To be sold by retail on the prescription of a specialist only

 Black Box Warning

Exacerbations of Hepatitis B, and different formulations of LAMIVIR Exacerbations of Hepatits B: Severe acute exacerbations of hepatitis b have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see special warnings and precautions for use). Important differences among lamivudine-containing products: LAMIVIR tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than lamivudine- HBV tablets (used to treat chronic HBV infection). Patients with HIV-1 infection should receive only dosage forms appropriate for the treatment of HIV-1 (see special warnings and precautions for use).

Qualitative And Quantitative Composition

Each film-coated tablet contains:

Lamivudine ……… 150 mg

Dosage Form and Strength

LAMIVIR is available as oral tablet

Clinical Particulars

Therapeutic Indications

LAMIVIR is indicated as an adjunct to other antiretroviral agents in progressive HIV infection.

Limitations of Use

 • The dosage of this product is for HIV-1 and not for HBV.

Posology and Method of Administration

Recommended Dosage for Adults Patients

The recommended dosage of LAMIVIR in HIV-1 infected adults is 300 mg daily, administered as either 150 mg taken orally twice daily, or 300 mg taken orally once daily with or without food.

If lamivudine is administered to a patient infected with HIV-1 and HBV, the dosage indicated for HIV-1 therapy should be used as part of an appropriate combination regimen (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Patients with Renal Impairment

Dosing of LAMIVIR is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2 (see PHARMACOLOGICAL PROPERTIES).

Creatinine Clearance (mL/min)	Recommended Dosage of Lamivudine
≥50	150 mg twice daily or 300 mg once daily
30–49	150 mg once daily
15–29	150 mg first dose, then 100 mg once daily
5–14	150 mg first dose, then 50 mg once daily
<5	50 mg first dose, then 25 mg once daily

No additional dosing of LAMIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis.

Contraindications

LAMIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

Special Warnings and Precautions for Use for Use

Patients with Hepatitis B Virus Co-infection

Post-treatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to the re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. 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.

Important Differences Among Lamivudine-Containing Products

Lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) than Lamivudine-HBV Tablets. Lamivudine-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in lamivudine-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. If treatment with Lamivudine-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, lamivudine tablets or another product containing the higher dose of lamivudine should be used as part of an appropriate combination regimen.

Emergence of Lamivudine-Resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV (see full prescribing information for lamivudine-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV -1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, 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. Treatment with lamivudine 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.

Pancreatitis

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur (see UNDESIRABLE EFFECTS).

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

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 (eg, trimethoprim). no data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.

Sorbitol

Coadministration 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 (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE and PHARMACOLOGICAL PROPERTIES).

Use in Special Populations

Patients with Renal Impairment

Reduction of the dosage of lamivudine is recommended for patients with impaired renal function (see POSOLOGY AND METHOD OF ADMINISTRATION).

Patients with Hepatic Impairment

Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pregnant Women

Risk Summary

Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population. The APR uses the MACDP as the 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 occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, 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 development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C_max) 35 times the recommended clinical dose.

Data

Human Data

Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester 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.

Lamivudine pharmacokinetics were studied in pregnant women 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 with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. 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 concentration (n = 8).

Animal Data

Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C_max) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C_max) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

Lactating Women

Risk Summary

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. Lamivudine is present in human milk. There is no information on the effects of lamivudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving LAMIVIR

Pediatric Patients

LAMIVIR is not approved for the use in pediatric patients

Geriatric Patients

Clinical trials of lamivudine did not include a 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 in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see POSOLOGY AND METHOD OF ADMINISTRATION AND PHARMACOLOGICAL PROPERTIES).

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, individuals should be informed that dizziness has been reported during treatment with lamivudine.

Undesirable Effects

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

• Lactic acidosis and severe hepatomegaly with steatosis (see BOXED WARNING, SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
• Exacerbations of hepatitis B (see BOXED WARNING, SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
• Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
• Pancreatitis (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE)
• Immune reconstitution syndrome (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE)

Clinical Trials Experience in Adult Subjects

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

The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1 infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough.

Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3

Adverse Reaction	Lamivudine 150 mg twice daily plus Zidovudine (n = 251)	Zidovudinea (n = 230)
Body as a Whole Headache Malaise and fatigue Fever or chills	35% 27% 10%	27% 23% 12%
Digestive Nausea Diarrhea Nausea and vomiting Anorexia and/or decreased appetite Abdominal pain Abdominal cramps Dyspepsia	33% 18% 13% 10% 9% 6% 5%	29% 22% 12% 7% 11% 3% 5%
Nervous System Neuropathy Insomnia and other sleep disorders Dizziness Depressive disorders	12% 11%   10% 9%	10% 7%   4% 4%
Respiratory Nasal signs and symptoms Cough	20% 18%	11% 13%
Skin Skin rashes	9%	6%
Musculoskeletal Musculoskeletal pain Myalgia Arthralgia	12% 8% 5%	10% 6% 5%

^a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

Pancreatitis: Pancreatitis was observed in 9 of the 2613 adult subjects (0.3%) who received lamivudine in the controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 AND EPV40001) for 48 weeks were similar.

