JAMP LAMIVUDINE TABLET

Canada - English - Health Canada

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Active ingredient:
LAMIVUDINE
Available from:
JAMP PHARMA CORPORATION
ATC code:
J05AF05
INN (International Name):
LAMIVUDINE
Dosage:
300MG
Pharmaceutical form:
TABLET
Composition:
LAMIVUDINE 300MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
Product summary:
Active ingredient group (AIG) number: 0128157005; AHFS: 08:18.08.20
Authorization status:
APPROVED
Authorization number:
02507129
Authorization date:
2020-10-27

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Page 1 of 43

PRODUCT MONOGRAPH

Pr

JAMP Lamivudine

Lamivudine Tablets, USP

150 mg and 300 mg

Antiretroviral Agent

JAMP Pharma Corporation

1310 rue Nobel

Boucherville, Quebec

J4B 5H3

Date of Approval:

October 23, 2020

Submission Control No: 235315

Page 2 of 43

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................... 3

SUMMARY PRODUCT INFORMATION ....................................................................3

INDICATIONS AND CLINICAL USE..........................................................................3

CONTRAINDICATIONS..............................................................................................4

WARNINGS AND PRECAUTIONS .............................................................................4

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

DRUG INTERACTIONS ............................................................................................ 17

DOSAGE AND ADMINISTRATION.......................................................................... 19

OVERDOSAGE.......................................................................................................... 21

ACTION AND CLINICAL PHARMACOLOGY ......................................................... 21

STORAGE AND STABILITY..................................................................................... 22

SPECIAL HANDLING INSTRUCTIONS ................................................................... 22

DOSAGE FORMS, COMPOSITION AND PACKAGING ........................................... 22

PART II: SCIENTIFIC INFORMATION.......................................................................... 24

PHARMACEUTICAL INFORMATION ..................................................................... 24

CLINICAL TRIALS.................................................................................................... 25

DETAILED PHARMACOLOGY ................................................................................ 28

MICROBIOLOGY ...................................................................................................... 31

TOXICOLOGY .......................................................................................................... 34

REFERENCES .......................................................................................................... 37

PART III: CONSUMER INFORMATION ........................................................................ 40

Page 3 of 43

Pr

JAMP Lamivudine

Lamivudine Tablets, USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

All Nonmedicinal

Ingredients

Oral

Tablets/ 150 mg

Tablets/ 300 mg

hypromellose, magnesium

stearate,

microcrystalline cellulose,

polyethylene

glycol, polysorbate 80, sodium

starch

glycolate and titanium dioxide

black iron oxide, hypromellose,

magnesium stearate,

microcrystalline

cellulose, polyethylene

glycol,

polysorbate 80, sodium starch glycolate

and titanium dioxide

INDICATIONS AND CLINICAL USE

JAMP Lamivudine (lamivudine) in combination with other antiretroviral agents is indicated for

the treatment of

HIV infection.

Pediatrics (< 18 years of age)

JAMP Lamivudine is indicated in pediatric patients weighing greater than or equal to 14 kg in

combination with other

antiretroviral agents.

Page 4 of 43

Geriatrics (≥ 65 years of age)

Clinical studies of lamivudine tablets 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.

CONTRAINDICATIONS

JAMP 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 section).

WARNINGS AND PRECAUTIONS

General

JAMP Lamivudine should not be administered concomitantly with other products containing

lamivudine

including HEPTOVIR Tablets and Oral solution, COMBIVIR Tablets, KIVEXA

Tablets, or TRIZIVIR Tablets.

JAMP Lamivudine should also not be administered concomitantly with emtricitabine containing

products,

including ATRIPLA Tablets, EMTRIVA Capsules, TRUVADA Tablets,

COMPLERA Tablets,

or STRIBILD Tablets.

Serious Warnings and Precautions

Post-Treatment Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are

infected with hepatitis B virus (HBV) and have discontinued lamivudine tablets.

Hepatic

function should be monitored closely with both clinical and laboratory

follow-up

for at least several months in patients who discontinue JAMP

Lamivudine.

If appropriate,

initiation of anti-hepatitis B therapy may be

warranted.

Pancreatitis in Pediatric Patients

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a

history of pancreatitis, or other significant risk factors for the development of

pancreatitis, JAMP Lamivudine

should be used with caution. Treatment with

JAMP Lamivudine

should be

stopped immediately if clinical signs, symptoms,

or laboratory abnormalities

suggestive of pancreatitis occur (see ADVERSE

REACTIONS section).

Page 5 of 43

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

patients.

Patients receiving JAMP Lamivudine 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.

Patients should be advised that current antiretroviral therapy, including

JAMP Lamivudine,

not been proven

to prevent the risk of transmission of HIV to others through sexual contact or

blood

contamination. Appropriate precautions should continue to be employed.

Endocrine and Metabolism

Serum lipids and blood glucose

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.

Page 6 of 43

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

JAMP Lamivudine or other nucleoside

analogues, particularly

to those with known risk factors for liver disease. Treatment with JAMP

Lamivudine 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 lamivudine tablets have shown that some patients with chronic

hepatitis B

virus (HBV) disease may experience clinical or laboratory evidence of recurrent

hepatitis upon

discontinuation of lamivudine tablets, which may have more severe consequences

in patients with

decompensated liver disease. If JAMP Lamivudine 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 (IRIS)

Immune reconstitution inflammatory syndrome has been reported in HIV-infected patients treated

with combination antiretroviral therapy, including lamivudine tablets. 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.

Page 7 of 43

Renal

Patients with Impaired Renal Function

Patients with impaired renal function may be at a greater risk of toxicity from JAMP Lamivudine

due to

decreased renal clearance of the drug. Consideration should be given to appropriate

reduction in

the dose of lamivudine (see DOSAGE AND ADMINISTRATION section).

Special Populations

Pregnant Women

Lamivudine

tablets has not been studied in pregnant women.

Therefore, JAMP Lamivudine

should not be used in pregnant

women unless the potential benefits to the mother outweigh the

potential risk to the fetus (see

DETAILED 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 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

lamivudine,

an Antiretroviral Pregnancy

Registry has been established. Healthcare providers are encouraged to register patients by calling

1-800-258-4263.

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.

Nursing Women

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 JAMP Lamivudine.

