METHOTREXATE SUBCUTANEOUS SOLUTION

Canada - English - Health Canada

Buy It Now

Active ingredient:
METHOTREXATE (METHOTREXATE SODIUM)
Available from:
ACCORD HEALTHCARE INC
ATC code:
L04AX03
INN (International Name):
METHOTREXATE
Dosage:
17.5MG
Pharmaceutical form:
SOLUTION
Composition:
METHOTREXATE (METHOTREXATE SODIUM) 17.5MG
Administration route:
SUBCUTANEOUS
Units in package:
1ML/5ML
Prescription type:
Prescription
Therapeutic area:
ANTINEOPLASTIC AGENTS
Product summary:
Active ingredient group (AIG) number: 0107545005; AHFS: 10:00.00
Authorization status:
APPROVED
Authorization number:
02491338
Authorization date:
2019-08-07

Documents in other languages

PRODUCT MONOGRAPH

Pr

METHOTREXATE SUBCUTANEOUS

Methotrexate Injection BP

50 mg / mL methotrexate (as methotrexate sodium)

Single-Use Pre-Filled Syringes

Sterile

Immunosuppressant

Accord Healthcare Inc.

3535 boul. St. Charles, Suite 704

Kirkland, QC H9H 5B9

Canada

Date of Preparation:

August 2, 2019

Control No. 214744

Page 2 of 33

Table of Contents

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

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

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

CONTRAINDICATIONS ................................................................................................................ 3

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

ADVERSE REACTIONS .............................................................................................................. 11

DRUG INTERACTIONS .............................................................................................................. 14

DOSAGE AND ADMINISTRATION .......................................................................................... 18

OVERDOSAGE

.............................................................................................................................. 19

ACTION AND CLINICAL PHARMACOLOGY ......................................................................... 20

STORAGE AND STABILITY ...................................................................................................... 21

SPECIAL HANDLING INSTRUCTIONS .................................................................................... 21

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

PART II: SCIENTIFIC INFORMATION ......................................................................................... 23

PHARMACEUTICAL INFORMATION ...................................................................................... 23

DETAILED PHARMACOLOGY .................................................................................................. 24

TOXICOLOGY .............................................................................................................................. 25

REFERENCES ............................................................................................................................... 26

PART III: CONSUMER INFORMATION ...................................................................................... 29

Page 3 of 33

Pr

METHOTREXATE

SUBCUTANEOUS

Methotrexate Injection BP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

All Nonmedicinal Ingredients

Subcutaneous

50 mg / mL single-use pre-

filled syringes

Sodium Chloride, Sodium Hydroxide and Water for

injection

INDICATIONS AND CLINICAL USE

METHOTREXATE SUBCUTANEOUS

(methotrexate

injection) is

indicated

Disease

Modifying Antirheumatic Drug (DMARD) in the following diseases where standard therapeutic

interventions fail:

Severe disabling psoriasis / psoriatic arthritis

Severe disabling rheumatoid arthritis (RA)

In the treatment of psoriasis, METHOTREXATE SUBCUTANEOUS should be restricted to

severe

recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of

therapy, but

only when the diagnosis has been established after dermatologic consultation.

Geriatrics:

The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to

diminished hepatic and renal function, as well as decreased folate stores in this population,

relatively low doses should be considered, and these patients should be closely monitored for

early signs of toxicity.

Pediatrics:

Safety and effectiveness in pediatric patients have not been established.

Limitation of Use

METHOTREXATE SUBCUTANEOUS is not indicated for the treatment of neoplastic diseases

CONTRAINDICATIONS

METHOTREXATE SUBCUTANEOUS (methotrexate injection) is contraindicated in:

Patients who are hypersensitive to this drug or to any ingredient in the formulation or

Page 4 of 33

component of the container.

For a complete listing, see the DOSAGE FORMS,

COMPOSITION AND PACKAGING section.

In patients with severe renal impairment including end stage renal disease with and

without

dialysis

(see

WARNINGS

AND

PRECAUTIONS-

Renal,

Special

populations and DOSAGE AND ADMINISTRATION-Special populations)

Pregnancy: Methotrexate can cause fetal death, embryotoxicity, abortion or teratogenic

effects when administered to a pregnant woman.

Women of childbearing potential should not be started on methotrexate until pregnancy is

excluded and should be fully counselled on the serious risk to the fetus should they

become pregnant while undergoing treatment. Pregnancy should be avoided if either

partner is receiving methotrexate (see WARNINGS AND PRECAUTIONS).

Nursing mothers: Due to the potential for serious adverse reactions in breast fed infants.

Patients with alcoholism, alcoholic liver disease or other chronic liver disease.

Patients with overt or laboratory evidence of immunodeficiency syndromes.

Patients with pre-existing blood dyscrasias, such as bone marrow hypoplasia,

leucopenia,thrombocytopenia or significant anemia.

With nitrous oxide anesthesia (see WARNINGS AND PRECAUTIONS:

Renal and DRUG INTERACTIONS- Drug-Drug Interactions).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

METHOTREXATE SUBCUTANEOUS (methotrexate injection) should be used only

physicians

whose

knowledge

experience

includes

immunosuppressant

therapy because of the possibility of serious toxic reactions (see

WARNINGS AND PRECAUTIONS: General).

Methotrexate has been reported to cause fetal death and/or congenital anomalies (see

Special Populations: Pregnant Women section below). Therefore, use is contraindicated

for women of childbearing potential until pregnancy is excluded and pregnant patients (see

CONTRAINDICATIONS).

General

Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported. It should

be emphasized to the patient that the recommended dose is taken weekly.

Because of the possibility of serious toxic reactions (which can be fatal), METHOTREXATE

SUBCUTANEOUS should be used only in patients with psoriasis or rheumatoid arthritis with

severe, recalcitrant, disabling disease that is not adequately responsive to other forms of therapy.

Deaths have been reported with the use of methotrexate in the treatment of psoriasis and

rheumatoid arthritis. Because of the possibility of serious toxic reactions the patient should be

informed by the physician of the risks involved and should be under a physician’s constant

supervision.

METHOTREXATE SUBCUTANEOUS has the potential for serious toxicity. Toxic effects

may be

related in frequency and severity to dose or frequency of administration but have been

Page 5 of 33

seen at all

doses. Because they can occur at any time during therapy, it is necessary to follow

patients on METHOTREXATE SUBCUTANEOUS closely. Most adverse reactions are reversible

if detected early. When such reactions do occur, the drug should be reduced in dosage or

discontinued

and appropriate corrective measures should be taken. If necessary, this could

include the use of leucovorin calcium and / or acute, intermittent hemodialysis with a high-flux

dialyzer (see

Overdosage). If METHOTREXATE SUBCUTANEOUS therapy is re-instituted, it

should be carried out

with caution, with adequate consideration of further need for the drug

and with increased alertness as to possible recurrence of toxicity.

Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This

results in a prolonged

terminal plasma half-life and unexpected toxicity.

In patients with

significant third space accumulations, it is advisable to evacuate the fluid before treatment and to

monitor plasma methotrexate levels.

METHOTREXATE SUBCUTANEOUS should be used with extreme caution in the presence of

debility.

Carcinogenesis and Mutagenesis

No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate

has been evaluated in a number of animal studies for carcinogenic potential with inconclusive

results. Although there is evidence that methotrexate causes chromosomal damage to animal

somatic

cells

human

bone

marrow

cells,

clinical

significance

remains

uncertain.

Assessment of the carcinogenic potential of methotrexate is complicated by conflicting evidence

of an increased risk of certain tumors in rheumatoid arthritis. Benefit should be weighed against

this potential risk before using methotrexate alone or in combination with other drugs, especially

in children or young adults.

Also, see TOXICOLOGY.

Gastrointestinal

vomiting,

diarrhea,

stomatitis

occurs,

resulting

dehydration,

METHOTREXATE

SUBCUTANEOUS should be discontinued until recovery occurs. Diarrhea and ulcerative

stomatitis

require

interruption

therapy;

otherwise,

hemorrhagic

enteritis and

death from

intestinal perforation may occur. METHOTREXATE SUBCUTANEOUS should be used with

extreme

caution in the presence of peptic ulcer disease or ulcerative colitis.

Unexpectedly

severe

(sometimes

fatal)

gastrointestinal

toxicity

have

been

reported

with

concomitant administration of methotrexate (usually in high dosage) along

with some non-

steroidal anti-inflammatory drugs (NSAIDs) (see DRUG INTERACTIONS).

Drug Interactions with Proton Pump Inhibitors (PPI): Use caution when administering high-dose

methotrexate to patients receiving proton pump inhibitor (PPI) therapy as concomitant use of

some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at

high dose), may elevate and prolong serum levels of methotrexate and / or its metabolite

hydromethotrexate, possibly leading to methotrexate toxicities (see DRUG INTERACTIONS:

Drug-Drug Interactions).

