Canada - English - Health Canada
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Lamivudine Tablets, USP
150 mg and 300 mg
JAMP Pharma Corporation
1310 rue Nobel
Date of Approval:
October 23, 2020
Submission Control No: 235315
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION ..................................................... 3
SUMMARY PRODUCT INFORMATION ....................................................................3
INDICATIONS AND CLINICAL USE..........................................................................3
WARNINGS AND PRECAUTIONS .............................................................................4
ADVERSE REACTIONS ..............................................................................................8
DRUG INTERACTIONS ............................................................................................ 17
DOSAGE AND ADMINISTRATION.......................................................................... 19
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
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Lamivudine Tablets, USP
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form /
Tablets/ 150 mg
Tablets/ 300 mg
glycol, polysorbate 80, sodium
glycolate and titanium dioxide
black iron oxide, hypromellose,
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
Pediatrics (< 18 years of age)
JAMP Lamivudine is indicated in pediatric patients weighing greater than or equal to 14 kg in
combination with other
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Geriatrics (≥ 65 years of age)
Clinical studies of lamivudine tablets did not include sufficient numbers of patients aged 65 and
determine whether they respond differently from younger patients. In general, dose
an elderly patient should be cautious, reflecting the greater frequency of decreased
or cardiac function and of concomitant disease or other drug therapy.
JAMP Lamivudine is contraindicated in patients with previously demonstrated
hypersensitivity to any of the components of the products (see
COMPOSITION, AND PACKAGING section).
WARNINGS AND PRECAUTIONS
JAMP Lamivudine should not be administered concomitantly with other products containing
including HEPTOVIR Tablets and Oral solution, COMBIVIR Tablets, KIVEXA
Tablets, or TRIZIVIR Tablets.
JAMP Lamivudine should also not be administered concomitantly with emtricitabine containing
including ATRIPLA Tablets, EMTRIVA Capsules, TRUVADA 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.
function should be monitored closely with both clinical and laboratory
for at least several months in patients who discontinue JAMP
initiation of anti-hepatitis B therapy may be
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
stopped immediately if clinical signs, symptoms,
or laboratory abnormalities
suggestive of pancreatitis occur (see ADVERSE
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Evidence for once-daily dosing using the 300 mg tablets is mainly in antiretroviral naive
Patients receiving JAMP Lamivudine or any other antiretroviral therapy may continue to develop
infections and other complications of HIV infection.
Therefore, patients should
close observation by physicians experienced in the treatment of patients with HIV-
Patients should be advised that current antiretroviral therapy, including
not been proven
to prevent the risk of transmission of HIV to others through sexual contact or
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.
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.
Pancreatitis has been observed in some patients receiving nucleoside analogues, including
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.
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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
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
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
Patients Co-infected with Hepatitis B virus
Clinical trials and marketed use of lamivudine tablets have shown that some patients with chronic
virus (HBV) disease may experience clinical or laboratory evidence of recurrent
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
Emergence of Lamivudine-Resistant HBV
In non–HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of
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 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.
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Patients with Impaired Renal Function
Patients with impaired renal function may be at a greater risk of toxicity from JAMP Lamivudine
decreased renal clearance of the drug. Consideration should be given to appropriate
the dose of lamivudine (see DOSAGE AND ADMINISTRATION section).
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
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
an Antiretroviral Pregnancy
Registry has been established. Healthcare providers are encouraged to register patients by calling
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.
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.
The safety and effectiveness of lamivudine tablets have been established in pediatric patients
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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
determine whether they respond differently from younger patients. In general, caution
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.
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
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
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
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.
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Most Common Adverse Events (> 10%)
Occurring in Subjects in EPV20001
Safety Population during 48 Weeks
300 mg q.d. plus
(n = 272)
150 mg b.i.d. plus
(n = 273)
At Least One Adverse Event
Viral respiratory infections
Ear, nose, & throat infections
> 10% of subjects in either treatment group.
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Severe Adverse Events (Grade 3/4) Occurring in More Than One
in EPV20001 Safety Population during 48 Weeks
300 mg q.d. plus
(n = 272)
150 mg b.i.d. plus
(n = 273)
At Least One Severe Adverse Event
Increased creatine phosphokinase levels
Increased liver function tests
Decreased white cells
Increased amylase levels
Ear, nose, & throat infections
Suicide & attempted suicide
Viral respiratory infections
General signs & symptoms
Lower respiratory infections
more than one subject in any treatment group.
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Most Frequent Clinical Adverse Events (≥ 5% Frequency)
Reported in Four Controlled Clinical Trials
(NUCA3001, NUCA3002, NUCB3001 and NUCB3002)
150 mg b.i.d.