Pediatrics

The safety and effectiveness of lamivudine tablets have been established in pediatric patients

Page 8 of 43

weighing greater than or equal to 14kg. Use of lamivudine tablets is supported by

pharmacokinetic trials and evidence from adequate and

well-controlled trials of lamivudine

tablets in adults and pediatric subjects (see DOSAGE AND ADMINISTRATION –

Recommended Dose and Dosage Adjustment, DETAILED PHARMACOLOGY,

Pharmacokinetics in Pediatric Patients and CLINICAL TRIALS – Pediatric Subjects).

Geriatrics (> 65 years of age)

Clinical studies of lamivudine tablets 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 JAMP Lamivudine in elderly

patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of

concomitant disease or other drug therapy.

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labelling:

Lactic acidosis and severe hepatomegaly (see WARNINGS AND PRECAUTIONS,

Lactic Acidosis and Severe Hepatomegaly with Steatosis)

Post-treatment exacerbations of hepatitis B (see WARNINGS AND PRECAUTIONS,

Post-Treatment Exacerbations of Hepatitis B)

Serum lipids and blood glucose (see WARNINGS AND PRECAUTIONS, Endocrine and

Metabolism)

Pancreatitis (see WARNINGS AND PRECAUTIONS, Pancreatitis; and WARNINGS

AND PRECAUTIONS, Pancreatitis is Pediatric Patients)

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

Adults

Selected clinical adverse events in therapy-naive patients receiving either lamivudine tablets

300 mg once

daily or lamivudine tablets 150 mg twice daily in combination

with RETROVIR

300 mg twice daily and efavirenz 600 mg once daily are listed in Table 1 and Table 2. The

most frequent clinical

adverse events (≥ 5% frequency) reported during therapy with

lamivudine tablets 150 mg b.i.d. plus

RETROVIR (AZT) 600 mg per day compared with

RETROVIR (AZT) are listed in Table 3.

Page 9 of 43

Table 1:

Most Common Adverse Events (> 10%)

a

Occurring in Subjects in EPV20001

Safety Population during 48 Weeks

Adverse Event

lamivudine tablets

300 mg q.d. plus

RETROVIR plus

Efavirenz

(n = 272)

lamivudine tablets

150 mg b.i.d. plus

RETROVIR plus

Efavirenz

(n = 273)

At Least One Adverse Event

Nausea

Dizziness

Fatigue

Dreams

Headaches

Rashes

Viral respiratory infections

Diarrhea

Ear, nose, & throat infections

Sleep disorders

Vomiting

Abdominal pain

Anorexia

Mood disorders

Musculoskeletal pain

Sinus disorders

Fever

> 10% of subjects in either treatment group.

Page 10 of 43

Table 2:

Severe Adverse Events (Grade 3/4) Occurring in More Than One

Subject

a

in EPV20001 Safety Population during 48 Weeks

Adverse Event

lamivudine tablets

300 mg q.d. plus

RETROVIR plus

Efavirenz

(n = 272)

lamivudine tablets

150 mg b.i.d. plus

RETROVIR plus

Efavirenz

(n = 273)

At Least One Severe Adverse Event

Increased creatine phosphokinase levels

Nausea

Increased liver function tests

Decreased white cells

Fatigue

Hypertriglyceridemia

Dizziness

Vomiting

<1%

Sleep disorders

Abdominal pain

<1%

Dreams

<1%

Increased amylase levels

<1%

Anxiety

<1%

Rashes

Anemia

<1%

Depressive disorders

<1%

Mood disorders

<1%

Skin infections

<1%

<1%

Ear, nose, & throat infections

<1%

<1%

Diarrhea

<1%

<1%

Headaches

<1%

<1%

Suicide & attempted suicide

<1%

<1%

Viral respiratory infections

<1%

<1%

Confusion

<1%

<1%

Migraines

<1%

<1%

General signs & symptoms

<1%

<1%

Malaise

<1%

Viral Infection

<1%

Lower respiratory infections

<1%

<1%

Hypotension

<1%

more than one subject in any treatment group.

Page 11 of 43

Table 3:

Most Frequent Clinical Adverse Events (≥ 5% Frequency)

Reported in Four Controlled Clinical Trials

(NUCA3001, NUCA3002, NUCB3001 and NUCB3002)

Adverse Event

lamivudine tablets

150 mg b.i.d.

plus

RETROVIR

(AZT)

(n = 251)

RETROVIR

(AZT)

(n = 230)

Body as a whole

Headache

Malaise and fatigue

Fever or chills

Digestive

Nausea

Diarrhea

Nausea and vomiting

Anorexia and/or decreased appetite

Abdominal pain

Abdominal cramps

Dyspepsia

Nervous

Neuropathy

Dizziness

Insomnia & other sleep disorders

Depressive disorders

Respiratory

Nasal signs & symptoms

Cough

Skin & appendages

Skin rashes

Musculoskeletal

Musculoskeletal pain

Myalgia

Arthralgia

Page 12 of 43

Other clinical adverse events reported in controlled clinical trials in association with lamivudine

tablets 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 lamivudine tablets 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.

most

frequent adverse events necessitating such permanent discontinuation of therapy with lamivudine

tablets

150 mg b.i.d. plus RETROVIR (AZT) 200 mg t.i.d. were nausea (2%), malaise and fatigue

(1%), and anemia (1%).

Page 13 of 43

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

Table 4.

Table 4:

Selected Laboratory Abnormalities in Studies of lamivudine tablets in Adults

Test (Abnormal Level)

24-Week Surrogate Endpoint

Studies (NUCA3001,

NUCA3002, NUCB3001,

NUCB3002)

Clinical Endpoint

Study* (NUCB3007)

Study EPV20001*

lamivudine

tablets

plus

RETROVIR

RETROVIR

lamivudine

tabl e ts

plus

current

therapy†

Placebo

plus

current

therapy†

lamivudine

tabl e ts

300 mg

q.d.♠

lamivudine

tabl e ts

150 mg

b.i.d.♠

Neutropenia

(ANC<750/mm

Anemia (Hgb<8.0 g/dL)

<1%

<1%

Thrombocytopenia

(platelets<50000/mm

<1%

<1%

ALT (>5.0 × ULN)

AST (>5.0 × ULN)

Bilirubin (>2.5 × ULN)

<1%

<1%

<1%

Amylase (>2.0 × ULN)

*The median duration on study was 12 months.