Page 6 of 33

Hematologic

METHOTREXATE SUBCUTANEOUS should be used with caution in patients with impaired

bone

marrow function and previous or concomitant wide field radiotherapy. METHOTREXATE

SUBCUTANEOUS may produce marked bone marrow depression

with resultant anemia,

aplastic anemia, pancytopenia, leucopenia neutropenia and / or thrombocytopenia. In patients

with malignancy and pre-existing hematopoietic impairment, the drug should be used with

caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leucopenia (WBC

<3000 / mm

) was seen in 2 patients, thrombocytopenia (platelets <1,000,000 / mm

) in 6 patients,

and pancytopenia in 2 patients.

In psoriasis and rheumatoid arthritis, METHOTREXATE SUBCUTANEOUS should be stopped

immediately

there

significant

drop

blood

counts.

Patients

with

profound

granulocytopenia and fever should be evaluated immediately and usually require parenteral

broad-spectrum antibiotic therapy.

Unexpectedly severe (sometimes fatal) bone marrow suppression and aplastic anemia have been

reported with concomitant administration of methotrexate (usually in high dosage) along with

some non-steroidal anti-inflammatory drugs (NSAIDs) (see DRUG INTERACTIONS).

Hepatic / Biliary / Pancreatic

METHOTREXATE SUBCUTANEOUS has the potential for acute and chronic hepatotoxicity.

Acutely, liver enzyme elevations are frequently seen after methotrexate administration and

are usually not a reason for modification of METHOTREXATE SUBCUTANEOUS therapy.

Liver enzyme

elevations are usually transient and

asymptomatic, and also do

appear

predictive of subsequent hepatic disease. Persistent liver abnormalities, and / or decrease of

serum albumin may be indicators of serious liver toxicity. Chronic toxicity is potentially fatal;

it generally has occurred after prolonged use (generally two years or more) and after a

total

cumulative

dose

least

grams.

Liver

biopsy

after

sustained

often

shows

histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be

preceded by symptoms or abnormal liver function tests in the psoriasis population. Periodic

liver

biopsies

usually

recommended

psoriatic

patients

under

long-term

treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or

cirrhosis in the rheumatoid arthritis population. In studies in psoriatic patients, hepatotoxicity

appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism,

obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate

of progression and reversibility of lesions is not known. Special caution is indicated in the

presence of pre-existing liver damage or impaired hepatic function.

Methotrexate has caused reactivation or worsening of hepatitis B and C infections, in some cases

resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of

methotrexate. Prior to treatment with methotrexate, clinical and laboratory evaluation should be

performed to evaluate preexisting hepatitis virus B and hepatitis virus C infection. Methotrexate

is not recommended for patients with active or chronic hepatitis B or C infection.

In psoriasis, liver damage and function tests, including serum albumin and prothrombin time,

should be performed several times prior to dosing, but are often normal in the face of developing

fibrosis or cirrhosis. These lesions may be detectable only by biopsy.

Page 7 of 33

The usual recommendation is to obtain a liver biopsy: 1) before the start of therapy or shortly

after initiation of therapy (4-8 weeks); 2) after a total cumulative dose of 1.5 grams; and 3) after

each

additional

grams.

Moderate

fibrosis

cirrhosis

normally

leads

discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder

histologic findings such as fatty change and low grade portal inflammation are relatively common

pre-therapy. Although these mild changes are usually not a reason to avoid or discontinue

methotrexate therapy, the drug should be used with caution.

Clinical experience with liver disease in rheumatoid arthritis is limited, but the same risk factors

would be anticipated. Liver function tests are also usually not reliable predictors of histological

changes in this population.

In rheumatoid arthritis, advanced age at first use of methotrexate and increasing duration of

therapy have been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver

function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid population.

Liver function tests should be performed at baseline and at 4-8 week intervals in patients

receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed

for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver

function test values, or chronic hepatitis B or C infection. During therapy, liver biopsy should be

performed if there are persistent liver function test abnormalities, or there is a decrease in serum

albumin below the normal range (in the setting of well controlled rheumatoid arthritis).

results

liver

biopsy

show

mild

changes

(Roenigk

grades

IIIa),

METHOTREXATE SUBCUTANEOUS may be continued and the patient monitored according

recommendations

listed

above.

METHOTREXATE

SUBCUTANEOUS

should

discontinued in any patient who displays persistently abnormal liver function tests and refuses

liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes (Roenigk

grade IIIb or IV).

There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies

both before and during treatment (after a cumulative dose of at least 1500 mg) and in 714

patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%)

case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more

sensitive for early fibrosis and its use may increase these figures. It is unknown whether even

longer use will increase these risks.

Immune

METHOTREXATE SUBCUTANEOUS should be used with extreme caution in the presence of

active infection, and is usually contraindicated in patients with overt or laboratory evidence of

immunodeficiency syndromes.

Immunization may be ineffective when given during methotrexate therapy. Immunization with

live virus vaccines is generally not recommended. There have been reports of disseminated

vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.

Hypogammaglobulinemia has been reported rarely.

Neurologic

Page 8 of 33

A transient acute neurologic syndrome has been observed in patients treated with high dosage

regimens. Manifestations of this neurologic disorder may include behavioural abnormalities,

focal sensorimotor signs, including transient blindness and abnormal reflexes. The exact cause is

unknown.

Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and

stroke-like episodes have been reported mostly in juveniles and adolescents given methotrexate

in combination with cytarabine.

Renal

Methotrexate is contraindicated in patients with severe renal impairment including end stage renal

disease

with

without

dialysis

(see

CONTRAINDICATIONS

DOSAGE

AND

ADMINISTRATION-Special populations). Methotrexate therapy in patients with mild and

moderate renal impairment should be undertaken with extreme caution, and at reduced dosages,

because renal dysfunction will prolong methotrexate elimination. Methotrexate may cause renal

damage that may lead to acute renal failure. Nephrotoxicity is due primarily to the precipitation of

methotrexate and 7-hydroxymethotrexate

in the renal tubules. Close attention to renal function

including adequate hydration, urine

alkalinization and measurement of serum methotrexate and

creatinine levels are essential for safe

administration.

Nephritis has been reported on co-administration with nitrous oxide anesthesia in rheumatoid

arthritis patients (see CONTRAINDICATIONS and DRUG INTERACTIONS: Drug-Drug

Interactions).

Respiratory

Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis is a

potentially dangerous lesion, which may occur at any time during therapy and which has been

reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary

symptoms (especially a dry non-productive cough) or a non-specific pneumonitis occurring

during methotrexate therapy may be indicative of a potentially dangerous lesion and require

interruption of treatment and careful investigation. Although clinically variable, the

typical

patient

with

methotrexate-induced

lung

disease

presents

with

fever,

cough,

dyspnea,

hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be

excluded.

This lesion can occur at all dosages.

Pulmonary alveolar haemorrhage has been reported with methotrexate. This event may also be

associated with vasculitis and other comorbidities. Prompt investigations should be considered

when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

Pneumonia

some

cases

leading

respiratory

failure)

occur.

Potentially

fatal

opportunistic

infections,

especially

Pneumocystis

carinii

pneumonia,

occur

with

METHOTREXATE SUBCUTANEOUS

therapy.

When

patient

presents

with

pulmonary

symptoms,

the possibility of Pneumocystis carinii should be considered.

Sexual Health

Fertility:

Page 9 of 33

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual

dysfunction and amenorrhea in humans, during and for a short period after cessation of therapy.

Reproduction:

Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. Therefore, the possible

risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed

with both male and female patients of childbearing potential. The absence of pregnancy must be

confirmed before METHOTREXATE SUBCUTANEOUS is used. If women of a sexually mature

age are

treated, effective contraception must be performed during treatment and from at least six

months

year

(see

WARNINGS

PRECAUTIONS

Special

Populations

Contraception in

females).

Methotrexate is contraindicated during pregnancy in non-oncological indications. If pregnancy

occurs during treatment with methotrexate and from six months to one year after, medical advice

should be given regarding the risk of harmful effects on the child associated with treatment and

ultrasonography examinations should be performed to confirm normal fetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first

trimester. Methotrexate has been shown to be teratogenic to humans; it has been reported to

cause

fetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular,

central nervous system and extremity-related). Methotrexate is a powerful human teratogen, with

an increased risk of spontaneous abortions, intrauterine growth restriction and congenital

malformations in case of exposure during pregnancy.

The risk of effects on reproduction should be discussed with both male and female patients

taking METHOTREXATE SUBCUTANEOUS.

Skin

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’s

Syndrome),

Stevens-Johnson

syndrome,

exfoliative

dermatitis,

skin

necrosis

erythema

multiforme

have

been

reported

children

adults

within

days

oral

methotrexate

administration. Reactions were noted after single or multiple, low, intermediate or high doses of

methotrexate in patients with rheumatoid arthritis or psoriasis. Recovery has been reported with

discontinuation of therapy.

