7 Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration.
(7.2) 7.1 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) [see Clinical Pharmacology (12.3) ] .
No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
7.2 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 Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ] .
10 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.
11 Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV.
The chemical name of lamivudine is (2R,cis)-4-amino-l-(2-hydroxymethyl-l,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 C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g per mol.
It has the following structural formula: Lamivudine USP is a white to off-white solid with a solubility of approximately 70 mg per mL in water at 20°C.
Lamivudine tablets USP are for oral administration.
Each scored 150 mg film-coated tablet and 300 mg film-coated tablet contains 150 mg and 300 mg of lamivudine USP and the following inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
14 The use of lamivudine is based on the results of clinical trials in HIV-1-infected subjects in combination regimens with other antiretroviral agents.
Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.
14.1 Adult Subjects Clinical Endpoint Trial NUCB3007 (CAESAR) was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1.
A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells per mm 3 (median = 122 cells per mm 3 ) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive.
The median duration on trial was 12 months.
Results are summarized in Table 9.
Number of Subjects (%) with at Least One HIV-1 Disease Progression Event or Death a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.
Endpoint Current Therapy (n = 460) Lamivudine plus Current Therapy (n = 896) Lamivudine plus an NNRTI a plus Current Therapy (n = 460) HIV-1 progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) Surrogate Endpoint Trials Dual Nucleoside Analogue Trials: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine.
These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination.
More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.
Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multicenter, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily.
A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), white (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells per mm 3 (median = 362 cells per mm 3 ), and median baseline plasma HIV-1 RNA of 4.66 log 10 copies per mL.
Outcomes of treatment through 48 weeks are summarized in Figure 1 and Table 10.
Virologic Response through Week 48, EPV20001 a,b (Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR.
b Responders at each visit are subjects who had achieved and maintained HIV-1 RNA less than 400 copies per mL without discontinuation by that visit.
Outcomes of Randomized Treatment through 48 Weeks (Intent-to-Treat) a Achieved confirmed plasma HIV-1 RNA less than 400 copies per mL and maintained through 48 weeks.
b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.
c Includes consent withdrawn, lost to follow-up, protocol violation, data outside the trial-defined schedule, and randomized but never initiated treatment.
Outcome Lamivudine 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) Lamivudine 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) Responder a 67% 65% Virologic failure b 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasons c 18% 14% The proportions of subjects with HIV-1 RNA less than 50 copies per mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine 300 mg once daily and 63% for subjects receiving lamivudine 150 mg twice daily.
Median increases in CD4+ cell counts were 144 cells per mm 3 at Week 48 in subjects receiving lamivudine 300 mg once daily and 146 cells per mm 3 for subjects receiving lamivudine 150 mg twice daily.
A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand.
A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells per mm 3 , median plasma HIV-1 RNA 4.8 log 10 copies per mL) were enrolled.
Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily.
In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies per mL were 61% (33 of 54) in the group randomized to once-daily lamivudine and 75% (39 of 52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies per mL were 54% (29 of 54) in the once-daily lamivudine group and 67% (35 of 52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells per mm 3 in the once-daily lamivudine group and 216 cells per mm 3 in the all-twice-daily group.
Figure 1 14.2 Pediatric Subjects Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy.
A total of 471 symptomatic, HIV-1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms.
The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white.
The mean baseline CD4+ cell count was 868 cells per mm 3 (mean: 1,060 cells per mm 3 and range: 0 to 4,650 cells per mm 3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm 3 and range: 0 to 1,555 cells per mm 3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL.
The median duration on trial was 10.1 months for the subjects receiving lamivudine plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy.
Results are summarized in Table 11.
Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint Lamivudine plus RETROVIR (n = 236) Didanosine (n = 235) HIV-1 disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Once-Daily Dosing ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects.
HIV-1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing lamivudine and abacavir, dosed twice daily according to World Health Organization recommendations.
After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of lamivudine and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks.
