3Tc Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.5 Missed Dose ........................................................................................................... 6

5 OVERDOSAGE .............................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8

7 WARNINGS AND PRECAUTIONS .................................................................................. 9

7.1 Special Populations............................................................................................... 10

7.1.1 Pregnant Women ........................................................................................... 10

7.1.2 Breast-feeding ................................................................................................ 11

7.1.3 Pediatrics ........................................................................................................ 11

7.1.4 Geriatrics ........................................................................................................ 12

8 ADVERSE REACTIONS ................................................................................................ 12

8.1 Adverse Reaction Overview .................................................................................. 12

8.2 Clinical Trial Adverse Reactions ............................................................................ 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................... 16

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 18

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 18

8.5 Post-Market Adverse Reactions ........................................................................... 20

9 DRUG INTERACTIONS ................................................................................................ 21

9.2 Drug Interactions Overview .................................................................................. 21

9.4 Drug-Drug Interactions ......................................................................................... 21

9.5 Drug-Food Interactions ......................................................................................... 23

9.6 Drug-Herb Interactions ......................................................................................... 23

9.7 Drug-Laboratory Test Interactions ........................................................................ 23

10 CLINICAL PHARMACOLOGY ....................................................................................... 23

10.1 Mechanism of Action ...................................................................................... 23

10.3 Pharmacokinetics ........................................................................................... 23

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 27

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 27

PART II: SCIENTIFIC INFORMATION ....................................................................................... 28

13 PHARMACEUTICAL INFORMATION ............................................................................ 28

14 CLINICAL TRIALS ........................................................................................................ 29

14.1 Clinical Trials by Indication ............................................................................. 29

15 MICROBIOLOGY ........................................................................................................ 35

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 38

PATIENT MEDICATION INFORMATION .................................................................................. 40

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

3TC (lamivudine) in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

1.1 Pediatrics

Pediatrics (< 18 years of age): 3TC is indicated in pediatric patients aged 3 months and older in combination with other antiretroviral agents.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Clinical studies of 3TC did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

2 CONTRAINDICATIONS

3TC is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the products (see section 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

3TC can be taken with or without food

Adults, Adolescents and Children weighing at least 25 kg

The recommended oral dose of 3TC for adults and adolescents weighing at least 25 kg is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily (see 7 WARNINGS AND PRECAUTIONS, 10 CLINICAL PHARMACOLOGY and 14 CLINICAL TRIALS).

Pediatrics (aged ≥ 3 months and weighing less than 25 kg)

The recommended oral dose of 3TC Oral Solution for pediatric patients is 5 mg/kg (0.5 mL/kg) twice daily or 10 mg/kg (1 mL/kg) once daily (see 7.1.3 Pediatrics, Lower Virologic Suppression with Oral Solutions in Pediatrics).

Scored Tablets

3TC is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing 3TC Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow 3TC Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of 3TC Tablets for HIV-1-infected pediatric patients is presented in Table 1. Patients changing between lamivudine oral solution and lamivudine tablets should follow the dosing recommendations that are specific for the formulation.

Table 1 Dosing Recommendations for 3TC Scored (150 mg) Tablets in Pediatric Patients

Pediatrics (less than 3 months of age)

The limited data available are insufficient to propose specific dosage recommendations (see 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics ).

The safety and efficacy have not been established for pediatrics less than 3 month of age. Health Canada has not authorized an indication for pediatric patients less than 3 month of age.

Hepatic Impairment

No dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

Renal Impairment

Patients with impaired renal function have increases in C_max and half-life of lamivudine with diminishing creatinine clearance. In addition, apparent total oral clearance of lamivudine decreases as creatinine clearance decreases. Doses of 3TC should be adjusted, as shown in Table 2 and Table 3 in accordance with creatinine clearance.

Table 2 Adjustment of Dosage of 3TC in Accordance With Creatinine Clearance in Adults, Adolescents and Children weighing ≥25 kg

There are no data available on the use of lamivudine in children with renal impairment. A reduction in the dose and/or an increase in the dosing interval should be considered in children aged at least three months and weighing less than 25 kg with a creatinine clearance of less than 50 mL/min. The same percentage reduction in the adult dose is recommended for pediatric patients with renal impairment.

Table 3 Adjustment of Dosage of 3TC in Accordance with Creatinine Clearance in Children aged ≥3 months and weighing less than 25 kg

4.5 Missed Dose

If you forget to take your medicine, take it as soon as you remember. Then continue as before.

