Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor

Lamivudine

Approved 19 Apr 2018OralTablet

The FDA lists this product in 39 strengths and forms.

Indications

Lamivudine is 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 is 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.

(1)

Contraindications

Lamivudine Tablets are contraindicated in patients with a previous hypersensitivity reaction to lamivudine. Lamivudine tablets are contraindicated in patients with previous hypersensitivity reaction to lamivudine. (4)

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)

5.1Patients 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.

Pregnancy and breastfeeding

8.1Pregnancy 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 (Cmax) 35 times the recommended clinical dose ( see Data ).

Data Human Data: Based on prospective reports from 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 (Cmax) 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 (Cmax) 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.

Adverse reactions

The following adverse reactions are discussed in other sections of the labeling: Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1)]. Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2)]. Pancreatitis [see Warnings and Precautions (5.3)]. Immune reconstitution syndrome [see Warnings and Precautions (5.4)]. The most common reported adverse reactions (incidence greater than equal to 15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

(6.1) The most common reported adverse reactions (incidence greater than equal to 15%) in pediatric patients subjects were fever and cough. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience Clinical Trials Experience in Adult Subjects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough.

Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with lamivudine 150 mg twice daily plus RETROVIR 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) Adverse Reaction Lamivudine 150 mg Twice Daily plus RETROVIR (n = 251) RETROVIR Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

(n = 230) Body as a Whole Headache 35% 27% Malaise & fatigue 27% 23% Fever or chills 10% 12% Digestive Nausea 33% 29% Diarrhea 18% 22% Nausea & vomiting 13% 12% Anorexia and/or decreased appetite 10% 7% Abdominal pain 9% 11% Abdominal cramps 6% 3% Dyspepsia 5% 5% Nervous System Neuropathy 12% 10% Insomnia & other sleep disorders 11% 7% Dizziness 10% 4% Depressive disorders 9% 4% Respiratory Nasal signs & symptoms 20% 11% Cough 18% 13% Skin Skin rashes 9% 6% Musculoskeletal Musculoskeletal pain 12% 10% Myalgia 8% 6% Arthralgia 5% 5% Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].

Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007) ULN = Upper limit of normal.

ND = Not done. Test (Threshold Level) 24-Week Surrogate Endpoint Trials The median duration on study was 12 months. Clinical Endpoint Trials Lamivudine Plus RETROVIR RETROVIR Either zidovudine monotherapy or zidovudine in combination with zalcitabine. Lamivudine plus Current Therapy Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine. Placebo plus Current Therapy Absolute neutrophil count (<750/mm 3 ) 7.2% 5.4 15% 13% Hemoglobin (<8.0 g/dL) 2.9% 1.8 2.2% 3.4% Platelets (<50,000/mm 3 ) 0.4% 1.3 2.8% 3.8% ALT (>5.0 x ULN) 3.7% 3.6 3.8% 1.9% AST (>5.0 x ULN) 1.7% 1.8 4.0% 2.1% Bilirubin (>2.5 x ULN) 0.8%

0.4ND ND Amylase

(>2.0 x ULN) 4.2% 1.5 2.2% 1.1% The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. Clinical Trials Experience in Pediatric Subjects Lamivudine oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials. Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with lamivudine 4 mg per kg twice daily plus RETROVIR 160 mg per m 2 3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300 Adverse Reaction Lamivudine plus RETROVIR (n = 236) Didanosine (n = 235) Body as a Whole Fever 25% 32% Digestive Hepatomegaly 11% 11% Nausea & vomiting 8% 7% Diarrhea 8% 6% Stomatitis 6% 12% Splenomegaly 5% 8% Respiratory Cough 15% 18% Abnormal breath sounds/wheezing 7% 9% Ear, Nose and Throat Signs or symptoms of ears Includes pain, discharge, erythema, or swelling of an ear.

Nasal discharge or congestion 7% 6% 8% 11% Other Skin rashes 12% 14% Lymphadenopathy 9% 11% Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine.

Three of these subjects died of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open-label lamivudine in combination with RETROVIR and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.3)].

Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (less than 1%) in Trial ACTG300. Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300 ULN = Upper limit of normal.

Test (Threshold Level) Lamivudine plus RETROVIR Didanosine Absolute neutrophil count (<400/mm 3 ) 8% 3% Hemoglobin (<7.0 g/dL) 4% 2% Platelets (<50,000/mm 3 ) 1% 3% ALT (>10 x ULN) 1% 3% AST (>10 x ULN) 2% 4% Lipase (>2.5 x ULN) 3% 3% Total Amylase (>2.5 x ULN) 3% 3% Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of lamivudine was assessed in the ARROW trial.

Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA

Lamivudine

Indications

Contraindications

Warnings and precautions

5.1Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical

Two medicines in one question?

5.2Lactic Acidosis and Severe Hepatomegaly with Steatosis

5.3Pancreatitis

5.4Immune Reconstitution Syndrome

5.5Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution

Interactions

7.1Drugs Inhibiting Organic Cation Transporters

7.2Sorbitol Coadministration

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Exposure Registry

Adverse reactions

6.1Clinical Trials Experience Clinical Trials Experience in Adult Subjects.

0.4ND ND Amylase

Composition

Strengths and forms

Official product information

At a glance

Guidelines