Lesions

of psoriasis

may be aggravated

by concomitant

exposure to

ultraviolet

radiation.

Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.

Special Populations

Pregnant Women:

METHOTREXATE

SUBCUTANEOUS

contraindicated

pregnant

patients

(see

CONTRAINDICATIONS

WARNINGS

AND

PRECAUTIONS).

METHOTREXATE

SUBCUTANEOUS can cause fetal death, embryotoxicity, abortion, or teratogenic effects when

administered to a pregnant woman. The risk of effects on reproduction should be discussed with

both male and female patients taking METHOTREXATE SUBCUTANEOUS.

Women of childbearing potential should not be started on METHOTREXATE SUBCUTANEOUS

until

pregnancy is excluded and should be fully counselled on the serious risk to the fetus should

Page 10 of 33

they

become

pregnant

while

undergoing

treatment. Effective

contraception

must

used

during

treatment with methotrexate and at least from 6 months to one year after. During

treatment

pregnancy tests should be repeated as clinically required (e.g. after any gap of

contraception).

Female patients of reproductive potential must be counselled regarding pregnancy

prevention and

planning.

Pregnancy

should

avoided

either

partner

receiving

METHOTREXATE

SUBCUTANEOUS.

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic

in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be

excluded. There are insufficient data to estimate the risks of malformations or miscarriage

following paternal exposure. As precautionary measures, sexually active male patients or their

female partners are recommended to use reliable contraception during treatment of the male patient

and from 6 months to one year after cessation of methotrexate. Men should not donate semen

during therapy or from 6 months to one year following discontinuation of methotrexate.

Nursing Women:

Because of the potential for serious adverse reactions from methotrexate in breast fed infants,

METHOTREXATE SUBCUTANEOUS is contraindicated in nursing mothers.

Pediatrics:

Safety and effectiveness in pediatric patients have not been established.

Geriatrics: The clinical pharmacology of methotrexate has not been well studied in older

individuals. Due to diminished hepatic and renal function, as well as decreased folate stores in

this population, relatively low doses should be considered, and these patients should be closely

monitored for early signs of toxicity.

Renal Impairment: METHOTREXATE SUBCUTANEOUS is contraindicated in patients with

severe

renal impairment (see CONTRAINDICATIONS

and DOSAGE AND ADMINISTRATION-

Special populations)

Monitoring and Laboratory Tests

General:

Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are

detected promptly. Baseline assessment should include a complete blood count (CBC) with

differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During

therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended:

hematology at least monthly, and hepatic enzyme levels and renal function every 1 to 2 months.

During initial or changing doses, or during periods of increased risk of elevated methotrexate

blood levels (e.g., dehydration), more frequent monitoring may also be indicated.

Liver:

Liver

biopsies

prior

METHOTREXATE

SUBCUTANEOUS therapy

indicated

routinely. Liver function tests (LFTs) should be determined prior to the initiation of therapy with

METHOTREXATE SUBCUTANEOUS and they should be monitored regularly throughout

Page 11 of 33

therapy. A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver

has not

been established. Transient liver function test abnormalities are observed frequently after

methotrexate administration and are usually not cause for modification of methotrexate therapy.

Persistent liver function test abnormalities just prior to dosing and / or

depression of serum

albumin may be indicators of serious liver toxicity and require evaluation.

Respiratory:

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected,

especially if baseline measurements are available.

Serum Level Monitoring:

Serum methotrexate level monitoring can significantly reduce methotrexate toxicity and

mortality.

Patients subject to the following conditions are predisposed to developing elevated or prolonged

methotrexate levels and benefit from routine monitoring of levels: eg, pleural effusion, ascites,

gastrointestinal

tract obstruction,

previous cisplatin

therapy,

dehydration,

aciduria,

impaired

renal function.

Some patients may have delayed methotrexate clearance in the absence of these features. It is

important that patients be identified within 48 hours since methotrexate toxicity may not be

reversible if adequate leucovorin rescue is delayed for more than 42 to 48 hours.

Monitoring of methotrexate concentrations should include determination of a methotrexate level

at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to

determine how long to continue leucovorin rescue).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In general, the incidence and severity of acute side effects are related to dose, frequency of

administration, and the duration of the exposure to significant blood levels of methotrexate to the

target organs. The most serious reactions are discussed in WARNINGS AND PRECAUTIONS.

That section should also be consulted when looking for information about

adverse reactions

with methotrexate.

The most frequently reported adverse reactions include ulcerative stomatitis, leucopenia, nausea,

and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue,

chills and fever, dizziness and decreased resistance to infection.

Adverse Drug Reactions by Organ System

Blood and lymphatic system disorders

Leukopenia, anaemia, thrombopenia, pancytopenia, agranulocytosis and severe courses of bone

marrow depression, lymphoproliferative disorders.

Cardiac disorders

Page 12 of 33

Pericarditis, pericardial effusion and pericardial tamponade.

Eye disorders

Visual disturbances and retinopathy.

Gastrointestinal disorders

Stomatitis, dyspepsia, nausea, loss of appetite, oral ulcers, diarrhoea, pharyngitis, enteritis,

vomiting, gastrointestinal ulcers, haematemesis, haematorrhea and toxic megacolon.

General disorders and administration site conditions

Allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis, infection, sepsis,

wound-healing impairment, hypogammaglobulinaemia and local damage (formation of sterile

abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration.

Hepatobiliary disorders

Elevated transaminases, cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum

albumin, acute hepatitis and hepatic failure.

Metabolism and nutrition disorders

Precipitation of diabetes mellitus.

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia and osteoporosis, osteonecrosis of jaw (secondary to lymphoproliferative

disorders).

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of

lymphoma and other lymphoproliferative disorders, which subsided in a number of cases once

treatment with methotrexate had been discontinued.

Nervous system disorders

Headache, tiredness, drowsiness, dizziness, confusion, depression, impaired vision, pain,

muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste),

convulsions, meningism, paralysis and leukoencephalopathy.

Renal and urinary disorders

Renal failure, severe nephropathy or renal failure, azotemia, dysuria, cystitis, hematuria,

urogenital dysfunction. Proteinuria has also been observed.

Reproductive system and breast disorders

Inflammation and ulceration of the vagina, loss of libido, impotence, gynaecomastia,

oligospermia, impaired menstruation and vaginal discharge.

Respiratory, thoracic and mediastinal disorders

Pneumonia, interstitial alveolitis / pneumonitis often associated with eosinophilia, symptoms

indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough,

short of breath and fever, pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of

Page 13 of 33

breath and bronchial asthma, pleural effusion, epistaxis, and pulmonary alveolar haemorrhage.

Skin and subcutaneous tissue disorders

Exanthema, erythema, pruritus, photosensitisation, loss of hair, increase in rheumatic nodules,

herpes zoster, vasculitis, herpetiform eruptions of the skin, urticarial, increased pigmentation, acne,

ecchymosis, tevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased

pigmentary changes of the nails, acute paronychia, furunculosis and telangiectasia.

Vascular disorders

Hypotension and thromboembolic events.

Other Adverse Drug Reactions

Adverse Reactions Reported in Rheumatoid Arthritis

Incidence greater than 10%: elevated liver enzymes 15%, nausea / vomiting 10%.

Incidence 3% to 10%: stomatitis, thrombocytopenia.

Incidence 1% to 3%: rash / pruritus / dermatitis, alopecia, diarrhea, dizziness, leucopenia and

pancytopenia.

Adverse Reactions in Psoriasis

The adverse reaction rates reported are very similar to those in the rheumatoid arthritis studies.

Rarely, painful psoriatic plaque erosions may appear.

Abnormal Hematologic and Clinical Chemistry Findings

Abnormal hematologic and clinical chemistry findings are discussed in WARNINGS AND

PRECAUTIONS – Monitoring and Laboratory Tests.