5 OVERDOSAGE

If overdosage occurs the patient should be monitored, and standard supportive treatment applied as required.

Administration of activated charcoal may be used to aid in the removal of unabsorbed active substance. General supportive measures are recommended.

Since lamivudine is dialyzable, continuous hemodialysis could be used in the treatment of overdose, although this has not been studied.

No specific signs or symptoms have been identified following acute overdose with lamivudine, apart from those listed as adverse reactions.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 4 –Dosage Forms, Strengths, Composition and Packaging

Dosage Forms

Tablets

3TC tablets 150 mg are white, modified diamond-shaped, scored, film-coated tablets and imprinted with "GX CJ7" on both faces. 3TC tablets 300 mg are grey, modified diamond-shaped, film-coated tablets and imprinted with "GX EJ7" on one face.

Oral Solution

3TC oral solution is a colourless to pale yellow, strawberry-banana flavour, clear liquid.

Packaging

Tablets

150 mg: Supplied in bottles of 60 tablets

300 mg: Supplied in bottles of 30 tablets.

Oral Solution

Supplied in 240 mL plastic bottles.

7 WARNINGS AND PRECAUTIONS

Please see 3 Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

General

3TC should not be administered concomitantly with other products containing lamivudine including HEPTOVIR Tablets and Oral solution, COMBIVIR Tablets, KIVEXA Tablets, TRIUMEQ Tablets, or DOVATO Tablets.

3TC should also not be administered concomitantly with emtricitabine containing products, including ATRIPLA Tablets, EMTRIVA Capsules, TRUVADA Tablets, COMPLERA Tablets, STRIBILD Tablets, GENVOYA Tablets, DESCOVY Tablets, BIKTARVY Tablets, SYMTUZA Tablets, or ODEFSEY Tablets.

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

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.

Diabetic patients should be advised that an adult dose of 3TC oral solution contains 3 g of sucrose.

Endocrine and Metabolism

Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders and blood glucose elevations should be managed as clinically appropriate.

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.

Hepatic/Biliary/Pancreatic

Pancreatitis

Pancreatitis has been observed in some patients receiving nucleoside analogues, including 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.

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. Female sex and obesity may be risk factors.

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 or other nucleoside analogues, 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 with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

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.

Emergence of Lamivudine-Resistant HBV

In non–HIV 1 infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine resistant HBV has been detected and has been associated with diminished treatment response (see full Product Monograph for HEPTOVIR for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV 1 infected patients who have received lamivudine containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) has been reported in HIV-infected patients treated with combination antiretroviral therapy, including 3TC. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium-complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), and tuberculosis (TB)], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, autoimmune hepatitis and Guillain-Barre 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 and sometimes can be an atypical presentation.

Renal Impairment

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 4.2 Recommended Dose and Dosage Adjustment).

7.1 Special Populations

7.1.1 Pregnant Women

3TC has not been studied in pregnant women. Therefore, 3TC should not be used in pregnant women unless the potential benefits to the mother outweigh the potential risk to the fetus (see 10 CLINICAL PHARMACOLOGY).

There have been 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. Findings of developmental toxicity were also observed in animal toxicology studies (see 16 NON-CLINICAL TOXICOLOGY).

There have also 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.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to ART (antiretroviral therapy), including 3TC, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients:

http://www.apregistry.com

Telephone: (800) 258-4263

Fax: (800) 800-1052

The Antiretroviral Pregnancy Registry has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,200 exposures during the first trimester, over 6, 900 exposures during the second/third trimester and included 135 and 198 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.6, 3.7%) and in the second/third trimester, 2.8% (2.4, 3.2%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine compared to the background rate.

7.1.2 Breast-feeding

HIV-1 infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Lamivudine is excreted in breast milk at similar concentrations to those found in serum. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving 3TC.

7.1.3 Pediatrics

The safety and effectiveness of 3TC have been established in pediatric patients aged 3 months and older. Use of 3TC is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of 3TC in adults and pediatric subjects (see 4.2 Recommended Dose and Dosage Adjustment, 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics, 14.1 Clinical Trials by Indication, Table 14 and 14.1 Clinical Trials by Indication, Study Results, Clinical Endpoint Study in Pediatric Patients).