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

♠Therapy was

lamivudine tablets

plus RETROVIR plus

efavirenz.

ULN = Upper limit of normal

ANC = Absolute neutrophil count

ND = Not done

Pediatric Patients

Selected clinical adverse events and physical findings with a ≥ 5% frequency during therapy with

lamivudine tablets 4 mg/kg twice daily plus RETROVIR (AZT) 160 mg/m

three times daily

compared with

didanosine in patients without, or with, minimal

(≤ 56 days ) prior antiretroviral

therapy are listed

in Table 5.

Page 14 of 43

Table 5:

Selected Clinical Adverse Events and Physical Findings

(≥ 5% Frequency) in Pediatric Patients in Study ACTG300

Adverse Event

lamivudine tablets

plus RETROVIR

(AZT)

(n = 236)

Didanosine

(n = 235)

Body as a whole

Fever

Digestive

Hepatomegaly

Nausea & vomiting

Diarrhea

Stomatitis

Splenomegaly

Respiratory

Cough

Abnormal breath sounds/wheezing

Ear, Nose and Throat

Signs or symptoms of ears*

Nasal discharge or congestion

Other

Skin rashes

Lymphadenopathy

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

Selected laboratory abnormalities experienced by patients without or minimal (≤ 56 days) prior

antiretroviral therapy are listed in Table 6.

Table 6:

Frequencies of Selected Laboratory Abnormalities in

Pediatric Patients in Study ACTG300

Test

(Abnormal Level)

lamivudine tablets

plus

RETROVIR

(AZT)

Didanosine

Neutropenia (ANC < 400/mm

Anemia (Hgb < 7.0 g/dL)

Thrombocytopenia (platelets < 50,000/mm

ALT (> 10 x ULN)

AST (> 10 x ULN)

Lipase (> 2.5 x ULN)

Total Amylase (> 2.5 x ULN)

ULN = Upper limit of normal.

ANC = Absolute neutrophil count.

Page 15 of 43

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-

experienced pediatric patients receiving lamivudine tablets 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 lamivudine tablets. 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 lamivudine tablets plus RETROVIR (AZT). Pancreatitis was

observed in one patient in this

study who received open-label lamivudine tablets 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 lamivudine tablets 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.

Post-Market Adverse Drug 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

Digestiv e:

stomatitis

Endocrine/Metabolic:

hyperglycemia, hyperlactatemia, lactic acidosis and hepatic

steatosis (see WARNINGS AND PRECAUTIONS section)

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

Page 16 of 43

Immune System:

Immune Reconstitution Inflammatory Syndrome (see

WARNINGS AND PRECAUTIONS: Immune section)

Musculoskeletal:

arthralgia, muscle disorders including very rarely rhabdomyolysis

Nervous:

headache, paresthesia, peripheral neuropathy

Other:

alopecia

Skin:

pruritus, rash, urticaria

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.

Page 17 of 43

Drug-Drug Interactions

Table 7:

Established or Potential Drug-Drug Interactions

Proper name

Effect

Clinical comment

Emtricitabine

Lamivudine may inhibit the

intracellular phosphorylation of

emtricitabine when the two

medicinal products are used

concurrently. Additionally, the

mechanism of viral resistance for

both lamivudine and emtricitabine

is mediated via mutation of the

same viral reverse transcriptase

gene (M184V) and therefore the

therapeutic efficacy of these

drugs

in combination therapy may

limited.

Lamivudine is not recommended for use in combination

with emtricitabine or emtricitabine-containing fixed dose

combinations.

Sorbitol

Coadministration of sorbitol

solution (3.2 g, 10.2 g, 13.4 g)

with a single 300 mg dose of

lamivudine oral solution resulted

in dose-dependent decreases of

14%, 32%, and 36% in

lamivudine exposure (AUC

) and

28%, 52%, and 55% in the C

of lamivudine in adults.

When possible, avoid use of lamivudine with sorbitol-

containing medicines or consider more frequent

monitoring of HIV-1 viral load when chronic

coadministration cannot be avoided (see Warnings and

Precautions).

Trimethoprim

Administration of trimethoprim, a

constituent of co-trimoxazole,

causes a 40% increase in

lamivudine plasma levels.

However, unless the patient has renal impairment, no

dosage adjustment of lamivudine is necessary. Lamivudine

has no effect on the pharmacokinetics of co-trimoxazole.

Administration of co-trimoxazole with the

lamivudine

tablets

/RETROVIR (AZT) combination in patients with

renal impairment should be carefully assessed.

The effect of co-administration of lamivudine tablets

with

higher doses

of co-trimoxazole for the treatment of

Pneumocystis

jiroveci pneumonia (also referred to as

PCP) and

toxoplasmosis has not been studied.

Zidovudine

Zidovudine has no effect on the

pharmacokinetics of lamivudine

(see ACTIONS AND CLINICAL

PHARMACOLOGY section)

A modest increase in C

(28%) was observed for

zidovudine when administered with lamivudine, however

overall exposure (AUC) was not significantly altered.

Zidovudine plasma levels are not significantly altered

when coadministered with lamivudine tablets.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Page 18 of 43

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

JAMP Lamivudine therapy should be initiated by a physician experienced in the management of

HIV infection.

Recommended Dose and Dosage Adjustment

JAMP Lamivudine can be taken with or without food.

Adults, Adolescents and Children weighing at least 25 kg

The recommended oral dose of JAMP Lamivudine 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 ACTIONS

AND CLINICAL PHARMACOLOGY, WARNINGS AND PRECAUTIONS and CLINICAL

TRIALS section).

Scored Tablets

JAMP Lamivudine 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 JAMP Lamivudine

Tablets, children should be assessed for the ability to swallow

tablets. The

recommended oral dosage of JAMP Lamivudine Tablets for HIV-1-infected

pediatric patients is presented in

Table 8.