(n = 251)
(n = 230)
Body as a whole
Malaise and fatigue
Fever or chills
Nausea and vomiting
Anorexia and/or decreased appetite
Insomnia & other sleep disorders
Nasal signs & symptoms
Skin & appendages
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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:
abdominal discomfort and pain (3%), abdominal distension (3%),
dyspepsia (2%), gastrointestinal discomfort and pain (3%), gastrointestinal
gas (4%), hyposalivation (2%), oral ulceration (1%)
muscle atrophy/weakness/tiredness (1%), muscle pain (2%)
mood disorders (1%), sleep disorders (4%), taste disturbances (1%)
breathing disorders (2%), general signs and symptoms (1%), pain (2%),
sexual function disturbances (1%), temperature regulation disturbance
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.
frequent adverse events necessitating such permanent discontinuation of therapy with lamivudine
150 mg b.i.d. plus RETROVIR (AZT) 200 mg t.i.d. were nausea (2%), malaise and fatigue
(1%), and anemia (1%).
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The frequencies of selected laboratory abnormalities (Grades 3 and 4) during therapy are listed in
Selected Laboratory Abnormalities in Studies of lamivudine tablets in Adults
Test (Abnormal Level)
24-Week Surrogate Endpoint
tabl e ts
tabl e ts
tabl e ts
Anemia (Hgb<8.0 g/dL)
ALT (>5.0 × ULN)
AST (>5.0 × ULN)
Bilirubin (>2.5 × ULN)
Amylase (>2.0 × ULN)
*The median duration on study was 12 months.
†Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.
plus RETROVIR plus
ULN = Upper limit of normal
ANC = Absolute neutrophil count
ND = Not done
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
didanosine in patients without, or with, minimal
(≤ 56 days ) prior antiretroviral
therapy are listed
in Table 5.
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Selected Clinical Adverse Events and Physical Findings
(≥ 5% Frequency) in Pediatric Patients in Study ACTG300
(n = 236)
(n = 235)
Body as a whole
Nausea & vomiting
Abnormal breath sounds/wheezing
Ear, Nose and Throat
Signs or symptoms of ears*
Nasal discharge or congestion
*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.
Frequencies of Selected Laboratory Abnormalities in
Pediatric Patients in Study ACTG300
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.
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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
agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%)
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
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
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
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
to once-daily dosing compared with subjects randomized to twice-daily
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
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
hyperglycemia, hyperlactatemia, lactic acidosis and hepatic
steatosis (see WARNINGS AND PRECAUTIONS section)
diarrhea, nausea, pancreatitis, rises in serum amylase,
upper abdominal pain, vomiting
pure red cell aplasia
transient rises in liver enzymes
Hemic and Lymphatic:
anemia, lymphadenophathy, neutropenia, splenomegaly,
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Immune Reconstitution Inflammatory Syndrome (see
WARNINGS AND PRECAUTIONS: Immune section)
arthralgia, muscle disorders including very rarely rhabdomyolysis
headache, paresthesia, peripheral neuropathy
pruritus, rash, urticaria
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
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.
administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the
disposition and elimination of lamivudine.
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Established or Potential Drug-Drug Interactions
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
in combination therapy may
Lamivudine is not recommended for use in combination
with emtricitabine or emtricitabine-containing fixed dose
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
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
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
/RETROVIR (AZT) combination in patients with
renal impairment should be carefully assessed.
The effect of co-administration of lamivudine tablets
of co-trimoxazole for the treatment of
jiroveci pneumonia (also referred to as
toxoplasmosis has not been studied.
Zidovudine has no effect on the
pharmacokinetics of lamivudine
(see ACTIONS AND CLINICAL
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.
Interactions with food have not been established.
Interactions with herbs have not been established.
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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
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
JAMP Lamivudine is also available as a scored tablet for HIV-1-infected pediatric patients
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
recommended oral dosage of JAMP Lamivudine Tablets for HIV-1-infected
pediatric patients is presented in
Dosing Recommendations for JAMP Lamivudine Scored (150 mg)
Tablets in Pediatric
Once-Daily Dosing Regimen
1 tablet (150 mg)
½ tablet (75 mg)
1 ½ tablets (225 mg)
2 tablets (300 mg)
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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.
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.
Adjustment of Dosage of JAMP Lamivudine in Accordance With Creatinine
Clearance in Adults, Adolescents and Children weighing ≥25 kg
Recommended Dosage of JAMP Lamivudine
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
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.
If you forget to take your medicine, take it as soon as you remember. Then continue as before.
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If overdosage occurs the patient should be monitored, and standard supportive treatment applied
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
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Lamivudine is a synthetic nucleoside analogue, an (-) enantiomer of a dideoxy analogue of
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
(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.
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
) 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
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
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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
150 mg twice daily with respect to
; however, C
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
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
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.