Lower Virologic Suppression with Oral Solutions in Pediatrics

An all-tablet antiretroviral regimen should be used when possible. When an all-tablet regimen cannot be used, 3TC oral solution may be used concomitantly with sorbitol-containing medicines only if the benefits of treatment outweigh possible risks, including lower virologic suppression. Consider more frequent monitoring of HIV-1 viral load when 3TC oral solution is used with chronically-administered, sorbitol-containing medicines (see 9.4 Drug-Drug Interactions).

Pediatric patients who received 3TC oral solution concomitantly with other antiretroviral oral solutions at any time up to 96 weeks in the ARROW study had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving 3TC tablets (see 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics; 15 MICROBIOLOGY, Resistance and 15 MICROBIOLOGY, Pediatrics). The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks was higher in patients who had received tablet formulations (71% [213/301] and 74% [221/300]) than in those who had received any solution formulations (57% [17/30] and 50% [13/26] for once-daily and twice-daily dosing, respectively.

7.1.4 Geriatrics

Clinical studies of 3TC did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of 3TC in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The following adverse reactions are discussed in the 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7 WARNINGS AND PRECAUTIONS sections:

• Lactic acidosis and severe hepatomegaly (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic)
• Post-treatment exacerbations of hepatitis B (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX)
• Serum lipids and blood glucose (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism)
• Pancreatitis (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and 3 SERIOUS WARNINGS AND PRECAUTIONS BOX – Pancreatitis in Pediatric Patients)

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adults

Selected clinical adverse events in therapy-naive patients receiving either 3TC 300 mg once daily or 3TC 150 mg twice daily in combination with RETROVIR 300 mg twice daily and efavirenz 600 mg once daily are listed in Table 5 and Table 6. The most frequent clinical adverse events (≥ 5% frequency) reported during therapy with 3TC 150 mg b.i.d. plus RETROVIR (AZT) 600 mg per day compared with RETROVIR (AZT) are listed in Table 7.

Table 5 Most Common Adverse Events (> 10%)^a Occurring in Subjects in EPV20001 Safety Population during 48 Weeks

Table 6 Severe Adverse Events (Grade 3/4) Occurring in More Than One Subject^a in EPV20001 Safety Population during 48 Weeks

Table 7 – Most Frequent Clinical Adverse Events (≥ 5% Frequency) Reported in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001 and NUCB3002)

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Selected clinical adverse events and physical findings with a ≥ 5% frequency during therapy with 3TC 4 mg/kg twice daily plus RETROVIR (AZT) 160 mg/m² three times daily compared with didanosine in patients without, or with, minimal (≤ 56 days ) prior antiretroviral therapy are listed in Table 8.

Table 8 – Selected Clinical Adverse Events and Physical Findings (≥ 5% Frequency) in Pediatric Patients in Study ACTG300

*Includes pain, discharge, erythema, or swelling of an ear.

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving 3TC alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with 3TC. Three of these patients died of complications of pancreatitis. In a second open-label study (NUCA2005), 12 patients (18%) developed pancreatitis. In Study ACTG300, pancreatitis was not observed in 236 patients randomized to 3TC plus RETROVIR (AZT). Pancreatitis was observed in one patient in this study who received open-label 3TC in combination with RETROVIR (AZT) and ritonavir following discontinuation of didanosine monotherapy.

Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study NUCA2002, six patients (9%) in Study NUCA2005, and two patients (< 1%) in Study ACTG300.

Once-Daily Dosing (ARROW: COL105677)

The safety of once-daily compared with twice-daily dosing of 3TC was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.

8.3 Less Common Clinical Trial Adverse Reactions

Other clinical adverse events reported in controlled clinical trials in association with 3TC 150 mg b.i.d. plus RETROVIR (AZT) 600 mg per day in at least 1% of patients were:

Gastrointestinal: abdominal discomfort and pain (3%), abdominal distension (3%), dyspepsia (2%), gastrointestinal discomfort and pain (3%), gastrointestinal gas (4%), hyposalivation (2%), oral ulceration (1%)

Musculoskeletal: muscle atrophy/weakness/tiredness (1%), muscle pain (2%)

Neurological: mood disorders (1%), sleep disorders (4%), taste disturbances (1%)

Other: breathing disorders (2%), general signs and symptoms (1%), pain (2%), sexual function disturbances (1%), temperature regulation disturbance (1%)

Skin: pruritis (1%), skin rashes (1%), sweating (1%)

Pancreatitis was observed in 9 of 2613 adult patients (0.3%) in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007.