Table 8:

Dosing Recommendations for JAMP Lamivudine Scored (150 mg)

Tablets in Pediatric

Patients

Weight

(kg)

Once-Daily Dosing Regimen

Twice-Daily Dosing

Total

Daily Dose

AM Dose

PM Dose

14 to

<20

1 tablet (150 mg)

½ tablet

(75 mg)

½ tablet (75 mg)

150 mg

20 to

<25

1 ½ tablets (225 mg)

½ tablet

(75 mg)

1 tablet

(150 mg)

225 mg

2 tablets (300 mg)

1 tablet

(150 mg)

1 tablet

(150 mg)

300 mg

Page 19 of 43

Pediatric patients weighing less than 14 kg:

JAMP Lamivudine is not recommended for pediatric patients weighing less than 14 kg because

appropriate dose adjustment is not possible in these patients.

Dose Adjustment

Patients with impaired renal function have increases in C

and half-life of lamivudine with

diminishing creatinine clearance. In addition, apparent total oral clearance of lamivudine

decreases as creatinine clearance decreases. Doses of JAMP Lamivudine may be adjusted, as

shown in Table 9, in accordance with creatinine clearance.

No dose adjustment is necessary in patients with moderate or severe hepatic impairment unless

accompanied by renal impairment.

Table 9:

Adjustment of Dosage of JAMP Lamivudine in Accordance With Creatinine

Clearance in Adults, Adolescents and Children weighing ≥25 kg

Creatinine clearance

(mL/min)

Recommended Dosage of JAMP Lamivudine

≥ 50

150 mg twice daily or 300 mg once daily

30 - 50

150 mg once daily

15 - 29

150 mg first dose, then 100 mg once daily

5 - 14

150 mg first dose, then 50 mg once daily

< 5

50 mg first dose, then 25 mg once daily

JAMP Lamivudine is not recommended in adult and pediatric patients weighing equal or greater

than 25 kg with creatinine clearance less than 30 mL/min because appropriate dose adjustment is

not possible in these patients.

JAMP Lamivudine is not recommended in pediatric patients with renal impairment weighing less

than 25 kg because appropriate dose adjustment is not possible in these patients.

Missed Dose

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

Page 20 of 43

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.

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.

ACTION AND CLINICAL PHARMACOLOGY

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.

TP shows significantly less affinity for host cell DNA polymerases and is a weak inhibitor of

mammalian α, β, and γ DNA polymerases.

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

) 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

increased in

proportion to dose over the range from 0.25 to 10 mg/kg.

For management of a suspected drug overdose, please contact your regional Poison Control

Centre immediately.

Page 21 of 43

The steady-state pharmacokinetic properties of the lamivudine tablets, 300 mg tablet once daily for

7 days compared to the lamivudine tablets, 150 mg tablet twice daily for 7 days were assessed in

a crossover study in 60 healthy volunteers.

Lamivudine tablets, 300 mg once daily resulted in

lamivudine exposures that

were similar to

lamivudine tablets,

150 mg twice daily with respect to

plasma AUC

24,ss

; however, C

max,ss

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

) to maximal

serum concentrations (C

) is about an hour. Absorption differences have been

observed

between adult and pediatric populations (see DETAILED PHARMACOLOGY, Special

Populations and Conditions, Pharmacokinetics in Pediatric Patients).

No dose adjustment is needed when coadministered with food as lamivudine bioavailability is

not altered, although a delay in t

and reduction in C

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.

STORAGE AND STABILITY

JAMP Lamivudine tablets should be stored between 15° and 30°C.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

JAMP Lamivudine tablets 150 mg are white, modified diamond-shaped, scored on both sides,

film-coated tablets containing

150 mg of lamivudine and engraved with "LMV" on one side

and "150” on the other side. Available in plastic bottles of 60 tablets and 100 tablets.

Page 22 of 43

JAMP Lamivudine tablets 300 mg are grey, modified diamond-shaped, film-coated tablets

containing 300 mg of lamivudine and engraved with “LMV” on one side and “300” on the other

side. Available in plastic bottles of 30 tablets and 100 tablets.

Tablets

Each JAMP Lamivudine 150 mg tablet contains 150 mg of lamivudine and the nonmedicinal

ingredients

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene

glycol,

polysorbate 80, sodium starch glycolate and titanium dioxide.

Each JAMP Lamivudine 300 mg tablet contains 300 mg of lamivudine and the nonmedicinal

ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose,

polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

Page 23 of 43

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

lamivudine

Chemical name:

2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3-

oxathiolan-5-yl]-,(2R-cis)

Molecular formula and molecular mass: C

229.3 g/mol

Structural formula:

Physicochemical properties:

Description:

Lamivudine is a white to off-white crystalline solid with a melting

point of 176°C.

Solubility:

Solvent

Temperature

(°C)

Solubility

(mg/mL)

Water

61.3

Water

98.1

Methanol

33.4

Ethanol

11.4

Acetone

0.94

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.

Page 24 of 43

CLINICAL TRIALS

Comparative Bioavailability Study

randomized,

double

blind,

single-dose,

two-way

crossover

study

JAMP

Lamivudine

(Lamivudine)

Tablets, 300 mg (JAMP Pharma Corporation) and

(Lamivudine)

Tablets, 300

mg (ViiV Healthcare ULC) administered as a 1 x 300 mg dose, was conducted in healthy, adult, male,

Asian subjects under fasting conditions.

The results from the 29 subjects who completed the study

are summarized in the table below

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Lamivudine

(1 × 300 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

Confidence

Interval

h/mL)

15624.97

15983.80 (22.20)

16286.38

16586.79 (20.20)

95.9

91.5-100.5

h/mL)

15976.34

16355.69 (22.90)

16607.21

16913.50 (20.20)

96.2

91.9-100.7

(ng/mL)

3635.76

3806.12 (31.70)

3672.16

3788.83 (25.60)

99.0

88.8-110.4

0.83(0.50-2.67)

0.83 (0.50-3.00)

4.30 (27.00)

4.19 (22.0)

JAMP Lamivudine (Lamivudine) Tablets 300 mg, by JAMP Pharma Corporation, Canada.

† Pr

(Lamivudine) Tablets 300 mg, by ViiV Healthcare ULC, purchased in

Canada.

Expressed as the median (range) only.

Expressed as the

arithmetic mean (%CV) only.

