2.1 HIV Counseling and Testing

H IV couns eli ng and t esting should be o f fe r ed to all p ati ents b efo re b e ginn ing t r e atm ent with lamivudine tablets (HBV) and p eriodi cal ly du ri ng t r e atm ent b ecau se of the risk of em e r g e n ce of resist ant - H I V -1 and limit ation of t reatm ent options if lamivudine tablets (HBV) is p re s crib ed to t r e at ch ronic h ep atitis B in fection in a p ati ent who h as un r e c ogni z ed H I V -1 in fection or acqui res H I V-1 in fection du ri ng t reatm e nt [s ee Warnings and Pr e cautions (5. 3 ) ].

2.2 Recommended Dosage for Adult Patients

The r e comm end ed o r al dos age of lamivudine tablets (HBV) is 100 mg on ce d ai l y.

2.3 Recommended Dosage for Pediatric Patients

The r e comm end ed o r al dos age of lamivudine tablets (HBV) for p edi at ric p ati ents a g ed 2 to 17 y e ars is 3 mg p er kg o n ce d ai ly up to a m a ximum d ai ly dos age of 100 m g. The o ral solution fo rmul ation should be p r es crib ed f or p ati ents r eq ui ring a do s a ge l ess th an 100 mg or if u n able to s wallow t abl ets.

2.4 Patients with Renal Impairment

Dos a ge r ecomm end atio ns for adult p ati ents with r edu ced r en al fu n ction are p rovid ed in Table 1 [s ee Clini cal P har ma cology (12. 3 ) ].



Table 1. Dosage of Lamivudine Tablets (HBV) in Adult Pa ti en ts wi th Renal I mpai r ment

Follo wing co r r ection of the dos a ge f or re n al imp ai rm ent, no addition al dos a ge modi fi cation of lamivudine tablets (HBV) is r equi red a ft er r outine (4 -hou r) h emodi a l ysis or p eriton eal di a l ysis [s ee Clini cal P har ma cology (12. 3 ) ].



Th ere are insu f fi ci ent d a ta to recomm end a sp eci f ic dos a ge of lamivudine tablets (HBV) in p edi at ric p ati ents with ren al imp ai rm ent.

2.5 Important Administration Instructions

• Lamivudine tablets (HBV) may be administered with or without food.

• The tablets and oral solution may be used interchangeably [see Clinical Pharmacology (12.3)].

• The oral solution should be used for doses less than 100 mg.

• Lamivudine tablets (HBV) should not be used with other medications that contain lamivudine or medications that contain emtricitabine

2.6 Assessing Patients during Treatment

Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B. During treatment, combinations of events such as return of persistently elevated ALT, increasing levels of HBV DNA over time after an initial decline below assay limit, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings may be considered as potentially reflecting loss of therapeutic response. Such observations should be taken into consideration when determining the advisability of continuing therapy with lamivudine tablets (HBV).



The optimal duration of treatment, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.

5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis

L a ctic a cidosis and s ev e re h ep atom eg a ly with st e atosis, in cluding fat al c as es, h ave b een repo rt ed with the use of nu cl eoside an al o g u es al one or in combin ation, in cluding lamivudine tablets (HBV) and oth er anti r et rovi rals. A m ajo ri ty of t h ese c as es h ave b e en in wom en. O b esi ty and p rolong ed nu cl eoside e xposu re m ay be risk fact o rs. Most of th ese rep o rts h ave d es cri b ed p ati ents r e ceivi ng nu cl eoside an al o g u es for t reatm ent of H IV in f e ction, but th ere h ave b een r epo rts of l actic acidosis in p ati ents re c eiving l amivudine for h ep atitis B. C aution should be e x ercis ed wh en administ eri ng lamivudine tablets (HBV) to a ny p ati ent with kno wn risk facto rs for liv er dis eas e; ho wev er, cas es  also have b een rep o rt ed in p ati ents with no kno wn risk fac to rs. Treatm ent with lamivudine tablets (HBV) should be susp end ed in a ny p ati ent who d ev elops clini cal or l abo rato ry findi n gs sug g estive of l actic a cid osis or p ronoun ced h e p at oto xi ci ty (whi ch m ay i n clude h ep atom eg a ly and st eatosis ev en in the abs en ce of m a rk ed t ran s amin ase el e v ations ).