Six percent (6%) of patients treated with 3TC 150 mg b.i.d. plus RETROVIR (AZT) 200 mg t.i.d. in controlled clinical trials permanently discontinued treatment due to an investigator-attributed drug-related adverse event, compared with 7% of patients receiving monotherapy with RETROVIR (AZT) and 13% of patients receiving RETROVIR (AZT) plus zalcitabine. The most frequent adverse events necessitating such permanent discontinuation of therapy with 3TC 150 mg b.i.d. plus RETROVIR (AZT) 200 mg t.i.d. were nausea (2%), malaise and fatigue (1%), and anemia (1%).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The frequencies of selected laboratory abnormalities (Grades 3 and 4) in adults during therapy are listed in Table 9.

Table 9 Selected Laboratory Abnormalities in Studies of 3TC in Adults

*The median duration on study was 12 months.

†Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.

^♠Therapy was 3TC plus RETROVIR plus efavirenz.

ULN = Upper limit of normal

ANC = Absolute neutrophil count

ND = Not done

Selected laboratory abnormalities experienced by pediatric patients without or minimal (≤ 56 days) prior antiretroviral therapy are listed in Table 10.

Table 10 – Frequencies of Selected Laboratory Abnormalities in Pediatric Patients in Study ACTG300

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

8.5 Post-Market Adverse Reactions

The following additional adverse experiences have been reported in post-marketing experience without regard to causality. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to lamivudine, or a combination of these factors.

Body as a whole: anaphylaxis, fatigue, fever, malaise, weakness

Digestive: stomatitis

Endocrine/Metabolic: hyperglycemia, hyperlactatemia, lactic acidosis and hepatic steatosis (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic)

Gastrointestinal: diarrhea, nausea, pancreatitis, rises in serum amylase,

upper abdominal pain, vomiting

Hematological: pure red cell aplasia

Hepatic: transient rises in liver enzymes

Hemic and Lymphatic: anemia, lymphadenophathy, neutropenia, splenomegaly, thrombocytopenia

Immune System: Immune Reconstitution Inflammatory Syndrome (see 7 WARNINGS AND PRECAUTIONS, Immune)

Musculoskeletal: arthralgia, muscle disorders including very rarely rhabdomyolysis

Nervous: headache, paresthesia, peripheral neuropathy

Other: alopecia

Skin: pruritus, rash, urticaria

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Lamivudine is predominantly eliminated by active organic cationic secretion.

The possibility of interactions with other drugs administered concurrently should be considered, particularly when the main route of elimination is renal.

Effect of lamivudine on the pharmacokinetics of other agents

In vitro, lamivudine demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K or organic cation transporter 3 (OCT3). Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.

Lamivudine is an inhibitor of OCT1 and OCT2 in vitro with IC50 values of 17 and 33 µM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).

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, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.

Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.

Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 11 – Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Lamivudine is a synthetic nucleoside analogue, an (-) 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. Lamivudine is metabolized by intracellular kinases to its triphosphate (TP), which is the active moiety (lamivudine triphosphate or L-TP). Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI), and is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. In vitro L-TP has an intracellular half-life of approximately 10.5 to 15.5 hours. L-TP is a substrate for and a competitive inhibitor of HIV reverse transcriptase (RT). Inhibition of RT is via viral DNA chain termination after nucleoside analogue incorporation. L-TP shows significantly less affinity for host cell DNA polymerases and is a weak inhibitor of mammalian α, β, and γ DNA polymerases.

10.3 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. The administration of tablets is bioequivalent to oral solution with respect to AUC_∞ and C_max in adults. Absorption differences have been observed between adult and pediatric populations (see 10.3 Pharmacokinetics, Special Populations and Conditions, Pediatrics ).

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.

Absorption and Bioavailability

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. After oral administration of 2 mg/kg to nine adults with HIV, the peak plasma lamivudine concentration (C_max) was 1.5 ± 0.5 µg/mL (mean ± S.D.). 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. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± S.D.) for the 150 mg tablet and 87% ± 13% for the oral solution.

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 was pharmacokinetically equivalent to 3TC 150 mg twice daily with respect to plasma AUC_24,SS. Intracellular lamivudine triphosphate concentrations in peripheral blood mononuclear cells were also pharmacokinetically equivalent with respect to AUC_24,SS and C_max24,SS.

3TC tablets were administered orally to 12 asymptomatic, HIV-infected patients on two occasions, once in the fasted state and once with food. There was no significant difference in systemic exposure (AUC) in the fed and fasted states; therefore, lamivudine tablets and oral solution may be administered with or without food. Absorption was slower in the fed state as shown by a 47% reduction in mean C_max from fasted values and a prolonged time to peak concentration.