Clinical Endpoint Study in Adults

NUCB3007 (CAESAR) was a multicentre, double-blind, placebo-controlled study comparing

continued current therapy [RETROVIR (AZT) alone (62% of patients) or RETROVIR (AZT)

with didanosine or zalcitabine (38% of patients)] to the addition of lamivudine tablets or

lamivudine tablets plus an investigational non-nucleoside reverse transcriptase inhibitor,

randomized 1:2:1.

A total of 1816

HIV-infected adults with 25 to 250 CD4 cells/mm

(median =

122 cells/mm

) at baseline were

enrolled: median age was 36 years, 87% were male, 84% were

nucleoside-experienced,

and 16% were therapy-naive. The median duration on study was 12

months. Results are summarized in

Table 10.

Page 25 of 43

Table 10: Number of Patients (%) With At Least One HIV Disease Progression Event or

Death

Endpoint

Current Therapy

(n = 460)

Lamivudine tablets

plus

Current Therapy

(n = 896)

Lamivudine tablets

plus a

NNRTI*

plus Current

Therapy

(n = 460)

HIV progression or death

90 (19.6%)

86 (9.6%)

41 (8.9%)

Death

27 (5.9%)

23 (2.6%)

14 (3.0%)

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

Surrogate Endpoint Study in Therapy-Naive Adults

EPV20001 is a multicentre, double-blind,

placebo-controlled study in which patients were

randomized 1:1 to receive lamivudine tablets 300 mg once daily or lamivudine tablets 150 mg

twice daily in combination

with zidovudine 300 mg twice daily and efavirenz 600 mg once

daily.

A total of 554 antiretroviral treatment-naive HIV-infected adults enrolled: male (79%),

Caucasian (50%),

median age of 35 years, baseline CD4 cell counts of 69 to 1089 cells/mm

(median = 362

cells/mm

), and median baseline plasma HIV RNA of 4.66 log

copies/mL.

Percentages of

patients with HIV RNA < 400 copies/mL and outcomes of treatment through are

summarized in

Table 11.

Table 11: Outcomes of Randomized Treatment through 48 weeks (Intent-to Treat)

Outcome

Lamivudine tablets

300 mg q.d. plus

RETROVIR

plus Efavirenz

(n = 278)

Lamivudine tablets

150 mg b.i.d. plus

RETROVIR

plus Efavirenz

(n = 276)

HIV RNA < 400 copies/mL

HIV RNA ≥ 400 copies/mL*

Discontinued due to clinical progression

< 1%

Discontinued due to adverse events

Discontinued due to protocol defined

virologic failure

Discontinued due to insufficient viral load

response

< 1%

Discontinued due to other reasons

*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 lamivudine tablets 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

lamivudine tablets 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

lamivudine tablets 300 mg once daily (61%) and patients

receiving lamivudine tablets 150 mg twice daily (62%). Similar

increases in median CD4+

cell counts were observed at Week 48 in patients receiving lamivudine tablets 300 mg once

Page 26 of 43

daily (144 cells/mm

) and patients receiving lamivudine tablets 150 mg twice daily

(146

cells/mm

Clinical Endpoint Study in Pediatric Patients

ACTG300 was a multicentre, randomized, double-blind study that provided for comparison of

lamivudine tablets plus RETROVIR (AZT) to didanosine monotherapy.

A total of 471

symptomatic, HIV- infected pediatric patients, without, or with, minimal (

56 days) prior

antiretroviral therapy,

were enrolled in these two treatment arms. The median age was 2.7

years (range 6 weeks to 14

years), 58% were female, and 86% were non-Caucasian. The mean

baseline CD4 cell count was

868 cells/mm

(mean: 1060 cells/mm

and range: 0 to 4650

cells/mm

for patients

5 years of age; mean: 419 cells/mm

and range: 0 to 1555 cells/mm

for patients > 5 years of age) and the

mean baseline plasma HIV RNA was 5.0 log

copies/mL.

The median duration on study was

10.1 months for the patients receiving lamivudine tablets

plus RETROVIR (AZT) and 9.2 months for patients

receiving didanosine monotherapy.

Results are summarized in Table 12.

Table 12: Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease

Progression or Death)

Endpoint

Lamivudine tablets

plus RETROVIR

(AZT)

(n = 236)

Didanosine

(n = 235)

HIV disease progression or death (total)

15 (6.4%)

37 (15.7%)

Physical growth failure

7 (3.0%)

6 (2.6%)

Central nervous system deterioration

4 (1.7%)

12 (5.1%)

CDC Clinical Category C

2 (0.8%)

8 (3.4%)

Death

2 (0.8%)

11 (4.7%)

Once-Daily Dosing

ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple

aspects of clinical management of HIV-1 infection in pediatric patients. HIV-1 infected,

treatment-naive subjects aged 3 months to 17 years were enrolled and treated with first-line

regimen containing lamivudine tablets and abacavir, dosed twice daily according to World

Health Organization recommendations.

After 36 weeks on treatment, subjects were given the

option to

participate in Randomization 3 of the ARROW trial, comparing the safety and

efficacy of once- daily with twice-daily dosing of lamivudine tablets and abacavir, in

combination with a third antiretroviral

drug for an additional 96 weeks.

Of the 1206 original subjects enrolled in the study, 669 participated in Randomization 3.

Virologic suppression was not a requirement for participation: at baseline (following a minimum

of 36 weeks of twice-daily treatment), 76% of subjects in the twice-daily cohort were

virologically suppressed, compared with 71% of subjects in the once-daily cohort.

The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is

shown in Table 13. The differences between virologic responses in the two treatment arms were

comparable across baseline characteristics for gender and age.

Page 27 of 43

Table 13: Proportions of Responders by HIV-1 RNA Copies Through 96 Weeks (From

Randomization to Once-Daily or Twice-Daily Dosing - Snapshot Analysis)

Lamivudine tablets

plus abacavir

Twice

Daily Dosing n =

N (%)

Lamivudine tablets

plus abacavir

Once

Daily Dosing n=

N (%)

Week 0 (After ≥36 Weeks on Treatment)

Virological Response

(<80 copies/mL)

250 (75)

237 (71)

Risk difference

-4.5% (95% CI -11.3% to +2.2%),

Week 48

Virological Response

(<80 copies/mL)

242 (73)

233 (69)

Risk difference

3.3% (95% CI - 10.2% to + 3.5%)

Week 96

Virological Response

(<80 copies/mL)

232 (70)

226 (67)

Risk difference

-2.4% (95% CI -9.4% to +4.6%)

The Lamivudine tablets 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).