5.2 Exacerbations of Hepatitis after Discontinuation of Treatment

Clini cal and l abo rato ry evid en ce of e x acer b ations of h ep atitis h ave o c cu r red aft er dis continu ation of lamivudine tablets (HBV) (t h ese h a ve b e en p rim ari ly d et ect ed by s e rum A LT el ev ations, in addition to the re-em e r g e n ce of HBV DNA common ly obs er v ed aft er stopping t r e atm ent; s ee Table 4 for mo re in fo rm ation reg ardi ng f r equ e n cy of postt reatm ent A LT e l ev ations) [s ee Ad verse R ea ctions (6. 1 ) ]. Althou gh most ev ents a pp ear to h a ve b een s el f-l imit ed, fat aliti es h ave b een rep o rt ed in some cas es. The cau s al rel ations hip of h ep atitis e x acerb at ion aft er dis continu ation of lamivudine tablets (HBV) h as not b een c l e a r ly es t ablish ed. P ati ents should be clos e ly monito red with both clin i cal and l abo r ato ry follo w -up for at l e ast s ev e r al months aft er stopping t reatm ent with lamivudine tablets (HBV). T h ere is insu ff i ci ent evid en ce to d e t ermine wh eth er r e-initi ation of lamivudine tablets (HBV) alt ers the cou rse of postt r eatm ent e x acerb ations of h ep atitis.

5.3 Risk of HIV-1 Resistance if Lamivudine Tablets (HBV) Is Used in Patients with Unrecognized or Untreated HIV-1 Infection

Lamivudine tablets (HBV) contain a lower lamivudine dose than the lamivudine dose used to treat HIV-1 infection with lamivudine tablets and oral solution or with lamivudine- containing antiretroviral fixed-dose combination products.



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

5.4 Emergence of Resistance-Associated HBV Substitutions

In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on– lamivudine tablets (HBV) re-appearance of HBV DNA after an initial decline below the solution-hybridization assay limit [see Microbiology (12.4)].Subjects treated with lamivudine tablets (HBV) (adults and children) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison with subjects treated with lamivudine tablets (HBV) without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations. In the controlled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their own previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including subjects from the liver transplant setting and from other clinical trials. In clinical practice, monitoring of ALT and HBV DNA levels during treatment with lamivudine tablets (HBV) may aid in treatment decisions if emergence of viral mutants is suspected.

6.1 Clinical Trials Experience

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

Clinical Trials Experience in  of Adult Subjects with Chronic HBV Infection

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



Table 2. Clinical Adverse Reactionsa Reported in Greater than or Equal to 10% of Subjects who Received Lamivudine Tablets (HBV) for 52 to 68 Weeks and at an Incidence Greater than Placebo (Trials 1 to 3)

a   Includes adverse events regardless of severity and causality assessment.

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



Table 3. Frequencies of Specified Laboratory Abnormalities Reported during Treatment at a Greater Frequency in Subjects Treated with Lamivudine Tablets (HBV) than with Placebo (Trials 1 to 3)a

a Includes subjects treated for 52 to 68 weeks.

b Includes observations during and after treatment in the 2 placebo-controlled trials that collected this information.

ULN = Upper limit of normal.



In subjects followed for up to 16 weeks after discontinuation of treatment, posttreatment ALT elevations were observed more frequently in subjects who had received lamivudine tablets (HBV) than in subjects who had received placebo. A comparison of ALT elevations between Weeks 52 and 68 in subjects who discontinued lamivudine tablets (HBV) at Week 52 and subjects in the same trials who received placebo throughout the treatment course is shown in Table 4.



Table 4. Posttreatment ALT Elevations with No-Active-Treatment Follow-up (Trials 1 and 3)

a Each subject may be represented in one or more category.

b During treatment phase.

c Comparable to a Grade 3 toxicity in accordance with modified WHO criteria.

ULN = Upper limit of normal.



Clinical Trials Experience in Pediatric Subjects with Chronic HBV Infection

Most commonly observed adverse reactions in the pediatric trials were similar to those in adult trials. Posttreatment transaminase elevations were observed in some subjects followed after cessation of lamivudine tablets (HBV).

6.2 Postmarketing Experience

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

Blood and Lympatic

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

Digestive

Stomatitis.

Endocrine and Metabolic

Hyperglycemia.

General

Weakness.

Hepatic and Pancreatic

Lactic acidosis and steatosis [see Warnings and Precautions (5.1)] ,posttreatment exacerbations of hepatitis [see Warnings and Precautions (5.2)] , pancreatitis.