Distribution

The apparent volume of distribution after IV administration of lamivudine was 1.3 ± 0.4 L/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 concentration-dependent, with 36% bound at 0.1 µg /mL and less than 10% bound at concentrations ≥ 1 mcg/mL. The distribution of lamivudine in whole human blood was studied in vitro. Over the concentration range of 0.1 to 100 µg/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 man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite which accounts for less than 5% of an oral 150 mg dose of lamivudine. Glucuronide conjugation has not been observed as a metabolic pathway for lamivudine in man.

Elimination

The majority of lamivudine is eliminated unchanged in urine. Within 4 hours after a single oral dose, 71% ± 16% (mean ± S.D.) of the dose is excreted unchanged in urine. Total clearance and terminal elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10.0 mg/kg.

The plasma lamivudine half-life after oral dosing is 18 to 19 h and the active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 h).

Special Populations and Conditions

Pediatrics: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of 3TC in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution according to the recommended dosage regimen achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV-1 infected adults. Pediatric subjects receiving lamivudine oral tablets according to the recommended dosage regimen achieved plasma concentrations of lamivudine similar to adults. Subjects receiving lamivudine oral tablets achieved higher plasma concentrations of lamivudine than subjects receiving oral solution because the weight-band–based dosing for the tablet formulation results in administration of higher mg/kg doses due to higher bioavailability of the tablets. The absolute bioavailability of both 3TC tablet and oral solution are lower in children than adults.

The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric patients aged 3 months through 12 years was evaluated in 3 studies (PENTA-15 [n=17], PENTA-13 [n=19], and ARROW PK [n=35]). These 3 studies were designed as 2 –period, crossover, open-label pharmacokinetic studies of twice-versus once-daily dosing of abacavir and lamivudine. These 3 studies demonstrated that once-daily dosing provides equivalent AUC_0-24 to twice-daily dosing of lamivudine at the same total daily dose for both the oral solution and tablet formulations. The mean C_max was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing.

Table 12 Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials

^a N = 16 for PENTA-15 C_max.

^b Five subjects in PENTA-13 received lamivudine tablets.

Distribution of lamivudine into cerebrospinal fluid was assessed in 38 pediatric patients. Cerebrospinal fluid concentrations were 3% to 47% of the concentration in a simultaneous serum sample. The true extent of penetration of relationship with any clinical efficacy is unknown.

Pregnancy and Breast-feeding: Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to non-pregnant adults.

Renal Insufficiency: The pharmacokinetic properties of lamivudine were determined in a small group of HIV-infected adults with impaired renal function, and are summarized in Table 13.

Table 13 Pharmacokinetic Parameters (Mean ± S.D.) After a Single 300 mg Oral Dose of Lamivudine in Three Groups of Adults With Varying Degrees of Renal Function (CrCl > 60 mL/min, CrCl = 10-30 mL/min, and CrCl < 10 mL/min)

These results show increases in C_max and half-life with diminishing creatinine clearance. Apparent total clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. T_max was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with reduced creatinine clearance (see 4.2 Recommended Dose and Dosage Adjustment).

11 STORAGE, STABILITY AND DISPOSAL

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

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

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: lamivudine

Chemical name: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl], (2Rcis)

Molecular formula and molecular mass: C₈H₁₁N₃O₃S, 229.3

Structural formula:

* * * chiral centre N N O NH₂ S O HO

Physicochemical properties:

Lamivudine is a white to off-white crystalline solid with a melting point of 176°C.

Solubility:

pKa and pH: The pH value of a 1% w/v solution in water is approximately 6.9. The pKa determined by UV is 4.30.

Distribution Coefficient: The distribution coefficient between n-octanol and water at pH 7.4 was -0.7 ± 0.2 when measured by HPLC.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

3TC (lamivudine) in combination with other antiretroviral agents for the treatment of HIV infection

Trial Design and Study Demographics

Table 14 Summary of patient demographics for clinical trials for the treatment of HIV infection

Study Results

Clinical Endpoint Study in Adults

Results are summarized in Table 15.

Table 15 Number of Patients (%) With At Least One HIV Disease Progression Event or Death

*An investigational non-nucleoside reverse transcriptase inhibitor not approved in Canada.

Surrogate Endpoint Study in Therapy-Naive Adults

Percentages of patients with HIV RNA < 400 copies/mL and outcomes of treatment through are summarized in Table 16.