DETAILED PHARMACOLOGY

Pharmacokinetics in Adults

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV- infected

adult patients after administration of single oral and intravenous (IV) doses ranging from 0.25 to

8 mg/kg.

Patients receiving multiple

doses of 150 or 300 mg b.i.d. have also been studied.

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

) was 1.5 ± 0.5 µg/mL (mean ± S.D.). The area under the plasma concentration versus time

curve (AUC) and C

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.

The steady-state pharmacokinetic properties of the lamivudine tablets 300 mg tablet once daily for

7 days compared to the lamivudine tablets 150 mg tablet twice daily for 7 days were assessed in a

crossover study in

60 healthy volunteers.

Lamivudine tablets 300 mg once daily was

pharmacokinetically

equivalent to lamivudine tablets

150 mg twice daily with respect to plasma

Page 28 of 43

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

Lamivudine 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 may be

administered with or without food. Absorption was slower in the fed state as

shown by a 47%

reduction in mean C

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

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.

In most single-dose studies in HIV-infected patients, the observed mean elimination half-life

) ranged from 5 to 7 hours. In one study with extended blood sampling, the mean elimination

half-life was 11.9 hours.

Special Populations and Conditions

Adults With Impaired Renal Function

The pharmacokinetic properties of lamivudine were determined in a small group of HIV-infected

adults with impaired renal function, and are summarized in Table 14.

Page 29 of 43

Table 14:

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)

Number of subjects

Creatinine clearance criterion

> 60 mL/min

10-30 mL/min

< 10 mL/min

Creatinine clearance (mL/min)

111 ± 14

28 ± 8

6 ± 2

(μg/mL)

2.6 ± 0.5

3.6 ± 0.8

5.8 ± 1.2

(μg·h/mL)

11.0 ± 1.7

48.0 ± 19

157 ± 74

Cl/F (mL/min)

464 ± 76

114 ± 34

36 ± 11

These results show increases in C

and half-life with diminishing creatinine clearance. Apparent

total clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. T

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

DOSAGE

AND ADMINISTRATION section).

Drug Interactions

The likelihood of adverse drug interactions with lamivudine is low due to limited metabolism

plasma protein binding and almost complete renal clearance. Coadministration of

zidovudine

results in a 13% increase in AUC

for zidovudine and a 28% increase in peak plasma

levels. While

statistically significant, these results are not considered to be clinically significant

with respect to

patient safety. Therefore, no dosage adjustments are necessary.

An interaction with trimethoprim,

a constituent of co-trimoxazole, causes a 40% increase in

lamivudine AUC

at therapeutic doses. This does not require dose adjustment unless the patient

also

has renal impairment (see DOSAGE AND ADMINISTRATION section).

Pharmacokinetics in Pediatric Patients

The pharmacokinetics of lamivudine have been studied after either single or repeat doses of

lamivudine tablets in 210 pediatric subjects Pediatric subjects receiving lamivudine oral

tablets

according to the recommended dosage regimen achieved plasma concentrations of

lamivudine

similar to adults. The absolute bioavailability of lamivudine tablets are lower in children than

adults.

The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric patients aged

3 to

12 years was evaluated in a study (ARROW PK [n=35]). This study was designed as 2 –period,

crossover, open-label

pharmacokinetic studies of twice-versus once-daily dosing of abacavir and

lamivudine.

This study

demonstrated that once-daily dosing provides equivalent AUC

0-24

to twice-

daily dosing

of lamivudine at the same total daily dose. The

mean C

was approximately 80%

higher with lamivudine once-daily dosing compared

with twice-daily dosing.

Page 30 of 43

Table 15:

Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat

Dosing of Lamivudine in a Pediatric Trial

Trial

(Number of Subjects)

ARROW PK

(n = 35)

Age Range

3-12 years

Formulation

Tablet

Parameter

Once

Daily

Twice

Daily

3.17

1.80

(mcg/mL)

(2.76,

(1.59, 2.04)

3.64)

(0-24)

13.0

12.0

(mcg

h/mL)

(11.4,

(10.7, 13.4)

14.9)

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.

Pharmacokinetics in Pregnancy

Following oral administration,

lamivudine pharmacokinetics in late pregnancy were similar to

non-pregnant adults.

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.

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).

Page 31 of 43

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 IC

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.

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

Page 32 of 43

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 DETAILED PHARMACOLOGY: Clinical Studies section). The data indicates that

through 48 weeks, lamivudine tablets once daily has been shown to be as effective as

lamivudine tablets twice daily, and the

use of lamivudine tablets once daily through 48 weeks

does not increase the incidence or the time to

emergence of resistance to lamivudine tablets 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 log

copies/mL and 4.6 log

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

Page 33 of 43

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 [

H]-thymidine uptake (Td) assays. In the CP assay, lamivudine was the least toxic of

the four compounds. [

H]-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 [

H]-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.

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

Page 34 of 43

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 and Mutagenicity

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).

Page 35 of 43

Reproduction and Teratology

A range of studies has been performed to assess the effects of repeated oral administration

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 F

and F

generation animals, and the development

of the F

and F

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

observed in juvenile males at 2000 mg/kg which was associated with slight to moderate

dilatation

of the seminiferous tubules.

Page 36 of 43

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Hart GJ, Orr DC, Penn CR, Figueiredo HT, Gray NM, Boehme RE, et al. Effects of (-)-

2’-Deoxy-3’-Thiacytidine (3TC)5’-Triphosphate on human immunodeficiency virus

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Lewis LL, Venzon D, Church J, Farley M, Wheeler S, Keller A, et al. Lamivudine in

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children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical

Trials Group Protocol 300 Study Team. J Pediatr 1998 Oct;133(4): 500-8.

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Am Acad Dermatol 1999; 41: 285-6.

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and antiretroviral activity of lamivudine alone or when coadministered with zidovudine

in human immunodeficiency

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sulfamethoxazole. Clin Pharmacol Ther 1996; 59: 550-8.

