is not being treated with medicines while taking LAMIVIR-HBV, the HIV-1 virus may develop resistance to certain HIV-1 medicines and become harder to treat.

Your healthcare provider should offer you counseling and testing for HIV-1 infection before you start treatment for hepatitis B with LAMIVIR-HBV and during treatment.

LAMIVIR-HBV tablets contain a lower dose of lamivudine than other medicines that contain lamivudine and are used to treat HIV-1 infection.

• Resistant Hepatitis B Virus (HBV). The hepatitis B virus can change (mutate) during your treatment with LAMIVIR-HBV and become harder to treat (resistant). If this happens, your liver disease can become worse and may lead to death. Tell your healthcare provider right away if you have any new symptoms

C. What is LAMIVIR-HBV?

LAMIVIR-HBV is a prescription medicine used to treat long-term (chronic) hepatitis B virus (HBV) when the disease is progressing and there is liver swelling (inflammation).

It is not known if LAMIVIR-HBV is safe and effective in:

• people with chronic HBV who have a severely damaged liver that is unable to work properly (decompensated liver disease)
• people with HIV-1, hepatitis C virus, or hepatitis D (delta) virus
• people who have had a liver transplant
• children with chronic HBV

LAMIVIR-HBV does not stop you from spreading HBV to others by sex, sharing needles, or being exposed to your blood. Avoid doing things that can spread HBV infection to others.

D. Do not take LAMIVIR-HBV:

• if you are allergic to lamivudine or any of the ingredients in LAMIVIR-HBV. See the end of this Patient Information leaflet for a complete list of ingredients in LAMIVIR-HBV.

E. What should I tell my healthcare provider before taking LAMIVIR-HBV?

Before taking LAMIVIR-HBV, tell your healthcare provider about all of your medical conditions, including if you:

• have HIV-1 infection
• have kidney problems
• have diabetes
• are pregnant or plan to become pregnant. It is not known if LAMIVIR-HBV will harm your unborn baby.
• are breastfeeding or plan to breastfeed. LAMIVIR-HBV can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take LAMIVIR-HBV or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Some medicines interact with LAMIVIR-HBV. Keep a list of your medicines to show your healthcare provider and pharmacist.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take LAMIVIR-HBV with other medicines.

LAMIVIR-HBV should not be taken if you also take other medicines that contain lamivudine or emtricitabine.

F. How should I take LAMIVIR-HBV?

• Take LAMIVIR-HBV exactly as your healthcare provider tells you to take it.
• If you miss a dose of LAMIVIR-HBV, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take.
• Stay under the care of a healthcare provider during treatment with LAMIVIR-HBV.
• LAMIVIR-HBV may be taken with or without food.
• Your healthcare provider may prescribe a lower dose if you have problems with your kidneys.
• If you take too much LAMIVIR-HBV, call your healthcare provider or go to the nearest hospital emergency room right away.

G. What are the possible side effects of LAMIVIR-HBV?

LAMIVIR-HBV may cause serious side effects, including:

• See "What is the most important information I should know about LAMIVIR-HBV?"
• Build-up of lactic acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take LAMIVIR-HBV. Lactic acidosis is a serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:

• feel very weak or tired
• unusual (not normal) muscle pain
• trouble breathing
• stomach pain with nausea and vomiting
• feel cold, especially in your arms and legs
• feel dizzy or light-headed
• have a fast or irregular heartbeat

Severe liver problems. Severe liver problems can happen in people who take LAMIVIR-HBV or similar medicines. In some cases these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take LAMIVIR-HBV. Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:

• your skin or the white part of your eyes

• turns yellow (jaundice)
• dark or “tea-colored” urine
• light-colored stools (bowel movements)
• loss of appetite for several days or longer
• nausea
• pain, aching, or tenderness on the right side of your stomach area

You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).

The most common side effects of LAMIVIR-HBV include ear, nose, and throat infections; sore throat; and diarrhea.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

H. How should I store LAMIVIR-HBV?

• Store LAMIVIR-HBV tablets below 30°C. Protect from light and moisture.

Keep LAMIVIR-HBV out of the reach of children.

I. General information about the safe and effective use ofLAMIVIR-HBV

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

Do not use LAMIVIR-HBV for a condition for which it was not prescribed. Do not give LAMIVIR-HBV to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about LAMIVIR-HBV that is written for health professionals.

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or License Number with Date

M/447/2007 Dated 23/12/2016

Date of Revision

13/03/2020