Of the 1,206 original ARROW subjects, 669 participated in Randomization 3.
Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.
The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12.
The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.
Virologic Outcome of Randomized Treatment at Week 96 a (ARROW Randomization 3) Outcome Lamivudine plus Abacavir Twice-Daily Dosing (n = 333) Lamivudine plus Abacavir Once-Daily Dosing (n = 336) HIV-1 RNA <80 copies/mL b 70% 67% HIV-1 RNA ≥80 copies/mL c No virologic data 28% 31% Discontinued due to adverse event or death 1% <1% Discontinued study for other reasons d 0% <1% Missing data during window but on study 1% 1% a Analyses were based on the last observed viral load data within the Week 96 window.
b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.
c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.
d Other includes reasons such as withdrew consent, loss to follow-up, etc.
and the last available HIV-1 RNA less than 80 copies per mL (or missing).
Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of lamivudine and abacavir (75% [458/610] and 72% [434/601]) than in those who had received solution formulation(s) (with lamivudine solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% [29/56] and 54% [30/56]), respectively [see Warnings and Precautions (5.5) ] .
These differences were observed in each different age group evaluated.
16 /STORAGE AND HANDLING Product: 63629-5014
RECENT MAJOR CHANGES
Warnings and Precautions, Use with Interferon- and Removed Ribavirin-Based Regimens (previous 5.3) 05/2019
8.5 Geriatric Use Clinical trials of lamivudine did not include 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 Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ] .
DOSAGE FORMS AND STRENGTHS
3 Lamivudine Tablets USP, 150 mg (Scored) White to off-white, film-coated, oval shaped tablets, debossed with ‘66’ and ‘Y’ on either side of the score line on one side and plain with a score line on the other side.
Lamivudine Tablets USP, 300 mg White to off-white, film-coated, oval shaped tablets, debossed with ‘67 Y’ on one side and plain on the other side.
Tablets: 150 mg, scored ( 3 ) Tablets: 300 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Lamivudine is an antiretroviral agent [see Microbiology (12.4) ] .
INDICATIONS AND USAGE
1 Lamivudine tablets are a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.
Limitations of Use: The dosage of this product is for HIV-1 and not for HBV.
Lamivudine tablets are a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Limitations of Use: The dosage of this product is for HIV-1 and not for HBV.
8.4 Pediatric Use The safety and effectiveness of lamivudine in combination with other antiretroviral agents have been established in pediatric patients aged 3 months and older.
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 because pediatric subjects who received lamivudine oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving lamivudine tablets in the ARROW trial [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.2) ] .
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine during pregnancy.
Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary Available data from the APR show no difference in the overall risk of birth defects for lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data).
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 (see Data).
Data Human Data: Based on prospective reports to the APR 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 the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S.
reference population of the MACDP.
The prevalence of 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.
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.
WARNING: EXACERBATIONS OF HEPATITIS B, and DIFFERENT FORMULATIONS OF LAMIVUDINE Exacerbations of Hepatitis 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 Warnings and Precautions (5.1) ].
Important Differences among Lamivudine-Containing Products Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV tablets and oral solution (used to treat chronic HBV infection).
Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions (5.1) ].
WARNING : EXACERBATIONS OF HEPATITIS B, and DIFFERENT FORMULATIONS OF LAMIVUDINE See full prescribing information for complete boxed warning.
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.
Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.
(5.1) Patients with HIV-1 infection should receive only dosage forms of lamivudin e appropriate for treatment of HIV-1.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported.
(5.1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.
(5.2) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis.
Discontinue treatment as clinically appropriate.
( 5.3 ) Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.
( 5.4 ) Lower virologic suppression rates and increased risk of viral resistance were observed in pediatric subjects who received lamivudine oral solution concomitantly with other antiretroviral oral solutions compared with those who received tablets.
An all-tablet regimen should be used when possible.
( 5.5 ) 5.1 Patients with Hepatitis B Virus Co-infection Posttreatment 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 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 EPIVIR-HBV tablets and EPIVIR-HBV oral solution.