Post-marketing Adverse Drug Reactions

Because these reactions are reported voluntarily from a population of uncertain size, it is generally

not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse events have also been reported during post-marketing experience with

methotrexate:

System Organ Class

Adverse Reaction

Infections and Infestations

Infections (including fatal sepsis);

Pneumonia; Pneumocystis carinii pneumonia;

Nocardiosis; Histoplasmosis; Cryptococcosis;

Herpes zoster; H. simplex hepatitis;

Disseminated H. simplex; Cytomegalovirus

infection (including cytomegaloviral

pneumonia); Reactivation of hepatitis B

infection; Worsening of hepatitis C infection

Page 14 of 33

Blood and Lymphatic System Disorders

Agranulocytosis; Pancytopenia; Leukopenia;

Neutropenia; Lymphadenopathy and

lymphoproliferative disorders (including

reversible); Eosinophilia; Anemia

megaloblastic; Renal vein thrombosis;

Lymphoma; Aplastic anemia;

Hypogammaglobulinemia

Nervous System Disorders

CSF pressure increased; Neurotoxicity;

Arachnoiditis; Paraplegia; Stupor; Ataxia;

Dementia; Dizziness; Paresthesia

Respiratory, Thoracic and Mediastinal

Disorders

Chronic interstitial pulmonary disease;

Alveolitis; Dyspnea; Chest pain; Hypoxia;

Cough; Plural effusion

Gastrointestinal Disorders

Intestinal perforation; Noninfectious

peritonitis; Glossitis; Nausea; Pancreatitis

Hepatobiliary Disorders

Hepatic failure

Skin and Subcutaneous Tissue Disorders

Drug reaction with eosinophilia and systemic

symptoms; Dermatitis; Petechiae

Musculoskeletal, Connective Tissue and

Bone Disorders

Osteonecrosis

Renal and Urinary Disorders

Proteinuria

Pregnancy, Puerperium and Perinatal

Conditions

Fetal death, Abortion

Reproductive System and Breast Disorders

Urogenital dysfunction

General Disorders and Administration Site

Conditions

Pyrexia; Chills; Malaise; Fatigue;

Anaphylactic reactions

Endocrine Disorders

Diabetes

Ophthalmologic Disorders

Transient blindness/vision loss

DRUG INTERACTIONS

Overview

Methotrexate competes with reduced folates for active transport across cell membranes by means

of a single carrier-mediated active transport process. Impaired renal function, as well as

concurrent use of drugs such as weak organic acids that undergo tubular secretion, can markedly

increase methotrexate serum levels. Laboratory studies demonstrate that methotrexate may be

displaced from plasma albumin by various compounds including sulfonamides, salicylates,

tetracyclines, chloramphenicol and phenytoin.

Serious Drug Interactions

of nitrous oxide anesthesia with methotrexate is contraindicated

(see

CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS - Renal and DRUG

INTERACTIONS - Drug-Drug Interactions)

Page 15 of 33

Drug-Drug Interactions

The drugs listed below are based on either drug interaction case reports or studies, or potential

interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as

contraindicated).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate.

Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported

to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic

(including bone marrow suppression and aplastic anemia) and gastrointestinal toxicity.

These

drugs have been reported to reduce the tubular secretion of methotrexate, in an animal

model, and

may enhance its toxicity by increasing methotrexate levels.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower

doses

METHOTREXATE

SUBCUTANEOUS.

treating

rheumatoid

arthritis

with

methotrexate, the

possibility of increased toxicity with concomitant use of NSAIDs including

salicylates

been

fully

explored.

Despite

potential

interactions,

studies

methotrexate in patients with

rheumatoid arthritis have usually included concurrent use of

constant dosage regimens of NSAIDs

without apparent problems.

Disease Modifying Antirheumatic drugs (DMARDs)

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, or sulfasalazine has

not been studied and may increase the incidence of adverse effects.

Packed Red Blood Cells

Care

should

exercised

whenever

packed

blood

cells

METHOTREXATE

SUBCUTANEOUS

are given concurrently. Patients receiving 24-hr methotrexate infusion and

subsequent transfusions

have showed enhanced toxicity probably resulting from prolonged

high serum-Methotrexate

concentrations.

Ciprofloxacin

Renal tubular transport is diminished by ciprofloxacin; use of METHOTREXATE

SUBCUTANEOUS

with this drug should be carefully monitored.

Radiotherapy

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis

and osteonecrosis.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. Combination of

METHOTREXATE

SUBCUTANEOUS and mercaptopurine may therefore require dose

adjustment.

Leflunomide

Methotrexate in combination with leflunomide may increase the risk of pancytopenia.

Drugs Highly Bound to Plasma Proteins

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of

Page 16 of 33

displacement by other highly bound drugs, such as sulfonylureas, aminobenzoic acid, salicylates,

phenylbutazone, phenytoin, sulfonamides, some antibiotics such as penicillins, tetracycline,

pristinamycin, probenecid, and chloramphenicol.

Probenecid

Renal

tubular

transport

also

diminished

probenecid;

METHOTREXATE

SUBCUTANEOUS with this drug should be carefully monitored.

Nephrotoxic Drugs

Although not documented, other nephrotoxic drugs such as aminoglycosides, Amphotericin B

and Cyclosporin could theoretically increase methotrexate toxicity by decreasing its elimination.

Penicillins and Sulfonamides

Penicillins

sulfonamides

reduce

renal

clearance

METHOTREXATE

SUBCUTANEOUS; hematologic and gastrointestinal toxicity have been observed in combination

with methotrexate.

Oral Antibiotics

Oral antibiotics such as tetracycline, chloramphenicol, and non-absorbable broad spectrum

antibiotics, may decrease intestinal absorption of METHOTREXATE SUBCUTANEOUS or

interfere

with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism

of the

drug by bacteria. For example: Neomycin, Polymyxin B, Nystatin and Vancomycin

decrease

methotrexate absorption, whereas Kanamycin increases methotrexate absorption.

Trimethoprim / sulfamethoxazole has been reported rarely to increase bone marrow suppression in

patients receiving methotrexate, probably by decreased tubular secretion and / or an additive

antifolate effect.

Theophylline

METHOTREXATE SUBCUTANEOUS may decrease the clearance of theophylline; theophylline

levels should be monitored when used concurrently with METHOTREXATE SUBCUTANEOUS.

Vitamins

Vitamin

preparations

containing

folic

acid

derivatives

decrease

responses

systemically administered METHOTREXATE SUBCUTANEOUS.

patients

with

rheumatoid

arthritis

psoriasis,

folic

acid

folinic

acid

reduce

methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver

enzymes.

Before taking a folate supplement, it is advisable to check B

levels, particularly in adults over

the age of 50, since folate administration can mask symptoms of B

deficiency.

Folate deficiency states may increase methotrexate toxicity.

Hepatoxins

The potential for increased hepatotoxicity when METHOTREXATE SUBCUTANEOUS is

Page 17 of 33

administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has

been

reported

such

cases.

Therefore,

patients

receiving

concomitant

therapy

with

METHOTREXATE

SUBCUTANEOUS

other

potential

hepatotoxic

agents

(e.g.,

leflunomide, azathioprine, sulfasalazine, retinoids) should be closely monitored for possible

increased risk of hepatotoxicity.

Proton Pump Inhibitors (PPI)

Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor

(PPI) therapy. Concomitant use of PPIs and high-dose methotrexate should be avoided

especially

in patients with renal impairment. Case reports and published population pharmacokinetic studies

suggest

that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole,

with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate

and/or its metabolite hydromethotrexate, possibly leading to methotrexate toxicities. In two of these

cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-

administered with PPIs, but was not observed when methotrexate was co-administered with

ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been

conducted.

Amiodarone

Amiodarone administration to patients receiving methotrexate treatment for psoriasis has

induced ulcerated skin lesions.

Diuretics

Bone marrow suppression and decreased folate levels have been described in the concomitant

administration of triamterene and methotrexate.

Psoralen Plus Ultraviolet Light (PUVA) Therapy

Skin cancer has been reported in few patients with psoriasis receiving a concomitant treatment

with methotrexate plus PUVA therapy (methoxalen and ultraviolet light).

Nitrous oxide

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism,

yielding

increased

toxicity

such

severe,

unpredictable

myelosuppression,

stomatitis,

neurotoxicity

(with

intrathecal

administration

methotrexate)

nephritis

(see

CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Renal). In case of

accidental co-administration, this effect can be reduced by the use of leucovorin rescue.

Drug-Food Interactions

The bioavailability of orally administered methotrexate is reduced by food, particularly milk

products.

Drug-Lifestyle Interactions

alcohol

with

METHOTREXATE

SUBCUTANEOUS

contraindicated

(see

CONTRAINDICATIONS). The effects of smoking, on the pharmacokinetics of methotrexate

have not been specifically studied.

Methotrexate may cause adverse reactions such as dizziness and fatigue which can affect the

Page 18 of 33

ability to drive or operate machinery.

DOSAGE AND ADMINISTRATION

Dosing Considerations

METHOTREXATE SUBCUTANEOUS should only be

prescribed by physicians, who are

familiar with

the various characteristics of the medicinal product and its mode of action. The

administration

should

routinely

done

health

professionals.

METHOTREXATE

SUBCUTANEOUS is injected

once weekly.

Parenteral drug products should be inspected visually for particulate matter and discolouration

prior to administration, whenever solution and container permit.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural

effusions). Such patients require especially careful monitoring for toxicity, and require dose

reduction or, in some cases, discontinuation of methotrexate administration.

Recommended Dose and Dosage Adjustments

Psoriasis

Recommended Starting Dose Schedules

Weekly single, SC dose schedule: 7.5 to 25 mg per week until adequate response is achieved.

The recommended initial dose is 7.5 mg of methotrexate once weekly.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response;

25 mg / week should not ordinarily be exceeded.

Once optimal clinical response has been achieved, the dosage schedule should be reduced to the

lowest

possible

amount

drug

longest

possible

rest

period.

METHOTREXATE SUBCUTANEOUS may permit the return to conventional topical therapy,

which should be

encouraged.