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
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.
Each JAMP Lamivudine 150 mg tablet contains 150 mg of lamivudine and the nonmedicinal
hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
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
Molecular formula and molecular mass: C
Lamivudine is a white to off-white crystalline solid with a melting
point of 176°C.
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.
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
Comparative Bioavailability Study
Tablets, 300 mg (JAMP Pharma Corporation) and
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
(1 × 300 mg)
From measured data
Arithmetic Mean (CV %)
% Ratio of
JAMP Lamivudine (Lamivudine) Tablets 300 mg, by JAMP Pharma Corporation, Canada.
(Lamivudine) Tablets 300 mg, by ViiV Healthcare ULC, purchased in
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,
A total of 1816
HIV-infected adults with 25 to 250 CD4 cells/mm
) at baseline were
enrolled: median age was 36 years, 87% were male, 84% were
and 16% were therapy-naive. The median duration on study was 12
months. Results are summarized in
Page 25 of 43
Table 10: Number of Patients (%) With At Least One HIV Disease Progression Event or
(n = 460)
(n = 896)
(n = 460)
HIV progression or death
*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
A total of 554 antiretroviral treatment-naive HIV-infected adults enrolled: male (79%),
median age of 35 years, baseline CD4 cell counts of 69 to 1089 cells/mm
(median = 362
), and median baseline plasma HIV RNA of 4.66 log
patients with HIV RNA < 400 copies/mL and outcomes of treatment through are
Table 11: Outcomes of Randomized Treatment through 48 weeks (Intent-to Treat)
300 mg q.d. plus
(n = 278)
150 mg b.i.d. plus
(n = 276)
HIV RNA < 400 copies/mL
HIV RNA ≥ 400 copies/mL*
Discontinued due to clinical progression
Discontinued due to adverse events
Discontinued due to protocol defined
Discontinued due to insufficient viral load
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
(68%) and patients with baseline HIV RNA ≤ 100,000 copies/mL (62%). In
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.
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
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
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
(mean: 1060 cells/mm
and range: 0 to 4650
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
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)
(n = 236)
(n = 235)
HIV disease progression or death (total)
Physical growth failure
Central nervous system deterioration
CDC Clinical Category C
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
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)
Daily Dosing n =
Daily Dosing n=
Week 0 (After ≥36 Weeks on Treatment)
-4.5% (95% CI -11.3% to +2.2%),
3.3% (95% CI - 10.2% to + 3.5%)
-2.4% (95% CI -9.4% to +4.6%)
The Lamivudine tablets plus abacavir once daily dosing group demonstrated non-inferiority to the
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
tested (<200c/mL, <400c/mL, <1000c/mL). Virologic outcomes between treatment
comparable across baseline characteristics (gender, age, or viral load at
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
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
equivalent to lamivudine tablets
150 mg twice daily with respect to plasma
Page 28 of 43
. Intracellular lamivudine triphosphate
concentrations in peripheral blood mononuclear
cells were also pharmacokinetically equivalent
with respect to AUC
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
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 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.
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
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
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 mL/min
Creatinine clearance (mL/min)
111 ± 14
28 ± 8
6 ± 2
2.6 ± 0.5
3.6 ± 0.8
5.8 ± 1.2
11.0 ± 1.7
48.0 ± 19
157 ± 74
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
significantly affected by renal function.
Based on these observations, it is recommended
dosage of lamivudine
be modified in patients with reduced creatinine clearance (see
AND ADMINISTRATION section).
The likelihood of adverse drug interactions with lamivudine is low due to limited metabolism
plasma protein binding and almost complete renal clearance. Coadministration of
results in a 13% increase in AUC
for zidovudine and a 28% increase in peak plasma
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
at therapeutic doses. This does not require dose adjustment unless the patient
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
according to the recommended dosage regimen achieved plasma concentrations of
similar to adults. The absolute bioavailability of lamivudine tablets are lower in children than
The pharmacokinetics of lamivudine dosed once daily in HIV-1-infected pediatric patients aged
12 years was evaluated in a study (ARROW PK [n=35]). This study was designed as 2 –period,
pharmacokinetic studies of twice-versus once-daily dosing of abacavir and
demonstrated that once-daily dosing provides equivalent AUC
of lamivudine at the same total daily dose. The
was approximately 80%
higher with lamivudine once-daily dosing compared
with twice-daily dosing.
Page 30 of 43
Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat
Dosing of Lamivudine in a Pediatric Trial
(Number of Subjects)
(n = 35)
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
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
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).
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
In antiretroviral therapy-naive patients, phenotypic resistance to lamivudine
more slowly on combination therapy than on lamivudine monotherapy.
experienced patients on lamivudine plus zidovudine,
no consistent pattern of changes in
phenotypic resistance to lamivudine or zidovudine was observed.
