Lamivudine Prescribing Information
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering LAMIVUDINE to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. 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).
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 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.
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.
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.
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 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.
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.
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.
Dosage and Administration
The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged 3 months and older is 4 mg per kg taken orally twice daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents.
Once daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection.
LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing LAMIVUDINE scored tablets, pediatric patients should be assessed for the ability to swallow tablets. For patients unable to safely and reliably swallow LAMIVUDINE tablets, the oral solution formulation should be prescribed
Weight (kg) | Twice-daily Dosing Regimen Using Scored 150-mg Tablet | ||
AM Dose | PM Dose | Total Daily Dose | |
| 14 to <20 | ½ tablet (75 mg) | ½ tablet (75 mg) | 150 mg |
| ≥20to <25 | ½ tablet (75 mg) | 1 tablet (150 mg) | 225 mg |
| ≥25 | 1 tablet (150 mg) | 1 tablet (150 mg) | 300 mg |
Warnings and Precautions, Related Products that are Recommended
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients
07/2016
Warnings and Precautions, Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution
Pediatric subjects who received LAMIVUDINE oral solution concomitantly with other antiretroviral oral solutions at any time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving LAMIVUDINE tablets
LAMIVUDINE scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Consider more frequent monitoring of HIV-1 viral load when treating with LAMIVUDINE oral solution.
LAMIVUDINE is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.
- The dosage of this product is for HIV-1 and not for HBV.
Dosing of LAMIVUDINE is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2
The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) 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 5 mg 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 AUC24,ss; however, Cmax,sswas 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 AUC24,ssand Cmax24,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 Cmaxwas 1.40 (1.17, 1.69) mcg per mL.
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.
Binding of lamivudine to human plasma proteins is low (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.
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 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.
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 |
Tmaxwas 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
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 be made after routine hemodialysis or peritoneal dialysis.
The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg per mL.
Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged over 3 months) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges over 3 months old
Creatinine Clearance (mL/min) | Recommended Dosage of |
| ≥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 LAMIVUDINE is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of LAMIVUDINE in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.
- LAMIVUDINE Scored Tablets
150 mg are white to off-white, film-coated, diamond- shaped tablets, debossed with “MCR” and “313” separated by functional score on one side and plain on other side with functional score.
- LAMIVUDINE Tablets
300 mg are Grey, film-coated, modified diamond-shaped tablets, debossed with “MCR” and “314” on one side and plain on other side.
Reduction of the dosage of LAMIVUDINE is recommended for patients with impaired renal function
Dosing of LAMIVUDINE is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2
Creatinine Clearance (mL/min) | Recommended Dosage of |
| ≥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 LAMIVUDINE is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of LAMIVUDINE in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.
The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) 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 5 mg 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 AUC24,ss; however, Cmax,sswas 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 AUC24,ssand Cmax24,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 Cmaxwas 1.40 (1.17, 1.69) mcg per mL.
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.
Binding of lamivudine to human plasma proteins is low (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.
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 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.
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 |
Tmaxwas 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
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 be made after routine hemodialysis or peritoneal dialysis.
The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. CSF samples were collected between 2 and 4 hours postdose. At the dose of 8 mg per kg per day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg per mL.
Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged over 3 months) studied previously. There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges over 3 months old