Rheumatoid Arthritis

Recommended Starting Dosage Schedules

Weekly single, SC dose schedule: 7.5 to 25 mg per week until adequate response is achieved.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; The

recommended initial dose is 7.5 mg of methotrexate once weekly, Depending on the individual

activity of the disease and tolerability by the patient, the initial dose may be increased gradually by

2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to

improve

for another 12 weeks or more. Upon achieving the therapeutically desired result, the

dose should be

reduced gradually to the lowest possible effective maintenance dose.

Page 19 of 33

Special Populations

Renal Impairment: Methotrexate is excreted to a significant extent by the kidneys, thus in

patients with renal impairment the health care provider may need to adjust the dose to

prevent accumulation of drug. The table below provided recommended starting doses in

renally impaired patients; dosing may need further adjustment due to wide inter subject pK

variability. METHOTREXATE SUBCUTANEOUS is contraindicated in patients with

severe renal

impairment (see CONTRAINDICATIONS).

Table 5: Dose Adjustments in Patients with Renal Insufficiency

Creatinine Clearance

% Standard Dose to Administer

(mL/min)

>80

Full Dose

<50

Use alternative therapy

Pediatrics (<18 years of age): Safety and effectiveness in pediatric patients have not

been

established (see WARNINGS AND PRECAUTIONS: Special Populations, Pediatrics).

Geriatrics (≥65 years of age): Due to diminished hepatic and renal function as well as

decreased folate stores in elderly population, relatively low doses (especially in rheumatoid

arthritis and psoriasis indications) should be considered and these patients should be closely

monitored for early

signs of toxicity. See Table 5 for reduced doses in patients with renal

impairment.

Missed Dose

If a scheduled dose is missed, contact your doctor for instructions.

OVERDOSAGE

Discontinue or reduce dosage at the first sign of ulceration or bleeding, diarrhea, or marked

depression of the hematopoietic system. Leucovorin is indicated to diminish the toxicity and

counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin

administration should begin as promptly as possible. As the time interval between methotrexate

administration and leucovorin initiation increases, the effectiveness of leucovorin in

counteracting

toxicity decreases. Monitoring of the serum methotrexate concentration is essential

in determining

the optimal dose and duration of treatment with leucovorin.

In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent

the precipitation of methotrexate and / or its metabolites in the renal tubules. Generally, neither

Page 20 of 33

standard

hemodialysis

peritoneal

dialysis

been

shown

improve

methotrexate

elimination.

However,

effective

clearance

methotrexate

been

reported

with

acute,

intermittent hemodialysis using a high-flux dialyzer.

There are published case reports of intravenous carboxypeptidase G2 treatment to hasten

clearance of Methotrexate in cases of overdoses.

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

immediately.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Methotrexate is a folate antagonist.

Methotrexate has immunosuppressive activity. This may be a result of inhibition of lymphocyte

multiplication. The mechanisms of action in the management of rheumatoid arthritis of the drug

is not known, although suggested mechanisms have included immunosuppressive and / or anti-

inflammatory effects.

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal

skin. This differential in proliferation rates is the basis for the use of methotrexate to control the

psoriatic process.

Pharmacokinetics

Absorption:

Methotrexate is generally completely absorbed following parenteral administration, and after

intramuscular injection peak serum concentrations occur in

30 to 60 minutes.

Distribution:

Methotrexate in serum is approximately 50% protein bound. After intravenous administration,

the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady -

state volume of distribution is approximately 0.4 to 0.8 L / kg (40% to 80% of body weight).

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts

when given orally or parenterally.

Metabolism:

After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated

forms

which

converted

back

methotrexate

hydrolase

enzymes.

These

polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate syntheses. Small

amounts of methotrexate polyglutamates may remain in tissues for extended periods. The

retention and prolonged drug action of these active metabolites vary among different cells,

tissues and tumours. A small amount of metabolism to 7-hydroxymethotrexate may occur at

doses commonly prescribed. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold

lower than the parent compound. Methotrexate is partially metabolized by intestinal flora after

oral administration.

Page 21 of 33

Excretion:

Renal excretion is the primary route of elimination and is dependent upon dosage and route of

administration. Excretion of single daily doses occurs through the kidneys in amounts from 80%

to 90% within 24 hours. Repeated daily doses result in more sustained serum levels and some

retention of methotrexate over each 24-hour period, which may result in accumulation of the

drug within the tissues. The liver cells appear to retain certain amounts of the drug for prolonged

periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired

renal function and may increase rapidly in the serum and in the tissue cells under such conditions.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic

amounts

when given orally or parenterally.

The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients

receiving treatment for psoriasis, or rheumatoid arthritis.

Methotrexate clearance rates vary widely and are generally decreased at higher doses.

Special Populations and Conditions

Nursing Women:

Methotrexate has been detected in human breast milk and is contraindicated during breast feeding.

The highest breast milk to plasma concentration ratio reached was 0.08: 1.

Renal Impairment: Since the renal excretion of methotrexate is the primary route of elimination

with 80% to 90% of the single daily doses of methotrexate excreted through the kidneys within 24

hours, methotrexate is retained in the presence of impaired renal function and may increase rapidly

in the serum and in the tissue cells under such conditions, thus in patients with renal impairment

the health care provider may need to adjust the dose to prevent accumulation of drug.

Hepatic Impairment: Hepatic excretion of methotrexate is a minor route of elimination.

However, the liver cells appear to retain certain amounts of the drug for prolonged periods even

after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver

damage or impaired hepatic function.

STORAGE AND STABILITY

Keep in a safe place out of the reach of children.

Store METHOTREXATE SUBCUTANEOUS between 15-25°C. Store it away from heat and

direct light.

Avoid freezing. Any unused solution should be discarded.

SPECIAL HANDLING INSTRUCTIONS

General:

Individuals who have contact with this drug or work in areas where these drugs are used, may be

Page 22 of 33

exposed to these agents in air or through direct contact with contaminated objects. Potential

health

effects may be reduced by adherence to institutional procedures, published guidelines and local

regulations for preparation, administration, transportation and disposal of hazardous drugs.

Safe Handling and Disposal:

Good medical practice will minimize exposure of persons involved with frequent handling of

this drug as outlined below:

Handling:

Methotrexate has no vesicant properties and does not show acute toxicity on topical contact with

the skin or mucous membranes. However, persons involved with handling this drug should avoid

contact with skin and inhalation of airborne particles.

DOSAGE FORMS, COMPOSITION AND PACKAGING

METHOTREXATE SUBCUTANEOUS (methotrexate injection) 50 mg / mL (as methotrexate

sodium) is available in single-use USP type I glass pre-filled syringes. Non-medicinal ingredients

include sodium chloride, sodium hydroxide and water for injection.

METHOTREXATE SUBCUTANEOUS is available as follows;

1 mL syringe with 0.15 mL solution for injection, equivalent to 7.5 mg methotrexate

1 mL syringe with 0.2 mL solution for injection, equivalent to 10 mg methotrexate

1 mL syringe with 0.25 mL solution for injection, equivalent to 12.5 mg methotrexate

1 mL syringe with 0.3 mL solution for injection, equivalent to 15 mg methotrexate

1 mL syringe with 0.35 mL solution for injection, equivalent to 17.5 mg methotrexate

1 mL syringe with 0.4 mL solution for injection, equivalent to 20 mg methotrexate

1 mL syringe with 0.45 mL solution for injection, equivalent to 22.5 mg methotrexate

1 mL syringe with 0.5 mL solution for injection, equivalent to 25 mg methotrexate

All syringes are available in cartons of 1 or 4 single-use USP type I glass pre-filled syringes with

embedded injection needles (type 27 G, ½ inch, made from stainless steel).

Page 23 of 33

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Methotrexate

Chemical name:

Methotrexate

N-[4-[[(

2,4-diamino-6-pteridinyl

methylamino

benzoyl

L- glutamic

acid

Amethopterin

4-Amino-4-deoxy-10-methylpteroyl-L-glutamic Acid

4-Amino-10-

methylfolic acid

Molecular formula and molecular mass: C

(454.45 g / mol)

Structural formula:

Physicochemical properties:

Physical Form: A yellow to orange-brown crystalline powder. Contains not more

than 12% water.

Methotrexate is a mixture of 4-amino-10-methylfolic acid and

closely related compounds and is

equivalent to not less than 94.0% of C

calculated on the anhydrous basis. The parenteral

solution is prepared with the

sodium salt, but potency is always expressed on the basis of the acid.

Solubility: Practically insoluble in water, chloroform, ether and alcohol, but freely soluble in dilute

solutions of mineral acids, alkali hydroxides and carbonates.

Note: methotrexate sodium is formed in situ during drug product manufacturing.

Page 24 of 33

DETAILED PHARMACOLOGY

Human Pharmacokinetics

Absorption

Methotrexate is generally completely absorbed following parenteral administration, and after

intramuscular injection peak serum concentrations occur in 30 to 60 minutes.