Selected laboratory abnormalities observed during therapy are summarized in Table 4.

Test (Threshold Level)	24-Week Surrogate Endpoint Trialsa		Clinical Endpoint triala
	Lamivudine plus zidovudine	Zidovudineb	Lamivudine plus current therapyc	Placebo plus current therapyc
Absolute neutrophil count (<750/mm3)	7.2%	5.4%	15%	13%
Hemoglobin (<8.0 g/dL)	2.9%	1.8%	2.2%	3.4%
Platelets (<50,000/mm3)	0.4%	1.3%	2.8%	3.8%
ALT (>5.0 x ULN)	3.7%	3.6%	3.8%	1.9%
AST (>5.0 x ULN)	1.7%	1.8%	4.0%	2.1%
Bilirubin (>2.5 x ULN)	0.8%	0.4%	ND	ND
Amylase (>2.0 x ULN)	4.2%	1.5%	2.2%	1.1%

^a The median duration on study was 12 months.

^b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

^c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.

ULN = Upper limit of normal.

ND = Not done.

The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of lamivudine. 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.

Body as a Whole: Redistribution/accumulation of body fat. (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, post-treatment exacerbation of hepatitis B (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Hypersensitivity: Anaphylaxis, urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus. 

Post-marketing reports of lamivudine received by pharmacovigilance program of India (PvPI) include hearing loss.By reporting side effects, you can help provide more information on the safety of this product.

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 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

There is no known specific treatment for overdose with lamivudine. If overdose occurs, the patient should be monitored and standard supportive treatment applied 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.

Pharmacological Properties

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue. 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 HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Pharmacodynamic Properties

Antiviral Activity

The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Lamivudine was not antagonistic to all tested anti-HIV agents. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.

Resistance

Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I).

HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates from Subjects with Virologic Failure

Trial EPV20001

Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level greater than or equal to 400 copies per mL) by Week 48. Twenty-eight subjects were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies per mL and 4.6 log10 copies per mL, respectively.

Genotypic analysis of on-therapy isolates from 22 subjects identified as virologic failures in the lamivudine once-daily group showed that isolates from 8 of 22 subjects contained a treatment-emergent lamivudine resistance-associated substitution (M184V or M184I), isolates from 0 of 22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), and isolates from 10 of 22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C).

Genotypic analysis of on-therapy isolates from subjects (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 5 of 22 subjects contained treatment-emergent lamivudine resistance substitutions, isolates from 1 of 22 subjects contained treatment-emergent zidovudine resistance substitutions, and isolates from 7 of 22 subjects contained treatment-emergent efavirenz resistance substitutions.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine once daily showed that isolates from 7 of 13 subjects showed an 85-to 299-fold decrease in susceptibility to lamivudine, isolates from 12 of 13 subjects were susceptible to zidovudine, and isolates from 8 of 13 subjects exhibited a 25-to 295-fold decrease in susceptibility to efavirenz.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine twice daily showed that isolates from 4 of 13 subjects exhibited a 29-to 159-fold decrease in susceptibility to lamivudine, isolates from all 13 subjects were susceptible to zidovudine, and isolates from 3 of 13 subjects exhibited a 21-to 342-fold decrease in susceptibility to efavirenz.

Trial EPV40001

Fifty subjects received lamivudine 300 mg once daily plus zidovudine 300 mg twice daily plus abacavir 300 mg twice daily and 50 subjects received lamivudine 150 mg plus zidovudine 300 mg plus abacavir 300 mg all twice-daily. The median baseline plasma HIV-1 RNA levels for subjects in the 2 groups were 4.79 log10 copies per mL and 4.83 log10 copies per mL, respectively. Fourteen of 50 subjects in the lamivudine once-daily treatment group and 9 of 50 subjects in the lamivudine twice-daily group were identified as virologic failures.

Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.

Phenotypic analysis of on-therapy isolates from subjects (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 subjects exhibited a 32-to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 subjects were susceptible to zidovudine.

Phenotypic analysis of on-therapy isolates from subjects (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 subject exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.

Cross-Resistance

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine-resistant HIV-1 mutants were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

Pharmacokinetics Properties

Pharmacokinetics in Adults

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1 infected-adult subjects after administration of single intravenous (I.V.) doses ranging from 0.25 to 8 mg per kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg per kg.

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

The steady-state pharmacokinetic 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 trial in 60 healthy subjects. 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 pharmacokinetics of lamivudine was evaluated in 12 adult HIV-1-infected subjects dosed with lamivudine 150 mg twice daily in combination with other antiretroviral agents. The geometric mean (95% CI) for AUC_(0-12) was 5.53 (4.58, 6.67) mcg.h per mL and for C_max was 1.40 (1.17, 1.69) mcg per mL.

Absorption and Bioavailability

Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet. 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 per mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C_max increased in proportion to the oral dose over the range from 0.25 to 10 mg per 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 per kg twice daily.

