3TC 150 mg

Overview

Information for the Patient

3TC

Special Handling Instructions

Not applicable.

Dosage and Administration

Pediatric Patients Less Than 3 Months of Age

Recommended Dose and Dosage Adjustment

Missed Dose

Pediatric Patients Aged ≥3 Months to 12 Years

3TC

Adjustment of Dosage of 3TC in Accordance with Creatinine Clearance in Children Aged 3 Months to 12 Years

Adults and Adolescents

Adverse Reactions

Gastrointestinal

Post-Market Adverse Drug Reactions

Clinical Trial Adverse Drug Reactions

Digestive

3TC

3TC

Frequencies of Selected Laboratory Abnormalities in Pediatric Patients in Study ACTG300

Other

Body as a Whole

Neurological

Musculoskeletal

3TC

Selected Laboratory Abnormalities in Studies of 3TC in Adults

Skin

Nervous

Hemic and Lymphatic

Hematological

Endocrine/Metabolic

Hepatic

Indications and Clinical Use

3TC (lamivudine) in combination with other antiretroviral agents is indicated for:

• the treatment of HIV infection.

  Overdosage

  For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.

  
  

  There is no known antidote for 3TC (lamivudine).

  
  

  If overdosage occurs the patient should be monitored, and standard supportive treatment applied as required. Although no data is available, administration of activated charcoal may be used to aid in the removal of unabsorbed drug. 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.

  
  

  Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose.

  
  

  One case of acute overdose in an adult ingesting 6 g of 3TC was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. One other adult patient in error ingested lamivudine 1200 mg per day plus zidovudine 1200 mg per day for approximately 2 weeks; he had a Grade 3 decrease in absolute neutrophil count that resolved upon reduction of doses of lamivudine and zidovudine. Two cases of pediatric overdose were reported in ACTG300. One case was a single dose of 7 mg/kg of 3TC; the second case involved the use of 5 mg/kg of 3TC twice daily for 30 days. There were no clinical signs or symptoms noted in either case.

  
  

  In Phase I studies, lamivudine was administered at doses up to 20 mg/kg per day (i.e., approximately five times the usual recommended dose in adults) without serious consequences.

  Dosage Forms, Composition and Packaging

  300 mg

  Each grey, modified diamond-shaped, film-coated tablet, imprinted with “GX EJ7" on one face contains: lamivudine 300 mg. Nonmedicinal ingredients: black iron oxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. Plastic bottles of 30.

  Oral Solution

  Each mL of colorless to pale yellow, strawberry-banana flavoured, clear liquid contains: lamivudine 10 mg. Nonmedicinal ingredients: artificial strawberry and banana flavours, citric acid (anhydrous), hydrochloric acid, methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), sodium hydroxide, sucrose and water. Each 150 mg (15 mL) contains 3 g of sucrose. Plastic bottles of 240 mL.

  Tablets

  
  
  

  150 mg

  Each, white, modified diamond-shaped, scored, film-coated tablet, imprinted with “GX CJ7” on both faces, contains: lamivudine 150 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. Plastic bottles of 60.

  
  
  

  Warnings and Precautions

  Renal

  
  
  

  Lactic Acidosis/Severe Hepatomegaly with Steatosis

  Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including lamivudine. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic acidosis include generalized weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnea and tachypnea).

  
  

  Caution should be exercised when administering 3TC to any patient, and particularly to those with known risk factors for liver disease. Treatment with 3TC should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

  Pediatrics

  The safety and pharmacokinetic properties of 3TC in combination with other antiretroviral agents have not been established in pediatric patients who are less than 3 months of age.

  Antiretroviral Pregnancy Registry

  To monitor maternal-fetal outcomes of pregnant women exposed to 3TC, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-387-7374).

  Pregnant Women

  There are no adequate and well-controlled studies in pregnant women.

  
  

  Consistent with passive transmission of the drug across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV. Reproductive studies in animals have not shown evidence of teratogenicity, and have shown no effect on male or female fertility. Lamivudine induced early embryolethality when administered to pregnant rabbits at exposure levels comparable to those achieved in man. Because animal reproductive toxicity studies are not always predictive of the human response, lamivudine should be used during pregnancy only if the potential benefits outweigh the potential risks.

  Hepatic/Biliary/Pancreatic

  Pancreatitis has been observed in some patients receiving lamivudine. However it is unclear whether this was due to treatment with the medicinal product or to the underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of lamivudine until diagnosis of pancreatitis is excluded.

  Immune Reconstitution

  During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB) which may necessitate further evaluation and treatment.