Distribution

After intravenous administration, the initial volume of distribution is approximately 0.18 L / kg

(18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L / kg

(40% to 80% of body weight). Methotrexate competes with reduced folates for active transport

across cell membranes by means of a single carrier-mediated active transport process. At serum

concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by

which

effective

intracellular

concentrations

achieved.

Methotrexate

serum

approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from

plasma

albumin

various

compounds

including

sulfonamides,

salicylates,

tetracyclines,

chloramphenicol, and phenytoin.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts

when given parenterally.

In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed

joints. Although salicylates did not interfere with this penetration, prior prednisone treatment

reduced penetration into inflamed joints to the level of normal joints.

Metabolism

After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated

forms, which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates

act as inhibitors of dihydrofolate reductase and thymidylate syntheses.

Small

amounts of

methotrexate polyglutamates may remain in tissues for extended periods.

retention and

prolonged drug action of these active metabolites vary among different cells, and

tissues. A small

amount of metabolism to 7-hydroxy methotrexate may occur at doses commonly prescribed. The

aqueous solubility of 7-hydroxy methotrexate is 3 to 5 fold lower than the parent compound.

Methotrexate is partially metabolized by intestinal flora after oral

administration.

Half-Life

The terminal half-life reported for Methotrexate is approximately three to ten hours for patients

receiving treatment for psoriasis, or rheumatoid arthritis.

Excretion

Renal excretion is the primary route of elimination and is dependent upon dosage and route of

administration. With IV administration, 80% to 90% of the administered dose is excreted

unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or

less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal

excretion

occurs

glomerular

filtration

active

tubular

secretion.

Non-linear

Page 25 of 33

elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients

at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such

as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate

serum levels. Excellent correlation has been reported between methotrexate clearance and

endogenous creatinine clearance.

Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed

drug clearance has been identified as one of the major factors responsible for methotrexate

toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more

dependent upon the duration of exposure to the drug rather than the peak level achieved. When a

patient has delayed drug elimination due to compromised renal function, a third space effusion,

or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

The potential for toxicity from delayed excretion is reduced by the administration of leucovorin

calcium during the final phase of methotrexate plasma elimination.

TOXICOLOGY

The acute toxicity (LD

) of methotrexate in mice ranges from 65 to 70 mg/kg intravenously and

45 to 90 mg / kg intraperitoneally

The acute oral toxicity (LD

) in rats is 317 mg / kg; subcutaneously, it is 58 mg / kg and

intraperitoneally it ranges from 80 to 464 mg / kg.

In a 22 month carcinogenicity study in rats that received methotrexate at doses of 0.1, 0.2 and

0.4 mg / kg / day, 5 days / week every other week, little or no effect of the drug was observed. It

has been concluded that methotrexate is apparently remarkably free from toxic effects when

otherwise lethal doses are administered utilizing an intermittent dosage schedule providing for a

recovery period of 9 days. For example, daily oral doses of 0.4 mg / kg are lethal doses both in

dogs and rats when administered for up to two weeks; when 0.5 mg / kg and 0.4 mg / kg doses,

respectively, were administered daily five times a week every other week for three months to

dogs and ten months to rats, they were found to be essentially without toxicity.

Methotrexate is often used clinically

in doses that are nearly

toxic and may

cause severe

depression of all blood cellular elements. Constant supervision is recommended and signs of

gastrointestinal ulceration and bleeding, including bleeding from the

mouth, bone marrow

depression, primarily of the white cell series and alopecia are indications of toxicity. In general,

toxicity is in direct proportion to dose and exposure time to methotrexate.

Toxicity of methotrexate to the bone marrow and gastrointestinal epithelium is not so much

dependent on dosage as on the duration of exposure of these organs to the drug and its extracellular

(plasma) concentration. For bone marrow and gastrointestinal tract, the critical time

factor has been

defined as about 42 hours and the critical plasma concentration as 2x10

M. Both

factors must be

exceeded for toxicity to occur to these organs.

Doses of methotrexate resulting in plasma levels in excess of 2x10

M circulating for greater than

42 hours will be toxic to both the bone marrow and gastrointestinal epithelium. This toxicity can

be minimized by the appropriate administration of Leucovorin Calcium.

Methotrexate may be hepatotoxic, particularly at high dosage and with prolonged therapy. Liver

atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported.

Page 26 of 33

REFERENCES

Psoriasis Chemotherapy

Roenigk HH Jr, Maibach HI, and Weinstein GD. Use of Methotrexate in Psoriasis. Arch

Derm. 1972; 105:363-365.

Roenigk HH Jr, Bergfeld WF, and Curits GH. Methotrexate for Psoriasis in Weekly Oral

Doses. Arch Derm. 1969; 99:86-93.

Rees RB, Bennett JH, Maibach HI, and Arnold HL. Methotrexate for Psoriasis. Arch Derm.

1971; 103:33-38.

Roenigk HH Jr, Maibach HI, and Weinstein GD. Methotrexate Therapy for Psoriasis. Arch

Derm. 1973; 108:35.

Weinstein GD. Methotrexate for Psoriasis. JAMA. 1973; 225:412.

McDonald CJ and Bertino JR. Parenteral Methotrexate in Psoriasis. Arch Derm. 1969;

100:655-668.

Weinstein GD. Methotrexate for Psoriasis. Dermatology Digest. 1973; 12:49-53.

Weinstein GD and Velasco J. Selective Action of Methotrexate on Psoriatic Epidermal

Cells. J of Investigative Dermatology. 1972; 59:121-127.

Coe RO and Bull FE. Cirrhosis Associated with Methotrexate Treatment of Psoriasis.

JAMA. 1968; 206:1515-1520.

Weinstein CD, et al. Cooperative Study. Psoriasis-Liver Methotrexate Interactions. Arch

Derm. 1973; 108:36-42.

Pearce HP and Wilson BB. Erosion of psoriatic plaques: An early sign of Methotrexate

toxicity. Am Acad Dermatol. 1996;35:835-838.

NSAID Interactions

Adams JD and Hunter GA. Drug interaction in psoriasis. Aust J Derm. 1976; 17:3940.

Bloom EJ, et al. Delayed clearance (CL) of Methotrexate (MTX) associated with antibiotics

and anti-inflammatory agents. Abstract, Clin Res. 1986; 34, No. 2:560A.

Daly H. et al. Interaction between Methotrexate and non-steroidal anti-inflammatory drugs.

Lancet. 1986; 557.

Daly H, et al. Methotrexate toxicity precipitated by azapropazone. Br J Derm. 1986;

114:733-735.

Page 27 of 33

Doolittle GC, et al. Early-onset pancytopenia in two patients with rheumatoid arthritis

receiving low-dose Methotrexate. Abstract 15C, Art. Rheum 1987; 30:S19, 1 Suppl.

Ellison NM, and Servi RJ. Acute renal failure and death following sequential intermediate-

dose Methotrexate and 5-FU: A possible adverse effect due to concomitant Indomethacin

administration. Cancer Treat Reps. 1985; 69(3):342-343.

Gabrielli A, et al. Methotrexate and non-steroidal anti-inflammatory drugs. Letter, Br Med J.

1987; 294:776.

Maiche AI. Acute renal failure due to concomitant action of Methotrexate and Indomethacin.

Letter, Lancet. 1986; 1390.

Mandel MA. The synergistic effect of salicylates on Methotrexate toxicity. Plastic and

Reconstructive Surg. 1976; 733-737.

Singh RR, et al. Fatal interaction between Methotrexate and Naproxen. Letter, Lancet. 1986;

1390.

Thyss A, et al. Clinical and pharmacokinetic evidence of a life-threatening interaction

between Methotrexate and Ketoprofen. Lancet. 1986; 256-258.

Interactions with Radiotherapy

Turner SL, et al. Radical external beam radiotherapy of r333 squamous carcinomas of the

oral cavity-Evaluation of the late morbidity and a watch policy for the clinically negative

neck. Radiotherapy & oncology. 1996;41:21-9.

Hemodialysis

Wall SM, et al. Effective clearance of Methotrexate using high-flux hemodialysis

membranes. Am J Kidney Dis. 1996; 28(6):846-854.

General

Kremer

Methotrexate

rheumatoid

arthritis.

Suggested

guidelines

monitoring

liver

toxicity. American

College

Rheumatology. Arthritis & Rheumatol.

1994; 37(3):316-328.

Goodman TA, et al. Methotrexate: adverse reactions and major toxicities. Rheumatic

Disease

Clinics of North America. 1994; 20(2):513-28.

Tett SE, et al. Use of Methotrexate in older patients. A risk-benefit assessment. Drugs &

Aging. 1996; 9(6):458-71.

Page 28 of 33

Said S, et al. Systemic treatment: Methotrexate. Clinics in Dermatology. 1997; 15(5):781-

Evans WE, et al. Applied Pharmacokinetics: Principles of therapeutic drug monitoring, 3rd

ed. Applied Therapeutics, Inc. Vancouver WA, 1992.