Hypersensitivity

Anaphylaxis, urticaria.

Musculoskeletal

Cramps, rhabdomyolysis.

Nervous

Paresthesia, peripheral neuropathy.

Respiratory

Abnormal breath sounds/wheezing.

Skin

Alopecia, pruritus, rash.

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 Clinical Pharmacology (12.3].Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided.

8.1 Pregnancy

Teratogenic Effects:



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 substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of 2.7% reported in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as a U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occur at less than 20 weeks gestation. Of over 11,000 women exposed to lamivudine in the APR, less than 1% were treated for HBV. The majority of women exposed to lamivudine in the APR were HIV-1-infected and were treated with higher doses of lamivudine compared with HBV mono-infected women. In addition to lamivudine, HIV-1-infected women were also treated with other concomitant medications for HIV-1 infection [see Data]. The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.



Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 60 times the recommended clinical dose [see Data].



Data



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



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



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 (Cmax) approximately 53 or more times higher than human exposure at the recommended daily dose. Evidence of early embryolethality in the absence of maternal toxicity was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 60 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 at plasma concentrations (Cmax) 104 times higher than human exposure.

8.2 Lactation

Risk Summary



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



There is no information available regarding the effects of the drug on the breastfed infant or on milk production.



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



Data



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

8.4 Pediatric Use

Lamivudine tablets (HBV) is indi cat ed for the t r e atm ent of ch ronic h ep atitis B vi rus in f ection in p edi at ric p ati ents ag ed 2 to 17 y e ars [s ee Indi cations and Usage (1 ), Clini cal Phar ma cology (12. 3 ), Clini cal Studi es (14.2 ) ]. The s afe ty and e f fi ca cy of lamivudine tablets (HBV) in p edi at ric p ati ents y ou n g er th an 2 y e ars h a ve not b een est ablish ed.

8.5 Geriatric Use

Clinical trials of lamivudine tablets (HBV) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of lamivudine tablets (HBV) 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 (2.4),Clinical Pharmacology (12.3)].

8.6 Patients With Impaired Renal Function

R edu ction of the dos a ge of lamivudine tablets (HBV) is r e c omm end ed for p ati ents w ith imp ai red ren al fu n ction [s ee Dos age and Ad ministration (2.4 ), Clini cal Phar ma col ogy (12. 3 ) ].

8.7 Patients With Impaired Liver Function

No dose adjustm ent for l amivudine is requi red f or p ati ents with imp ai red h ep atic fun ction.

12.1 Mechanism of Action

L amivudine is an antivi ral a g ent with activity against HBV  [s ee Mi crobiology (12. 4 ) ].

12.3 Pharmacokinetics

Pharmacokinetics in Adults

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



Absorption and Bioavailability: Following single oral doses of 100 mg, the peak serum lamivudine concentration (Cmax) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0 to 24h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (Cmax), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably.



After oral administration of lamivudine once daily to HBV-infected adults, the AUC and Cmax increased in proportion to dose over the range from 5 mg to 600 mg once daily.



Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg per mL oral solution.



Effects of Food on Oral Absorption:  Lamivudine tablets (HBV) may be administered with or without food.The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states.



Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 asymptomatic HIV-1-infected subjects was 1.3 ± 0.4 L per kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight.



Binding of lamivudine to human plasma proteins is less than 36% and independent of dose. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.



Metabolism: Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite (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 (t1/2)  ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg per kg.



Specific Populations

Patients With Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy adults and in adults with impaired renal function, with and without hemodialysis (Table 5).



Table 5. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Oral Dose of Lamivudine in Adults With Varying Degrees of Renal Function

Exposure (AUC), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment [see Dosage and Administration (2.4)].



Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL per min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.



It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.



Pediatric Patients With Renal Impairment: The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.



Patients With Hepatic Impairment: The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6). Subjects were stratified by severity of hepatic impairment.



Table 6. Pharmacokinetic Parameters (Mean ± SD) Dose-Normalized to a Single 100-mg Dose of Lamivudine in Adults With Normal or Impaired Hepatic Function

a Hepatic impairment assessed by aminopyrine breath test.



Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine tablets (HBV) have not been established in the presence of decompensated liver disease [see Indications and Usage (1)] .



Patients Post-Hepatic Transplant: Fourteen HBV-infected adult subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of lamivudine tablets (HBV) have not been established in this population [see Indications and Usage (1)] .