  Special Populations

  
  
  

  Hematologic

  Very rare occurrences of pure red cell aplasia have been reported with lamivudine use. Discontinuation of lamivudine has resulted in normalization of hematologic parameters in patients with suspected lamivudine-induced pure red cell aplasia.

  Immune

  Patients receiving 3TC or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close observation by physicians experienced in the treatment of patients with HIV-associated diseases.

  General

  The safety profile of combination therapy with 3TC (lamivudine) and other antiretroviral agents reflects the individual safety profile of each component. The individual product monographs for each drug in the combination regimen should be consulted before combination therapy is initiated.

  
  

  Evidence for once-daily dosing using the 300 mg tablets is mainly in antiretroviral naive patients.

  
  

  Trough levels of lamivudine in plasma and of intracellular triphosphate were lower with once-daily dosing than with twice-daily dosing. Furthermore, the C_max levels of lamivudine in plasma were higher with once-daily dosing than with twice-daily dosing (see Action and Clinical Pharmacology). The clinical significance of these observations is not known.

  
  

  The clinical status of the patient and the adverse event profile of 3TC should be borne in mind when considering the patient's ability to drive or operate machinery.

  Endocrine and Metabolism

  
  
  

  Patients with Impaired Renal Function

  Patients with impaired renal function may be at a greater risk of toxicity from 3TC due to decreased renal clearance of the drug. Consideration should be given to appropriate reduction in the dose of lamivudine (see Dosage and Administration).

  Fat Redistribution

  Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

  
  

  Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

  Patients Co-infected with Hepatitis B Virus

  Clinical trials and marketed use of 3TC have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of 3TC, which may have more severe consequences in patients with decompensated liver disease. If 3TC is discontinued in a patient with HIV and HBV coinfection, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

  Nursing Women

  Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum (1 to 8 µg/mL). It is recommended that mothers taking lamivudine do not breastfeed to avoid risking postnatal transmission of HIV infection and potential adverse effects from lamivudine in nursing infants.

  Use With Interferon- and Ribavirin-Based Regimens

  In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 3TC should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of 3TC should be considered as medically appropriate.

  
  
  

  Storage and Stability

  3TC tablets should be stored between 2 and 30°C.

  
  

  3TC oral solution should be stored between 2 and 25°C.

  Action and Clinical Pharmacology

  Pharmacokinetics

  The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single oral, multiple oral and intravenous (IV) doses ranging from 0.25 to 10 mg/kg. After oral administration of 2 mg/kg, the peak plasma lamivudine concentration (C_max) was 1.5±0.5 µg/mL (mean±S.D.) and half-life was 2.6±0.5 hours. There were no significant differences in half-life across the range of single doses (0.25 to 8 mg/kg). The area under the plasma concentration versus time curve (AUC) and C_max increased in proportion to dose over the range from 0.25 to 10 mg/kg.

  
  

  The steady-state pharmacokinetic properties of the 3TC 300 mg tablet once daily for 7 days compared to the 3TC 150 mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. 3TC 300 mg once daily resulted in lamivudine exposures that were similar to 3TC 150 mg twice-daily with respect to plasma AUC_24,ss; however, C_max,ss was 66% higher and the trough value was 53% lower compared to the 150 mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC_24,ss and C_max24,ss; however, trough values were lower compared to the 150 mg twice-daily regimen.

  
  

  The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

  
  

  Lamivudine is well absorbed from the gut, and the bioavailability of oral lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time (t_max) to maximal serum concentrations (C_max) is about an hour.

  
  

  No dose adjustment is needed when coadministered with food as lamivudine bioavailability is not altered, although a delay in t_max and reduction in C_max have been observed. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.

  
  

  Coadministration of zidovudine results in a 13% increase in AUC_∞ for zidovudine and a 28% increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.

  Mechanism of Action

  Lamivudine is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. The sugar ring of lamivudine is novel in that it contains a sulphur at the 3´ position as a second heteroatom. Intracellularly, lamivudine is phosphorylated to its active 5´-triphosphate metabolite (lamivudine triphosphate or L-TP), which has an intracellular half-life of approximately 10.5 to 15.5 hours. The principal mode of action of lamivudine is inhibition of HIV reverse transcription via viral DNA chain termination. In addition, L-TP inhibits both the RNA- and DNA-dependent DNA polymerase activities of reverse transcriptase (RT), and is a weak inhibitor of mammalian α, β, and γ DNA polymerases.

  
  
  

  Contraindications

  3TC (lamivudine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products (see Dosage Forms, Composition and Packaging).

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