Green JA, et al. Drug interactions with cytotoxic agents. Cancer Topics. 1990; 7(11); 126-

128.

Nierenberg W, et al. Toxic reaction to Methotrexate in a patient receiving penicillin and

furosemide: a possible interaction. Arch-Dermatol. 1983; 119(6): 449-50.

Squire EN, et al. Unexpected adverse effects of Methotrexate (MTX) when used in the

treatment

of steroid-dependent

asthma. Ann

Allergy-Asthma-lmmunol. 1996;

76(1):106

(Abs).

Glynn

Barnhart

Effect

low-dose

Methotrexate

deposition

glucocorticoids and theophylline. J Allergy Clin Immunol. 1991; 88(2):180-86.

Glynn

Barnhatt

Effect

Methotrexate

prednisolone

theophylline

pharmacokinetics. Pharmacotherapy. 1990; 10(3):255.

METOJECT

SUBCUTANEOUS 50 mg/mL methotrexate (as methotrexate sodium),

Control # 223139, Product Monograph, Medexus Inc., (March 20, 2019)

IMPORTANT PLEASE READ

Page 29 of 33

PART III: CONSUMER INFORMATION

Pr

METHOTREXATE SUBCUTANEOUS

Methotrexate Injection BP

This leaflet

is

part

III of

a

three-part

"Product

Monograph" published when METHOTREXATE

SUBCUTANEOUS was approved for sale in Canada

and

is

designed

specifically

for

Consumers.

This

leaflet

is a summary and will not tell you everything

about

METHOTREXATE

SUBCUTANEOUS.

Contact your doctor

or pharmacist if you have any

questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

METHOTREXATE SUBCUTANEOUS

belongs

group of

medicines known as immunosuppressants. It is

used to treat

psoriasis and rheumatoid arthritis.

What it does:

rheumatoid

arthritis,

methotrexate

acts

inflammatory

cells

that

cause

joint

swelling.

METHOTREXATE SUBCUTANEOUS therapy is used

to control psoriasis and

rheumatoid arthritis but it will not

cure them. Some normal

cells in the body may be affected

as well.

Ask your doctor if you have any questions about why it

been prescribed for you.

When it should not be used:

Do not take METHOTREXATE SUBCUTANEOUS if

you:

Are allergic to methotrexate or any component of

drug (see What the nonmedicinal ingredients

are).

Some of the symptoms of an allergic reaction

methotrexate may include rash, itching or hives

on the

skin, swelling of the face, lips, tongue or other

parts of

body,

shortness

of breath,

wheezing

or troubled

breathing.

Have any blood disorders including:

bleeding

from

lack

blood

cells

called

platelets.

low iron in the blood (anemia).

Have an immune system disorder such as AIDS

(autoimmune

deficiency

syndrome)

HIV,

virus

which causes AIDS.

Have an infection.

Have severe kidney problems.

Have severe liver disorder.

Suffer from alcoholism or alcoholic liver disease.

Have a stomach ulcer.

Have inflammation and bleeding from the rectum,

with

abdominal pain and diarrhea (ulcerative colitis).

Are pregnant (see section “Pregnancy and Fertility”).

breastfeeding

(see

section

“Pregnancy

Fertility”).

You are on dialysis

You are going to receive a general anesthetic called

nitrous oxide. It is also known as laughing gas.

What the medicinal ingredient is:

Methotrexate (meth-o-TREX-ate).

What the nonmedicinal ingredients are:

Sodium

chloride,

sodium

hydroxide

water

injection.

What dosage forms it comes in:

METHOTREXATE

SUBCUTANEOUS (methotrexate

injection)

mL (as

methotrexate

sodium)

available in single-use pre-filled syringes.

METHOTREXATE SUBCUTANEOUS is available as

follows;

1 mL syringe with 0.15 mL solution for

injection,

equivalent to 7.5 mg methotrexate

1 mL syringe with 0.2 mL solution for injection,

equivalent to 10 mg methotrexate

1 mL syringe with 0.25 mL solution for injection,

equivalent to 12.5 mg methotrexate

1 mL syringe with 0.3 mL solution for

injection,

equivalent to 15 mg methotrexate

1 mL syringe with 0.35 mL solution for injection,

equivalent to 17.5 mg methotrexate

1 mL syringe with 0.4 mL solution for

injection,

equivalent to 20 mg methotrexate

1 mL syringe with 0.45 mL solution for injection,

equivalent to 22.5 mg methotrexate

1 mL syringe with 0.5 mL solution for

injection,

equivalent to 25 mg methotrexate

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

should

plan

have

children

while

taking

METHOTREXATE SUBCUTANEOUS

or for a while after

stopping

treatment.

(Talk

to your doctor for further

details.)

Use a reliable method of birth control to prevent

pregnancy.

Before Using This Medicine

Before you begin treatment with METHOTREXATE

SUBCUTANEOUS, you should talk to your doctor

about

the good this medicine will do as well as the

risks of using

In deciding to use a medicine, the risks of taking the

medicine must be weighed against the good it will do.

IMPORTANT PLEASE READ

Page 30 of 33

This

is a decision you and your doctor will make. For

METHOTREXATE SUBCUTANEOUS, the following

should be

considered:

Allergies:

Tell your doctor if you have ever had any unusual

allergic reaction to methotrexate.

Pregnancy and Fertility:

Tell your doctor if you are pregnant or if you plan to

have

children.

METHOTREXATE

SUBCUTANEOUS during pregnancy

or if you are

trying to become pregnant. Methotrexate

can cause

birth

defects,

harm

unborn

child

cause

miscarriage. It is associated with malformations of

skull, face, heart and blood vessels, brain and

limbs.

Therefore,

very

important

that

methotrexate is not

given to pregnant patients or

patients planning to

become pregnant. In women of

child-bearing age, any

possibility of pregnancy must

excluded

with

appropriate

measures,

e.g.

pregnancy test before

starting treatment.

You must avoid becoming pregnant whilst taking

methotrexate

from

months

year

after

treatment

is stopped by using reliable contraception

throughout

this time. If you do become pregnant

during treatment

or suspect you might be pregnant,

speak to your doctor

as soon as possible. You should

be offered advice

regarding the risk of harmful

effects on the child

through treatment. Tell your

doctor right away if you

think you have become

pregnant

while

taking

METHOTREXATE

SUBCUTANEOUS.

If you wish to become pregnant you should consult

your doctor, who may refer you for specialist

advice

before the planned start of treatment.

Methotrexate temporarily affects sperm and egg

production. Methotrexate can cause miscarriage and

severe birth defects. You must avoid becoming

pregnant

when

using

methotrexate

months

to one year after treatment has stopped.

Male Fertility

Methotrexate may be genotoxic. This means that the

medicine may cause genetic mutation. Methotrexate

can affect sperm production with the potential to

cause

birth defects. Therefore, you should avoid

fathering a

child or to donate semen whilst taking

methotrexate

and from 6 months to one year after

treatment is

stopped.

Breast-feeding:

Stop breast feeding prior to and during treatment

with

METHOTREXATE SUBCUTANEOUS.

Children:

METHOTREXATE SUBCUTANEOUS is not for

use in

children.

Older adults:

Side effects may be more likely to occur in the

elderly,

who are usually more sensitive to the effects

METHOTREXATE SUBCUTANEOUS.

Other medicines:

When

taking

METHOTREXATE

SUBCUTANEOUS, it is important that your doctor

know if you are taking any other prescription or

non-

prescription medicine. They should also be

told if you

have ever been treated with x-rays or

cancer

medicines or if you drink alcohol.

Other medical problems:

The presence of other medical problems may affect the use

of METHOTREXATE

SUBCUTANEOUS. Tell

your

doctor if you

have any other medical problems, especially:

Alcohol abuse (or history of)

Chickenpox

(including

recent

exposure)

Herpes

zoster (shingles)

Colitis

Disease of the immune system

Gout (or history of)

Kidney stones (or history of)

Infection

Intestine blockage

Kidney disease

If you are dehydrated or have a lot of

vomiting,

diarrhea, or sweating.

Liver disease, including hepatitis B and C infection

Mouth sores or inflammation

Stomach ulcer

Precautions while using this medicine

It is very important that your doctor check your progress

regular visits to make sure that

this

medicine

working

properly and to check for unwanted effects.

Do not drink alcohol while taking METHOTREXATE

SUBCUTANEOUS. Alcohol can increase the chance of

liver problems.

Some

patients

take

METHOTREXATE

SUBCUTANEOUS

become

more

sensitive

sunlight than they are

normally. Avoid too much sun

exposure and do not use a

sunlamp until you see how you

react to the sun, especially

if you tend to burn easily.