Pregnant Women: The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers were similar at similar doses. Lamivudine pharmacokinetics were studied in 36 pregnant women with HIV during 2 clinical trials conducted in South Africa (3 to 6 times the recommended daily dosage for HBV). 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.



Pediatric Patients: Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine Tmax was 0.5 to 1 hour. In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults.



Geriatric Patients: The pharmacokinetics of lamivudine after administration of lamivudine tablets (HBV) to subjects over 65 years have not been studied [see Use in Specific Populations (8.5)].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.



Drug Interaction Studies

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



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



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



Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.



Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.



Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC (0 to 24), 14%, 32%, and 36% in the AUC (∞), and 28%, 52%, and 55% in the Cmax of lamivudine.



Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.



Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

12.4 Microbiology

Mechan i sm of Act i on

L amivudine is a s ynth et ic nu cl eoside a n al o gu e. I nt racellul ar l y, l amivudine is phospho r y l at ed to its active 5′ -t riphosph ate m et abolit e, l amivudine t riphosph at e, 3 TC -TP. The p rin cip al mode of action of 3 TC - TP is the inhibition of the R NA- and D NA­ d ep end ent po l ym e r ase activiti es of H BV re v erse t r ans cript ase (rt) via D NA ch ain t ermin ation aft er in c o rpo ration of the nu cl eotide an al o g ue into vi ral DNA. 3 TC -TP is a weak inhibitor of m amm ali an α, β, and γ -DNA po l y m era s es.

Ant i v iral Act i v i t y

A ctivi ty of l amivudine ag ainst H BV in c ell cultu re w as ass ess ed in H BV D NA-t r ans f e ct ed 2.2.15 cells, H B611 cells, and in fect ed hu m an p ri m a ry h ep at o c y t es. EC 50 v alu es (the co n cent r ation of d r ug n ee d ed to red u ce the l ev el of e xt racellul ar H BV D NA by 50 %) v ari ed from 0.01 µM (2 .3 ng p er m L) to 5.6 µM (1.3 m cg p er m L) d e p end ing upon the d u ration of e xposu re of cells to l amivudin e, the cell mod el s yst em, and the p roto col us ed. S ee the E P I V IR p res cribi ng in fo rm ation for in fo rm ation r eg ardi ng activi ty of l amivudine ag ainst H I V.

Res istance

L amivudin e-resist ant isol at es w ere id enti fi ed in subj ects with vi rolo gic b reakth ro u gh, d efin ed wh en using solution h y b ri di z ation ass ay as the d et e ction of H BV D NA in s erum on 2 or mo re o cc asions aft er faili ng to d et e ct H BV DNA on 2 or m o re o c c asions and d efin ed wh en using PCR ass ay as a g rea t er th an 1 lo g10 (10 -fold) in c r ease in s erum HBV DNA from n adir du ri ng t r e atm ent in a subj ect who h ad an initi al vi rolo gic resp ons e.

L amivudin e -resist ant HBV isol at es d ev elop rtM2 04 V /I substitutions in the YM DD motif of the cat a l ytic dom ain of the vi ral re v erse t rans cript as e. rtM204 V /I substitutions are f r equ ent ly accomp an i ed by oth er s ubstitutions (rt V173 L, r t L180M) whi ch enh a n ce t he l ev el of l amivudine resist an ce or act as com p ens ato ry substitutions i mp roving r epli cation e f fi c i en c y. Oth er substitutions d et ect ed in l amivudin e-resist ant HBV isol at es in clude r t L8 0I and rt A181 T.

In 4 cont roll ed clini cal t r i als in adults with H B e Ag -positive ch ronic h e p atitis B vi rus in fection (C HB ), YM D D -mut ant H BV w as d et e ct ed in 81 of 335 subj ects r eceivi ng lamivudine tablets (HBV) 100 mg on ce d ai ly for 52 w e eks. The p r ev a l en ce of YM DD substitutions was l ess th an 10% in each of th ese t ri a ls for subj ects studi ed at 24 weeks and i n cr e as ed to an av e ra ge of 24% (ra n ge in 4 t ri als: 16% to 32 %) at 52 w e eks. In limit ed d ata from a lo n g - t e rm follo w-up t ri al in subj ects who continu ed 100 mg p er d ay lamivudine tablets (HBV) aft er o ne of th e se t ri als, YM DD substitutions fu rth er in creas ed f rom 18% (10 of 57) at 1 y ear to 41% (20 of 49 ), 53% (27 of 51 ), and 69% (31 of 4 5) af t er 2, 3, and 4 y ea rs of t r e atm ent, resp ectiv e l y. O v er the 5 - y ear t reatm ent p eriod, the p ropo rtion of subj ects who d ev elop ed YM DD-mut ant H BV at a ny time was 6 9% (40 of 58 ).