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Pluda JM, Cooley TP, Montaner JS, Shay LE, Reinhalter NE, Warthan SN, et al. A phase

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four optical isomers of 2’, 3-Dideoxy-3’-Thiacytidine (BCH-189) against human

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virus type 1 in human lymphocytes.

Antimicrobial Agents &

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(lamivudine) 150 mg and 300 mg tablets. Control # 226212, Product

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Page 40 of 43

PART III:

CONSUMER INFORMATION

Pr

JAMP Lamivudine

Lamivudine Tablets, USP

This leaflet is part III of a three-part "Product

Monograph" published when JAMP Lamivudine was

approved for sale

in Canada and is designed specifically

for Consumers. Please read this leaflet carefully before

you start to take

your medicine. You may need to read

this leaflet again

during your treatment. This leaflet is a

summary and will

not tell you everything about JAMP

Lamivudine. Contact your doctor or

pharmacist if you

have any questions about the drug.

JAMP Lamivudine is intended for use in combination with

other

antiretroviral medicines. Please read the information

given

with these other medicines before you take JAMP

Lamivudine.

What the medication is used for:

The Human Immunodeficiency Virus (HIV) is a retrovirus (a

type of virus). Infection with HIV damages the immune

system and can lead to Acquired Immune Deficiency

Syndrome (AIDS) and other related illnesses.

JAMP Lamivudine belongs to a group of antiretroviral

medicines called

nucleoside analogue reverse transcriptase

inhibitors (NRTIs)

and is used in combination with other

antiretrovirals to treat

HIV infection.

What it does:

JAMP Lamivudine is not a cure for HIV infection or AIDS; it

reduces the

amount of virus in your body and keeps it at a

low level. JAMP Lamivudine

also increases the CD4 cell

count in your blood. CD4 cells

are a type of white blood

cells that are important in helping

your body fight infection.

When it should not be used:

JAMP Lamivudine should not be taken if

you previously had an allergic reaction (hypersensitivity)

to the active ingredient lamivudine which is included in

medicines called TRIZIVIR, COMBIVIR or KIVEXA, or

any other ingredients found in JAMP Lamivudine (see

“What the

important nonmedicinal ingredients are”

section).

What the medicinal ingredient is:

Each JAMP Lamivudine (150 mg) tablet contains 150 mg of

lamivudine.

Each JAMP Lamivudine (300 mg) tablet

contains 300 mg of lamivudine.

What the important nonmedicinal ingredients are:

Each 150 mg JAMP Lamivudine tablet also contains

hypromellose, magnesium stearate, microcrystalline

cellulose, polyethylene glycol, polysorbate 80, sodium

starch

glycolate and titanium dioxide.

Each 300 mg JAMP Lamivudine tablet also contains black iron

oxide,

hypromellose, magnesium stearate,

microcrystalline

cellulose, polyethylene glycol, polysorbate 80,

sodium starch

glycolate and titanium dioxide.

What dosage forms it comes in:

JAMP Lamivudine 150 mg tablets are white, modified

diamond-shaped,

scored on both sides, film-coated tablets

engraved with "LMV" on one side and "150" on the other side,

containing 150 mg lamivudine. Available in plastic

bottles of

60 tablets and 100 tablets.

JAMP Lamivudine 300 mg tablets are grey, modified diamond-

shaped, film-coated tablets engraved with "LMV" on one side

and "300" on the other side, containing

300 mg lamivudine.

Available in plastic bottles of 30 tablets 100 tablets.

Before taking JAMP Lamivudine, tell your doctor or pharmacist:

About all your medicines and medical conditions,

including vitamins, herbal supplements and

nonprescription drugs

If you have kidney or liver disease (including hepatitis B

or C)

ABOUT THIS MEDICATION

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

If you also have a hepatitis B infection, you should not

stop taking JAMP Lamivudine without instructions from

your doctor as

your hepatitis may worsen/reoccur. Your

doctor will

monitor your condition for several months

after stopping

treatment with JAMP Lamivudine.

Parents or guardians should be advised to monitor pediatric

patients for signs and symptoms of pancreatitis

(inflammation of the pancreas; see Serious Side Effects

table). If symptoms of pancreatitis occur, contact your

doctor.

Page 41 of 43

If you have had previous use of any NRTI class medicine

If you are pregnant, planning to become pregnant,

breastfeeding, or planning to breastfeed

Other Special Warnings

Remember that treatment with JAMP Lamivudine does not

reduce the risk of

passing the infection onto others. You will

still be able to pass

HIV by sexual contact or by blood transfer

and you should use

appropriate precautions.

Some people taking medicines for HIV infection develop

other conditions, which can be serious, such as:

a high level of lactic acid in the blood and fatty liver

(these may be more common if you are obese or a

woman)

lower blood cell count

pancreatitis

old infections flaring up

You need to know about important signs and symptoms to

look out for while you’re taking JAMP Lamivudine. Read the

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

section.

It is important that your doctor know about all your symptoms

even if you think they are not related to HIV infection. Your

doctor may need to change the dose of your medicine.

Your blood sugar levels (glucose) or levels of fats (lipids) in

your blood may increase with HIV treatment. Your doctor

may order blood tests for you.

Use Of This Medicine During Pregnancy And

Breastfeeding

If you are pregnant, or planning to become pregnant soon, you

must inform your doctor before taking any medicine. The safe

use of JAMP Lamivudine in pregnancy has not been

established. Your doctor will decide whether you should

continue to be treated with JAMP Lamivudine if you are

pregnant. If you take Lamivudine while you are pregnant, talk

to your doctor about how you can be included in the

Antiretroviral Pregnancy Registry. You can call 1-800-258-

4263.

Babies and infants exposed to Nucleoside Reverse

Transcriptase Inhibitors (NRTIs) during pregnancy or labour

show minor temporary increases in blood levels of lactate.

The clinical importance of these temporary increases is

unknown.

These findings do not affect current recommendations to use

antiretroviral therapy in pregnant women to prevent

transmission of HIV to their babies. There have been very rare

reports of disease that affect the neonatal (babies) nervous

system such as delayed development and seizures. The long

term effects of JAMP Lamivudine are not known.

It is recommended that HIV-infected women do not breastfeed

their infants in order to avoid transmission of HIV from mother

to child. The active substance in JAMP Lamivudine is found in

human breast

milk.