Table 16 Outcomes of Randomized Treatment through 48 weeks (Intent-to Treat)

*Includes HIV RNA measurements collected after discontinuation of study medication.

^◊Includes consent withdrawn, lost to follow up, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment

In patients receiving 3TC 300 mg once daily, the proportion of patients with HIV RNA < 400 copies/mL at Week 48 was similar for patients with baseline HIV RNA > 100,000 copies/mL (68%) and patients with baseline HIV RNA ≤ 100,000 copies/mL (62%). In patients receiving 3TC twice daily, the proportion of patients with HIV RNA < 400 copies/mL at week 48 was 53% for patients with baseline HIV-RNA

> 100,000 copies/mL and 67% in patients with baseline HIV RNA ≤ 100,000 copies/mL. The proportion of patients with HIV RNA < 50 copies/mL (via Roche Ultrasensitive assay) at Week 48 were similar between patients receiving 3TC 300 mg once daily (61%) and patients receiving 3TC 150 mg twice daily (62%). Similar increases in median CD4+ cell counts were observed at Week 48 in patients receiving 3TC 300 mg once daily (144 cells/mm³) and patients receiving 3TC 150 mg twice daily (146 cells/mm³).

Clinical Endpoint Study in Pediatric Patients

Results are summarized in Table 17.

Table 17 Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Once-Daily Dosing

The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 18. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 18 Proportions of Responders by HIV-1 RNA Copies Through 96 Weeks (From Randomization to Once-Daily or Twice-Daily Dosing - Snapshot Analysis)

The 3TC plus abacavir once daily dosing group demonstrated non-inferiority to the twice daily group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of <80 c/mL at Week 48 and including Week 96 (the secondary endpoint) for all other thresholds tested (<200c/mL, <400c/mL, <1000c/mL). Virologic outcomes between treatment arms were comparable across baseline characteristics (gender, age, or viral load at randomization).

15 MICROBIOLOGY

Virology

Lamivudine is a potent inhibitor of HIV-1 and HIV-2 in vitro. 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. Lamivudine does not act as a chain terminator of mitochondrial DNA synthesis. Lamivudine has little effect on mammalian cell mitochondrial DNA content and does not interfere with normal cellular deoxynucleotide metabolism (in vitro).

In Vitro Activity

The relationships between in vitro susceptibility of HIV to lamivudine and the inhibition of HIV replication in humans or clinical response are still being investigated. The anti-HIV activity of nucleoside analogues in vitro can vary depending on the viral strain, cell type, and assay used to measure such activity. To assess the activity of lamivudine, a number of virus/cell combinations were used, and inhibitory activity was measured in different assays by determination of IC₅₀ and IC₉₀ values. Lamivudine demonstrated anti-HIV-1 and anti-HIV-2 activities in all virus/cell combinations tested.

The antiviral activity of lamivudine has been studied in combination with other antiretroviral compounds using HIV-1-infected MT-4 cells as the test system. No antagonistic effects were seen in vitro with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Resistance

In nonclinical studies, lamivudine-resistant isolates of HIV have been selected in vitro. A known mechanism of lamivudine resistance is the change in the 184 amino acid of RT from methionine to either isoleucine or valine. In vitro studies indicate that zidovudine-resistant viral isolates can become sensitive to zidovudine when they acquire the 184 mutation. The clinical relevance of such findings remains, however, not well defined.

For isolates collected in clinical studies, phenotypic resistance data showed that resistance to lamivudine monotherapy developed within 12 weeks. Evidence in isolates from antiretroviral-naive patients suggests that the combination of lamivudine and zidovudine delays the emergence of mutations conferring resistance to zidovudine. Combination therapy with lamivudine plus zidovudine did not prevent phenotypic resistance to lamivudine. However, phenotypic resistance to lamivudine did not limit the antiretroviral activity of combination therapy with lamivudine plus zidovudine. In antiretroviral therapy-naive patients, phenotypic resistance to lamivudine emerged more slowly on combination therapy than on lamivudine monotherapy. In the zidovudine-experienced patients on lamivudine plus zidovudine, no consistent pattern of changes in phenotypic resistance to lamivudine or zidovudine was observed.

Pediatrics

Pediatric subjects receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions (abacavir, nevirapine/efavirenz or zidovudine) in the ARROW study developed viral resistance more frequently than those receiving tablets.