In a cont roll ed t ri al, t r ea tm ent -n aive subj ects with H B eA g -positive C HB w ere t r eat ed with lamivudine tablets (HBV) or lamivudine tablets (HBV) plus ad e fovir dipivoxil combin ation t h era p y. Follo wing 104 weeks of th e ra p y, YM DD-mut ant HBV was d et ect ed in 7 of 40 (18 %) subj ects re c eiving combin ation th era py co mp ared with 15 of 35 (4 3 %) subj ects r e ceivi ng th e ra py with on ly lamivudine tablets (HBV). In anoth er cont roll ed t ri al, combi n ation th era py was ev alu a t ed in adult subj ects with H B e Ag -positive C HB who h ad YM DD-mut ant H BV and diminish ed clini cal and vi rolo gic response to lamivudine tablets (HBV). Follo wing 52 weeks of lamivudine tablets (HBV) plus ad efovir dipivoxil combin ation th era py (n = 46) or th era py with on ly lamivudine tablets (HBV) (n = 49 ), YM DD-mut ant H BV was d et ec t ed l ess f r equ e nt ly in subj ects r e ceivi ng combin ation th era p y, 6 2% v ersus 96 %.

A publish ed t ri al sug g es t ed th at the rat es of l amivudine resist an ce in subj e cts t reat ed f or H B eA g -n eg ative C HB app ear to be mo re v ar i able (0% to 27% at 1 y e ar a nd 10% to 56% at 2 y e ars ).

Ped iat ric Sub je cts: In a cont roll ed t ri al in p edi at ric subj ects, YM DD-mut ant H BV was d et ec t ed in 31 of 1 66 (19 %) subj ects r e c eiving lamivudine tablets (HBV) for 52 w eeks. F or a su b g roup th at rem ain ed on th e ra py with lamivudine tablets (HBV) in a follo w-up t ri al, YM DD s ubstitutions in creas ed from 24% (29 of 12 1) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of t reatm ent with lamivudine tablets (HBV).



Cross-Resistance: HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (30 fold) and telbivudine (greater than 100 fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (I169T/M250V and T184G/S202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis

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

Mutagenesis

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

Impairment of Fertility

Lamivudine did not affect male or female fertility in rats at oral doses up to 4,000 mg per kg per day, associated with concentrations approximately 70 times (male) or 104 times (females) higher than the concentrations (Cmax) in humans at the dose of 100 mg [see Use in Specific Populations (8.1)].

13.2 Animal Pharmacology & OR Toxicology

14.1 Clinical Studies of Lamivudine Tablets (HBV) in Adult Patients

The s afe ty and e f fi c a cy of lamivudine tablets (HBV) 100 mg on ce d ai ly v ersus pl a ce bo were ev alu at ed in 3 cont roll ed t ri als in subj ects with comp ens at ed ch ron ic h ep at itis B vi rus in fection. All subj ects were a g ed 16 y e ars or ol d er and h ad ch ronic h e p atitis B vi rus in fection (s erum H Bs A g -positive f or at l e ast 6 months) accomp an i ed by evid en ce of H BV r epli cation (s erum H B eA g -positive and pos itive for s erum H BV DN A) and p e rsist ent ly e l ev at ed A LT l ev els and/or ch ronic in fl amm ation on liv er biop sy com p atible with a di a gnosis of ch ro nic vi ral h ep atitis. The results of th ese t ri als a re summ ari z ed b elo w.

• Tri al 1 was a randomi z ed, doubl e-blind t ri al of lamivudine tablets (HBV) 100 mg on ce d ai ly v e rsus pl acebo f or 52 w e eks follo wed by a 16 - week n o -t r eatm ent p eriod in 141 t r e atm ent -n aive US subj ects.
• Tri al 2 was a randomi z ed, doubl e-blind, 3 -arm t ri al th at comp ared lamivudine tablets (HBV) 25 mg on ce d ai ly v e rsus lamivudine tablets (HBV) 100 mg on ce d ai ly v e rsus pl acebo for 52 weeks in 358 Asi an subj ects.
• Tri al 3 was a randomi z ed, p arti al l y -blind t ri al co ndu ct ed p rim ari ly in No r th Am eri ca and Eu rope in 238 subj ects who h ad on goi ng evid en ce of active c h ronic h e p atitis B d espite p revious t reatm ent with int erferon al fa. T he t ri al comp ared lamivudine tablets (HBV) 100 mg on ce d ai ly for 52 w e eks, follo wed by eith er lamivudine tablets (HBV) 1 00 mg or m at chi ng pl a ce bo on ce d ai ly for 16 weeks ( A rm 1 ), v e rsus pl acebo on ce d ai ly for 68 weeks ( A rm 2 ).