You are recommended not to breastfeed your baby while

taking JAMP Lamivudine.

Remember: this medicine is for you. Never give it to

someone else. It may harm them even if their symptoms are

the same as yours.

It is important that your doctor knows about all your medicines

so that you get the best possible treatment. Tell your doctor

about all your medicines, including vitamin supplements,

herbal remedies or homeopathic remedies, including those you

have bought yourself.

JAMP Lamivudine should not be taken with emtricitabine.

Some medicines may affect how JAMP Lamivudine works, or

make it more

likely that you’ll have side effects. These

medicines include:

sorbitol-containing medicines (usually liquids) used

regularly.

trimethoprim-sulphamethoxazole (also known as co-

trimoxazole; an antibiotic used to treat Pneumocystis

jiroveci pneumonia (often referred to as PCP) or

toxoplasmosis).

Usual dose:

Take JAMP Lamivudine exactly as your doctor has advised

you and try

not to miss any doses. If you are unsure about

how to take it,

ask your doctor or pharmacist.

JAMP Lamivudine can be taken with or without food.

Adults, Adolescents and Children (weighing at least 25 kg):

Twice-a-day dosing: swallow one tablet (150 mg) two times a

day. For

once-a-day dosing: swallow one tablet (300 mg) once

a day.

Dosing

Schedule

Tablets

Once a day

One 300 mg tablet

Twice a day

One 150 mg tablet

INTERACTIONS WITH THIS MEDICATION

PROPER USE OF THIS MEDICATION

Page 42 of 43

If you have a kidney problem, your dose may be altered.

Please follow the instructions of your doctor.

Children (weighing 14 kg to less than 25 kg): if you are

giving JAMP Lamivudine to a child, carefully follow the

instructions of your doctor.

Tablets:

For children able to swallow tablets as determined by the

doctor/parent:

Children weighing 14 to less than 20 kg: one-half of a scored

JAMP Lamivudine tablet twice daily or one tablet taken once

daily.

Children weighing at least 20 kg and less than 25 kg: one-half

of a scored JAMP Lamivudine tablet taken in the morning and

one whole

tablet taken in the evening or one and a half tablets

taken once

daily.

Overdose:

Changes to your/your child’s immune system (Immune

Reconstitution Inflammatory Syndrome) can happen when

you/your child start taking HIV-1 medicines. Your/your child’s

immune system may get stronger and begin to fight infections

that have been hidden in your/your child’s body for a long time.

Autoimmune disorders (when the immune system attacks

healthy body tissue), may also occur after you start taking

medicines for HIV infection. Examples of this include: Grave's

disease (which affects the thyroid gland), Guillain-Barré

syndrome (which affects the nervous system), polymyositis

(which affects the muscles), or autoimmune hepatitis (which

affects the liver). Autoimmune disorders may occur many

months after the start of treatment. Look for any other

symptoms such as:

high temperature (fever), redness, rash or swelling

fatigue

joint or muscle pain

numbness or weakness beginning in the hands and feet

and moving up towards the trunk of the body

palpitations (chest pain) or rapid heart rate

If you notice these or any symptoms of inflammation or

infection, tell your doctor immediately.

Always tell your doctor or pharmacist about any undesirable

effects, even those not mentioned in this leaflet. If you feel

unwell in any other way that you do not understand, tell your

doctor or pharmacist.

Missed Dose:

It is important to take this medicine as prescribed to ensure

you get maximum benefit. If you forget to take a dose, take it

as soon as you remember, and then continue as before. Do not

double dose to make up for forgotten individual doses.

Like all medicines, JAMP Lamivudine can have side effects.

For this reason

it is very important that you inform your

doctor about any

changes in your health.

Consult your doctor at your next visit if any of the following

undesirable events occur:

Headaches, nausea, vomiting, upper abdominal pain,

diarrhea, fever, rash, fatigue, a general feeling of being

unwell, or a numbness, tingling sensation or sensation of

weakness in your limbs.

JAMP Lamivudine may also cause a decrease in certain

types of blood

counts (including red blood cells, white

blood cells and

platelets) and increase in certain liver

enzymes.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

If you have taken too much

JAMP Lamivudine, contact a

health care practitioner, hospital emergency

department or

regional Poison Control Centre immediately,

even if there

are no symptoms.

Page 43 of 43

Store JAMP Lamivudine tablets between 15° and 30°C.

As with all medicines, keep JAMP Lamivudine out of the

reach and sight of

children.

Do not take your medicine after the expiry date shown on the

bottle and/or the carton.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated with

the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-

products/medeffect-canada/adverse-reaction-

reporting.html) for information on how to

report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical

advice.

This leaflet does not tell you everything about your medicine. If

you have any questions or are not sure about anything, then ask

your doctor or pharmacist. You may need to read this leaflet

again. Please do not throw it away until you are no longer

taking JAMP Lamivudine.

If you want more information about JAMP Lamivudine:

Talk to your healthcare professional

Find the full Product Monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada website

(https://health-products.canada.ca/dpd-bdpp/index-eng.jsp);

or by contacting the sponsor, JAMP Pharma Corporation,

at: 1-866-399-9091.

This leaflet was prepared by JAMP Pharma Corporation

1310 rue Nobel, Boucherville,

Québec, Canada, J4B 5H3

Date of Approval: October 23, 2020

HOW TO STORE IT

MORE INFORMATION

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist

O nly

i f

severe

In all

cases

Rare

Allergic reactions and

symptoms such as

swelling of eyes, face,

lips, throat, sudden

wheeziness, chest pain

and tightening, skin

rash or hives anywhere

on the body.

Lactic acidosis (high

level of lactic acid in

the blood) and

symptoms such as

weight loss, fatigue,

malaise, nausea,

vomiting, abdominal

pain, and shortness of

breath.

Swollen and fatty liver

(severe hepatomegaly

with steatosis) and

symptoms such as

nausea, vomiting,

abdominal pain,

weakness and diarrhea.

Blood problems and

symptoms such as

anemia (lowered red

blood cell count)

resulting in fatigue,

breathlessness, and

low white blood cell

count making you

more prone to

infections.

Pancreatitis

(inflammation of the

pancreas) and

symptoms such as

severe stomach

cramps, nausea,

vomiting.

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