EPIVIR-HBV was developed for patients with chronic hepatitis B.
The formulation and dosage of lamivudine in EPIVIR-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 EPIVIR-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, lamivudine oral solution, 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 EPIVIR-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.
5.2 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.
5.3 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 Adverse Reactions (6.1) ].
5.4 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 systems respond 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.
5.5 Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Pediatric subjects who received lamivudine oral solution (at weight band-based doses approximating 8 mg per kg per day) 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 [see Clinical Pharmacology (12.3) , Microbiology (12.4) , Clinical Studies (14.2) ].
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.
An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol [see Clinical Pharmacology (12.3) ] .
Consider more frequent monitoring of HIV-1 viral load when treating with lamivudine oral solution.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).
Patients with Hepatitis B or C Co-infection Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued.
Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.1) ] .
Differences in Formulations of Lamivudine Advise patients that lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV tablets and oral solution.
If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine tablets (not EPIVIR-HBV) should be used [see Warnings and Precautions (5.1) ] .
Lactic Acidosis/Hepatomegaly with Steatosis Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals.
Advise patients to stop taking lamivudine if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.2) ].
Risk of Pancreatitis Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.3) ] .
Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when lamivudine is started [see Warnings and Precautions (5.4) ].
Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution Advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received lamivudine oral solution concomitantly with other antiretroviral oral solutions [see Warnings and Precautions (5.5) ] .
Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine during pregnancy [see Use in Specific Populations (8.1) ] .
Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2) ] .
Missed Dosage Instruct patients that if they miss a dose of lamivudine, to take it as soon as they remember.
Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2) ] .
The brands listed are trademarks of their respective owners and are not trademarks of the Aurobindo Pharma Limited.
DOSAGE AND ADMINISTRATION
2 • Adults: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily.
( 2.1 ) • Pediatric Patients Aged 3 Months and Older: Administered either once or twice daily.
Dose should be calculated on body weight (kg) and should not exceed 300 mg daily.
( 2.2 ) • Patients with Renal Impairment: Doses of lamivudine tablets must be adjusted in accordance with renal function.
( 2.3 ) 2.1 Recommended Dosage for Adult Patients The recommended dosage of lamivudine tablets 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 Warnings and Precautions (5.1) ] .
2.2 Recommended Dosage for Pediatric Patients 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 may be prescribed [see Warnings and Precautions (5.5) ] .
The recommended oral dosage of lamivudine tablets for HIV-1-infected pediatric patients is presented in Table 1.
Dosing Recommendations for Lamivudine Scored (150 mg) Tablets in Pediatric Patients Weight (kg) Twice-Daily Dosing Regimen Using Scored 150 mg Tablet Once-Daily Dosing Regimen a AM Dose PM Dose Total Daily Dose 14 to <20 1 tablet (150 mg) ½ tablet (75 mg) ½ tablet (75 mg) 150 mg ≥ 20 to <25 1½ tablets (225 mg) ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥25 2 tablets (300 mg) b 1 tablet (150 mg) 1 tablet (150 mg) 300 mg a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies (14.2) ] .
b Patients may alternatively take one 300 mg tablet, which is not scored.
Oral Solution The recommended dosage of lamivudine oral solution in HIV-1-infected pediatric patients aged 3 months and older is 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents [see Clinical Pharmacology (12.3) ] .
Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ] .
2.3 Patients with Renal Impairment Dosing of lamivudine tablets is adjusted in accordance with renal function.
Dosage adjustments are listed in Table 2 [see Clinical Pharmacology (12.3) ] .
Adjustment of Dosage of Lamivudine in Adults and Adolescents (Greater than or Equal to 25 kg) in Accordance with Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of Lamivudine ≥50 150 mg twice daily or 300 mg once daily 30 to 49 150 mg once daily 15 to 29 150 mg first dose, then 100 mg once daily 5 to 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 tablets is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of lamivudine tablets in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.