P rin cip al endpoint comp arisons for the histolo g ic and s erol o gic out com es in subj ects receivi ng lamivudine tablets (HBV) (100 mg d ai l y) or p l acebo in th ese t ri als are sho wn in the follo wing t abl es.

Table 7. His tologic Response at W eek 52 a m ong Adult Sub jects Re c eiving Lamivudine Tablets (HBV)100 mg On ce Daily or Pla cebo

a  Imp ro v em ent was d efin ed as a g r e at er th an or eq u al to 2 -point d ecr e ase in the Knod ell Histolo gic Activi ty Ind ex (H A I) at W eek 52 com p ared with p r et reatm ent HA I. Subj ects with missing d ata at b a s eline were e x clud ed.



Table 8. HB eAg S ero conv ert e rsa at W eek 52 a mong Adult Sub jects R eceiving Lamivudine Tablets (HBV) 100 mg On ce Daily or Pla cebo

a Th ree - compon ent s er o c onv ersion was d e fin ed as W eek 52 v alu es sho wi ng loss of H B e A g, g ain of HB eAb, and redu ction of H BV DNA to b elow the solution - h yb ridi z ation ass ay limit. Subj ects with n e g ative b as eline H B e Ag or HBV DNA ass ay we re e x clud ed from the an a l ysis.

Normalization of serum ALT levels was more frequent with treatment of lamivudine tablets (HBV) compared with placebo in Trials 1, 2, and 3.



The m ajo ri ty of subj ects t reat ed with lamivudine tablets (HBV) sho wed a d ec r ease of H BV D NA to b elow the ass ay limit ear ly in the co u rse of th e ra p y. Ho wev e r, r e app e a ran ce of ass a y - d et ect ab le H BV D NA du ri ng t r e atm ent with lamivudine tablets (HBV) was obs erv ed in app ro xi m at e ly o n e-thi rd of subj ects aft er this initi al respons e.

14.2 Clinical Studies of Lamivudine Tablets (HBV) in Pediatric Subjects

The s afe ty and e f fi c a cy of lamivudine tablets (HBV) w ere ev alu at ed in a doubl e-blind clini cal t ri al in 286 subj ects a g ed f rom 2 to 17 y e ars, who w ere r andomi z ed (2:1) to recei ve 52 weeks of lamivudine tablets (HBV) (3 mg p er kg on ce d ai ly to a m a ximum of 100 mg on ce d ai l y) or pl a c ebo. All subj ects h ad comp ens a t ed ch ronic h e p atitis B a ccomp ani ed by evid en ce of h ep atitis B vi rus repli cation (positive s er um H B e Ag and positive for s erum H BV D NA by a res e arch b ran ch e d -c h ain DNA as s a y) and p e rsist ent ly el ev at ed s erum A LT l e v els. The combin ation of loss of H B e Ag and r edu ction of H BV D NA to b e low the ass ay limit of the res e a rch as s a y, ev alu at ed at W eek 52, w as obs erv ed in 23% of s ubj ects t reat ed with lamivudine tablets (HBV) and 1 3% of pl acebo -t r eat ed subj e cts. No rm ali z ation of s erum A LT was a chi ev ed and m aint ain ed to W eek 52 mo re freq u ent ly in subj e cts t reat ed with lamivudine tablets (HBV) comp ared with pl acebo (55% v ersus 13 %). As in the adult co nt roll ed t ri als, most subj ects t reat ed with lamivudine tablets (HBV) h ad d e c rea s es in H BV D NA b elow the as s ay limit ear ly in t r e atm e nt, but about on e-thi rd of subj ects with this initi al response h ad r e a pp eara n ce of ass a y - d et ec t able H BV DNA du ri ng t re atm ent. Adol es cents ( a g ed 13 to 17 y e ars) sh o wed l ess evid e n ce of t r e atm ent eff e ct th an you n g er p edi at ric subj e cts.