Cross-Resistance

The potential for cross-resistance between HIV reverse transcriptase inhibitors and protease inhibitors is low because of the different enzyme targets involved. Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a < 4-fold decrease in susceptibility to didanosine and zalcitabine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardized and results may vary according to methodological factors. HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients treated for ≥ 1 year with the combination of zidovudine and didanosine or zalcitabine. The pattern of resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile, Phe77→Leu, Phe116→Tyr and Gln151→Met) from monotherapy, with mutation 151 being most significant for multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also result in resistance to zalcitabine, lamivudine, and stavudine.

Multiple-drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.

The relationship between in vitro susceptibility of HIV to lamivudine and the clinical response to therapy remain under investigation.

Study EPV20001

Genotypic and phenotypic analysis of on-therapy HIV-1 isolates from patients with virologic failure (see 14 CLINICAL TRIALS). The data indicates that through 48 weeks, 3TC once daily has been shown to be as effective as 3TC twice daily, and the use of 3TC once daily through 48 weeks does not increase the incidence or the time to emergence of resistance to 3TC or other study drugs in the regimen. The clinical relevance of genotypic and phenotypic changes associated with lamivudine therapy has not been fully established.

Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level ≥ 400 copies/mL) by Week 48. Twenty-eight patients were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of patients in the lamivudine once-daily group and lamivudine twice-daily groups were 4.9 log₁₀ copies/mL and 4.6 log₁₀ copies/mL, respectively.

Genotypic analysis of on-therapy isolates from 22 patients identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 patients contained treatment-emergent mutations associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 patients contained treatment-emergent mutations associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 patients contained a treatment-emergent lamivudine resistance-associated mutation (M184I or M184V).

Genotypic analysis of on-therapy isolates from patients (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 patients contained treatment-emergent zidovudine resistance mutations, isolates from 7/22 contained treatment-emergent efavirenz resistance mutations, and isolates from 5/22 contained treatment-emergent lamivudine resistance mutations.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine once daily showed that isolates from 12/13 patients were susceptible to zidovudine; isolates from 8/13 patients exhibited a decrease in susceptibility to efavirenz, and isolates from 7/13 patients showed a decrease in susceptibility to lamivudine.

Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from patients (n = 13) receiving lamivudine twice daily showed that isolates from all 13 patients were susceptible to zidovudine; isolates from 4/13 patients exhibited a decrease in susceptibility to efavirenz, and isolates from 4/13 patients exhibited a decrease in susceptibility to lamivudine.

Cytotoxicity

The results of cytotoxicity studies in various assays have shown little cytotoxic action with lamivudine. Cytotoxicity of lamivudine was compared with that of zidovudine, zalcitabine, and didanosine in four T-lymphoblastoid cell lines; one monocyte/ macrophage-like cell line; one B-lymphoblastoid cell line; and peripheral blood lymphocytes (PBLs) using both cell proliferation (CP) and [³H]-thymidine uptake (Td) assays. In the CP assay, lamivudine was the least toxic of the four compounds. [³H]-thymidine uptake results demonstrated a similar trend to those from the CP assays. Lamivudine had no cytotoxic effect when incubated for 10 days with phytohemagglutinin (PHA)-activated human lymphocytes or human macrophages.

The cytotoxicity of combinations of lamivudine with zidovudine, zalcitabine, or didanosine was evaluated in PHA-activated PBLs and CEM cells by measuring cellular uptake of [³H]-thymidine. Lamivudine greatly reduced the cytotoxicity of zalcitabine, slightly reduced the cytotoxicity of zidovudine in some cases, and did not alter the cytotoxicity of didanosine.

In myelotoxicity studies in vitro, lamivudine demonstrated no toxic effects against erythroid, granulocyte-macrophage, pluripotent, or stromal progenitor cells from healthy human donors. Lamivudine was not toxic to human hematopoietic supportive stroma, nonadherent hematopoietic cells, or stromal fibroblasts and produced minimal changes in cytokine (GM-CSF) production from mitogen-stimulated bone marrow stromal cells. Lamivudine was less toxic than zidovudine, zalcitabine, ara-C, 3FT, and stavudine in these studies. In another study, lamivudine was not toxic to activated human T-cells.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

Acute toxicity studies have been performed in the mouse and rat. The acute oral administration of very high doses of lamivudine (two doses of 2000 mg/kg) in mice was associated with transient increases in sexual activity in males and general activity in males and females. There were no deaths and no evidence of target organ toxicity. Therefore the maximum non-lethal oral dose of lamivudine in mice is greater than two doses of 2000 mg/kg.