Effects of Food on Oral Absorption

Lamivudine tablets may be administered with or without food. An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (T_max: 3.2 ± 1.3 hours) compared with the fasted state (T_max: 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. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states.

Distribution

The apparent volume of distribution after I.V. administration of lamivudine to 20 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%. 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 ( approximately 5% of an oral dose after 12 hours).Serum concentrations of this metabolite have not been determined. Lamivudine is not significantly metabolized by cytochrome 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 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 (t_1/2) 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

Patients with Renal Impairment

The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 1).

Parameter	Creatinine Clearance Criterion (Number of Subjects)
	>60 mL/min (n = 6)	10-30 mL/min (n = 4)	<10 mL/min (n = 6)
Creatinine clearance (mL/min)	111 ± 14	28 ± 8	6 ± 2
Cmax (mcg/mL)	2.6 ± 0.5	3.6 ± 0.8	5.8 ± 1.2
AUC∞ (mcg•h/mL)	11.0 ± 1.7	48.0 ± 19	157 ± 74
Cl/F (mL/min)	464 ± 76	114 ± 34	36 ± 11

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 POSOLOGY AND METHOD OF ADMINISTRATION).

Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased 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 should be made after routine hemodialysis or peritoneal dialysis.

Patients with 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. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Pregnant Women

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.

Geriatric Patients

The pharmacokinetics of lamivudine after administration of lamivudine to subjects over 65 years have not been studied (see USE IN SPECIFIC POPULATIONS).

Male and Female Patients

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

Racial Groups

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

Non-Clinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg

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. Lamivudine showed no evidence of in-vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection.

Impairment of Fertility

In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Description

Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and 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:

Pharmaceutical Particulars

Incompatibilities

None

Shelf-life

As mentioned on strip

Packaging Information

Strip of 10 tablets

Storage and Handling Instructions

Protect from moisture

Patient Counselling Information

What is the most important information I should know about LAMIVIR?

LAMIVIR can cause serious side effects, including:

• Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking LAMIVIR. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death.

• Do not run out of LAMIVIR Refill your prescription or talk to your healthcare provider before your LAMIVIR is all gone.
• Do not stop LAMIVIR without first talking to your healthcare provider
• If you stop taking LAMIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.

• Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with LAMIVIR and become harder to treat (resistant).

What is LAMIVIR?

LAMIVIR contains lamivudine

LAMIVIR is used together with other antiretroviral medicines for the treatment of adult patients with HIV-1 infection.

 HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

Who should not take LAMIVIR?

Do not take LAMIVIR if you are allergic to lamivudine or any of the ingredients in LAMIVIR.

What should I tell my healthcare provider before taking LAMIVIR?

• Before you take LAMIVIR, tell your healthcare provider if you:
• have or have had liver problems, including hepatitis B or C virus infection.
• have kidney problems.
• have diabetes.
• are pregnant or plan to become pregnant. Taking LAMIVIR during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take LAMIVIR
• You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby

Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements

Some medications interact with LAMIVIR Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with LAMIVIR.

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 with other medicines.

How should I take LAMIVIR?

• Take LAMIVIR exactly as your healthcare provider tells you to take it.
• If you miss a dose of LAMIVIR, 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
• LAMIVIR may be taken with or without food.
• Do not run out of LAMIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
• If you take too much LAMIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of LAMIVIR?

• LAMIVIR can cause serious side effects including:
• See “What is the most important information I should know about LAMIVIR?”

Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take LAMIVIR. Lactic acidosis is a serious medical emergency that can cause 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
• feel cold, especially in your arms and legs
• unusual (not normal) muscle pain
• feel dizzy or light-headed
• trouble breathing
• have a fast or irregular heartbeat
• stomach pain with nausea and vomiting
• Hearing loss

Serious liver problems can happen in people who take LAMIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). 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
• loss of appetite for several days or longer turns yellow (jaundice)
• nausea
• dark or “tea-colored” urine
• pain, aching, or tenderness on the right side
• light-colored stools (bowel movements) of your stomach area

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

Risk of inflammation of the pancreas (pancreatitis).

Patients may be at risk for developing pancreatitis during treatment with LAMIVIR if they:

• have taken nucleoside analogue in the past
• have a history of pancreatitis medicines
• have other risk factors for pancreatitis

Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving LAMIVIR to your child if their symptoms and blood test results show that your child may have pancreatitis

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking LAMIVIR.

The most common side effects of LAMIVIR in adults include:

• headache
• nasal signs and symptoms
• nausea
• diarrhea
• generally, not feeling well
• cough
• tiredness
• rash,
• pain,
• depression and
• asthenia

Post-marketing reports of lamivudine received by pharmacovigilance program of India (PvPI) include hearing loss.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of LAMIVIR Call your doctor for medical advice about side effects.

How to store LAMIVIR? 

Store in a cool and dry place

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 Licence Number With Date

M/447/2007 dated 23.12.2016

Date of Revision

24/02/2020