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
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
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
The relationship between in vitro susceptibility of HIV to lamivudine and the clinical response to
therapy remain under investigation.
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
Fifty-three of 554 (10%) patients enrolled in EPV20001 were identified as virological
(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
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
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.
The results of cytotoxicity studies in various assays have shown little cytotoxic action with
Cytotoxicity of lamivudine was compared with that of zidovudine,
didanosine in four T-lymphoblastoid cell lines; one monocyte/ macrophage-like cell line; one B-
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 [
Lamivudine greatly reduced the cytotoxicity of zalcitabine, slightly reduced the
zidovudine in some cases, and did not alter the cytotoxicity of didanosine.
In myelotoxicity studies in vitro, lamivudine demonstrated no toxic effects against erythroid,
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
zalcitabine, ara-C, 3FT, and stavudine in these studies. In another study, lamivudine
was not toxic to activated human T-cells.
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
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
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
generation animals, and the development
of the 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
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
of the seminiferous tubules.
Page 36 of 43
Aboulker JP, Babiker A, Carriere I, Darbyshire JH, Debré M, Delgado A et al. A
trial of the addition of lamivudine or matching placebo to
current nucleoside analogue reverse transcriptase inhibitor therapy in HIV-infected
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Angel JB, Hussey EK, Hall ST, Donn KH, Morris DM, McCormack JP, et al.
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infected patients. Drug Invest. 1993; 6(2): 70-4.
Arenas-Pinto A, Grant AD, Edwards S, Weller IVD. Lactic acidosis in HIV infected
patients: a systematic review of published cases. Sex Transm Infect 2003: 79: 340-344.
Boubaker K, Flepp M, Sudre P, Furreri T, Haensel A, Hirschel B, et al. Hyperlactatemia
and Antiretroviral therapy: The Swiss HIV Cohort Study. HIV/AIDS CID 2000; 33:
Cammack N, Rouse P, Marr CLP, Reid PJ, Boehme RE, Coates JAV, et al. Cellular
metabolism of (-) enantiomeric 2’deoxy-3’-thiacytidine.
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Coates JAV, Cammack N, Jenkinson HJ, Jowett AJ, Jowett MI, Pearson BA, et al. (-)-2’-
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Lamivudine-induced pure red cell aplasia. American J of Hematology 2000; 65(3): 189-
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(lamivudine) 150 mg and 300 mg tablets. Control # 226212, Product
ViiV Healthcare ULC, Date of revision: July 3, 2019.
Page 40 of 43
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
antiretroviral medicines. Please read the information
with these other medicines before you take JAMP
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
nucleoside analogue reverse transcriptase
and is used in combination with other
antiretrovirals to treat
What it does:
JAMP Lamivudine is not a cure for HIV infection or AIDS; it
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
important nonmedicinal ingredients are”
What the medicinal ingredient is:
Each JAMP Lamivudine (150 mg) tablet contains 150 mg of
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
glycolate and titanium dioxide.
Each 300 mg JAMP Lamivudine tablet also contains black iron
hypromellose, magnesium stearate,
cellulose, polyethylene glycol, polysorbate 80,
glycolate and titanium dioxide.
What dosage forms it comes in:
JAMP Lamivudine 150 mg tablets are white, modified
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
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
If you have kidney or liver disease (including hepatitis B
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
monitor your condition for several months
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
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
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
lower blood cell count
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
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
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-
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
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
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
sorbitol-containing medicines (usually liquids) used
trimethoprim-sulphamethoxazole (also known as co-
trimoxazole; an antibiotic used to treat Pneumocystis
jiroveci pneumonia (often referred to as PCP) or
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
once-a-day dosing: swallow one tablet (300 mg) once
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.
For children able to swallow tablets as determined by the
Children weighing 14 to less than 20 kg: one-half of a scored
JAMP Lamivudine tablet twice daily or one tablet taken once
Children weighing at least 20 kg and less than 25 kg: one-half
of a scored JAMP Lamivudine tablet taken in the morning and
tablet taken in the evening or one and a half tablets
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
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.
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
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
If you have taken too much
JAMP Lamivudine, contact a
health care practitioner, hospital emergency
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
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.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
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
or by contacting the sponsor, JAMP Pharma Corporation,
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
SERIOUS SIDE EFFECTS, HOW OFTEN THEY
HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect
Talk with your
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,
pain, and shortness of
Swollen and fatty liver
with steatosis) and
symptoms such as
weakness and diarrhea.
Blood problems and
symptoms such as
anemia (lowered red
blood cell count)
resulting in fatigue,
low white blood cell
count making you
more prone to
(inflammation of the
symptoms such as