The acute intravenous administration of lamivudine at 2000 mg/kg was well tolerated by both mice and rats and was not associated with any target organ toxicity. A number of non-specific clinical signs were observed which were more severe in rats but were all of relatively short duration.

Long-Term Toxicity

In repeat-dose toxicity studies, lamivudine was very well tolerated in the rat at oral doses up to 2000 mg/kg b.i.d. for 6 months. Treatment-related effects were restricted to minor hematological (mainly red cell parameters), clinical chemistry and urinalysis changes, and the mucosal hyperplasia of the cecum (in the 6-month study). The no (toxicologically important) effect level was 450 mg/kg b.i.d.

In the dog, oral doses of 1500 mg/kg b.i.d. in males and 1000 mg/kg b.i.d. in females for a period of 12 months were well tolerated. Treatment-related changes included reductions in red cell counts at all dose levels associated with increased MCV and MCH, and reductions in total leucocyte, neutrophil and lymphocyte counts in high dose animals, but with no effect on bone marrow cytology. Deaths were seen in females dosed with 1500 mg/kg b.i.d. in a 3-month study but not in a 12-month study, using a dose of 1000 mg/kg b.i.d.

When administered orally for one month, at a dose of 1000 mg/kg b.i.d., lamivudine demonstrated low hematotoxic potential in the mouse, and did not significantly enhance the hematotoxicity of zidovudine or interferon α.

Carcinogenicity: Traditional 24-month carcinogenicity studies using lamivudine have been conducted in mice and rats at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at recommended therapeutic doses. The following results should be noted. In mice, there appeared to be an increased incidence of histiocytic sarcoma in female mice treated with 180 mg/kg/day (6 of 60 mice) and 2000 mg/kg/day (5 of 60 mice) when compared to control mice (two control groups with 1 of 60 and 2 of 60 mice). There did not appear an increased incidence in histiocytic sarcoma in female mice treated with 600 mg/kg/day (3 of 60 mice). It should be noted that the control incidence of this type of tumour in this strain of mice can be as high as 10% similar to that found in the 180 and 2000 mg/kg/day groups. In rats, there appeared to be an increased incidence of endometrial epithelial tumours in female rats treated with 3000 mg/kg/day (5 of 55 rats) when compared to control rats (two control groups each with 2 of 55 rats). There did not appear to be an increased incidence for endometrial tumours in rats treated with 1000 mg/kg/day (2 of 55 rats) or 300 mg/kg/day (1 of 55 rats). It should be noted that there did not appear to be an increased incidences of any proliferative non-neoplastic epithelial lesions in treated female rats when compared to control rats, and the incidence of adenocarcinoma (5/55 or 9%) was only slightly higher than recorded controls at the laboratory where the study was conducted (4/50 or 8%). The statistical significance of the findings in mice and rats varied with the statistical analysis conducted, and therefore, the statistical and hence, the clinical significance of these findings are uncertain. However, based on the similarity to historical control data, it was concluded that the results of long-term carcinogenicity studies in mice and rats for lamivudine did not seem to show a carcinogenic potential relevant for humans.

Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg (approximately 65 times the recommended human dose based on body surface area comparisons).

Reproductive and Developmental Toxicology: A range of studies has been performed to assess the effects of repeated oral administration of lamivudine upon mammalian reproduction and development.

In a rat fertility study, except for a few minor changes in high dose (2000 mg/kg b.i.d) animals, the overall reproductive performance of the F₀ and F₁ generation animals, and the development of the F₁ and F₂ generation, was unaffected by treatment with lamivudine.

Lamivudine was not teratogenic in the rat or rabbit, at doses up to 2000 mg/kg b.i.d. and 500 mg/kg b.i.d., respectively. In the rabbit a slight increase in the incidence of pre-implantation loss at doses 20 mg/kg b.i.d. and above indicates a possible early embryolethal effect. There was no such effect in the rat. These marginal effects occurred at relatively low doses, which produced plasma levels comparable to those achieved in patients.

In a peri-/post-natal/juvenile toxicity study in rats, some histological inflammatory changes at the ano-rectal junction and slight diffuse epithelial hyperplasia of the caecum were observed in dams and pups at the high dose level. An increased incidence of urination upon handling was also seen in some offspring receiving 450 or 2000 mg/kg. In addition, a reduction in testes weight was observed in juvenile males at 2000 mg/kg which was associated with slight to moderate dilatation of the seminiferous tubules.