You should not receive certain vaccinations while taking

METHOTREXATE

SUBCUTANEOUS. Discuss this

with your

doctor. Avoid anyone who has had oral polio

vaccine for at

least six weeks. Do not get close to them or

stay in the same

room for very long. If this is not possible,

IMPORTANT PLEASE READ

Page 31 of 33

wear a mask over

your nose and mouth.

Some side effects such as dizziness and fatigue may affect

the ability to drive or operate machinery. These activities

should be avoided. If you have any concerns, please

consult

your doctor.

METHOTREXATE SUBCUTANEOUS can lower the

number of

white blood cells in your blood temporarily,

increasing the

chance of getting an infection. It can also

lower the number

of platelets, which are necessary for

proper blood clotting.

If this happens, there are certain

precautions you can take,

especially when your blood

count is low to reduce the risk

of infection or bleeding:

If you can, avoid people with infections. Check with

your doctor immediately if you think you are getting

an infection or if you get a fever or chills, cough or

hoarseness, lower back or side pain, or painful or

difficult urination.

Check with your doctor immediately if you notice

unusual bleeding or bruising; black, tarry stools;

blood

in urine or stools; or pinpoint red spots on

your skin.

Be careful when using a regular toothbrush, dental

floss, or toothpick. Check with your doctor before

having any dental work done.

Do not touch your eyes or the inside of your nose

unless you have just washed your hands.

Be careful not to cut yourself when you are using

sharp objects such as scissors or a razor.

Avoid

contact

sports

other

situations

where

bruising

or injury could occur.

Methotrexate can cause sudden bleeding in the lungs.

This

is called Pulmonary alveolar haemorrhage. If you

suddenly spit or cough up blood you must go to the

hospital

right away. You will need emergency care. This

occurs in

patients with some existing health problems.

Some

examples are rheumatic disorder (such as pain in

your

joints) or vasculitis such as swelling in an artery or

vein.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor and pharmacist what prescription and

non-

prescription

medications

taking.

METHOTREXATE

SUBCUTANEOUS

may interact

with other medicines such

acetyl salicyclic acid (ASA) and other pain killers

nonsteroidal

anti-inflammatory

drugs

(NSAIDs)

some antibiotics (including penicillins tetracycline,

and sulfonamides, and medicines to prevent malaria

pyrimethamine)

some epilepsy treatments

some cancer treatments

some vaccines

some medicines used to lower your cholesterol

(including cholestyramine)

azathioprine (used to prevent transplant

organ

rejection)

cytarabine (used to treat leukemia)

leflunomide (used to treat rheumatoid arthritis)

mercaptopurine (used to treat leukemia)

nitrous oxide anaesthesia

probenicid (used to treat gout)

retinoid medicines (used to treat acne)

sulfonylureas (used to treat diabetes)

sulfasalazine

(used

treat

Crohn's

disease,

rheumatoid arthritis and ulcerative colitis)

theophylline (used to treat asthma)

the vitamin folic acid

phenytoins

proton pump inhibitors (PPI). They are drugs used to

treat acid related stomach problems. Some PPIs are

omeprazole, esomeprazole, and pantoprazole.

amiodarone (used to treat irregular heart beat)

triamterene (diuretic or “water pill”)

PUVA therapy (used to treat skin conditions)

It is very important to tell your doctor about all other

medicines you are taking including those you buy without

prescription. You may need to receive different amounts

your medicine or you may need to receive different

medicines.

Tell any doctor that is treating you that you are taking

METHOTREXATE SUBCUTANEOUS.

If you have not told your doctor or pharmacist about any

above,

tell

them

before

given

METHOTREXATE SUBCUTANEOUS.

PROPER USE OF THIS MEDICATION

Take METHOTREXATE SUBCUTANEOUS only as

Do not take METHOTREXATE SUBCUTANEOUS

if you are

going to receive a general anesthetic called

nitrous oxide.

It is also known as laughing gas. When

used together,

they can cause:

Myelosupression (a condition in which the

bone

marrow cannot make enough blood

cells),

Mouth sores,

Inflammation of the mouth,

Inflammation of the kidneys,

Damage to the nervous system

IMPORTANT PLEASE READ

Page 32 of 33

directed by

your doctor. Do not take more or less of it,

and do not take

it more often than your doctor ordered.

exact

amount

medicine

need

been

carefully worked out. Taking

too much may increase the

chance of side effects, while

taking too little may not

improve your condition.

The dose is given once a week only. It is given by your

health care professional.

Each METHOTREXATE SUBCUTANEOUS syringe

can be used

only one time.

While

using

METHOTREXATE

SUBCUTANEOUS, your

doctor may want you to drink

extra fluids so that you will

pass more urine. This will

help the drug to pass from the

body, and will prevent

kidney problems and keep your

kidneys working well.

METHOTREXATE

SUBCUTANEOUS

commonly

causes nausea

and vomiting. Even if you begin to feel ill,

do not stop

using this medicine without first checking

with your doctor.

Ask your doctor for ways to lessen these

effects.

Always keep the syringe out of the reach of children.

Usual adult dose:

The dose

of METHOTREXATE

SUBCUTANEOUS

will be

different for different patients. The dose that is

used may

depend on a number of things, including what

the medicine

is being used for, the patient's size,

whether or not

other medicines are also being taken. If

have

questions

about

proper

dose

METHOTREXATE

SUBCUTANEOUS,

your

doctor.

The doctor may decrease your dose if you have problems

with your kidneys.

Overdose

think

have

taken

much

METHOTREXATE SUBCUTANEOUS, contact your

healthcare professional, hospital emergency department

or regional poison control centre immediately, even if

there are no symptoms.

Missed Dose

If you missed a scheduled dose, or have any doubts

concerns

about

missed

doses,

contact

your

doctor for

instruction

SIDE EFFECTS AND WHAT TO DO ABOUT

THEM

Along

with

their

needed

effects,

medicines

like

METHOTREXATE SUBCUTANEOUS can sometimes

cause

unwanted effects. Also, because of the way these

medicines

act on the body, there is a chance that they

might cause

other unwanted effects that may not occur

until months or

years after the medicine is used. These

delayed effects may

include certain types of cancer, such

as leukemia. Discuss

these possible effects with your

doctor.

The most common side effects include:

Upset stomach, stomach pain, vomiting, nausea,

loss

appetite,

dizziness,

chills

fever,

diarrhea or

sores on lips or mouth.

A fall in the number of white blood cells. This may

reduce your resistance to infection and increase

your

chances of cold sores, blood poisoning or

swelling of

blood vessels.

Less common side effects are:

Headaches, hair loss, mood changes, confusion,

ringing in the ears, sore eyes, skin rashes.

A fall in the number of other blood cells. This may

increase

your

chances

bruising,

bleeding

tiredness.

Damage to the lungs.

Harm to the unborn baby.

Rarely and generally at higher doses for treatment of other

diseases, METHOTREXATE

SUBCUTANEOUS can

cause other

side effects including:

Liver damage, kidney damage, pain or difficulty

urinating, lower back or side pain, blood in urine or

stools, dark urine

Fits, blurred vision, short term blindness

Drowsiness, weakness

Hoarseness

Bloody vomit, black tarry stools or pin-point red

spots on the skin

Reddening or whitening of the skin, acne,

boils,

itching yellow skin or eyes

Impotence

loss

interest

sex,

decreased

fertility,

abortion

Diabetes, thinning of the bones, painful muscles

joints

More rarely, it can cause:

Skin rash and other skin disorders.

Cancer of lymph glands, sudden death.

Severe allergic reactions.

Lymphoproliferative

disorders

(excessive

growth of

white blood cells.

Although the frequency is unknown, it can cause:

Bone damage in the jaw (secondary to excessive

growth of white blood cells).

IMPORTANT PLEASE READ

Page 33 of 33

Bleeding from the lungs.

Methotrexate can cause abnormal test results. Your doctor

will decide when to perform tests and will interpret the

results. This includes blood and urine tests to check how

your kidneys are working.

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

seek

immediate

medical help

Only if

severe

In all

cases

Common

Diarrhea or

mouth ulcers

Sore throat, fever,

chills, or swelling of

glands

Inflammation of

the lungs: Persistent

dry, non- productive

cough, shortness of

breath and fever.

Less

common

Chest pain, cough,

shortness of breath or

fever

Unusual bleeding or

bruising

Rare

Signs of severe

allergic

reaction:

Skin rash, itching,

chest

tightness,

wheezing, dizziness,

hives, faintness,

rapid

heartbeat,

shortness of breath,

and/or a swollen

face, lips or tongue

Pain or difficulty

urinating, lower back

or side pain, blood in

urine

or stools, dark

urine

Renal Failure/

kidney damage

(inability of the

kidneys to work

properly): swelling

of the

hands, ankles

or feet. Nausea,

vomiting.

Blood in the

urine.

Changes in

frequency or amount

of urine.

Unknown

Pulmonary alveolar

haemorrhage:

suddenly spit or

cough up blood

This is not a complete list of side effects.

For any

unexpected

effects

while

taking

METHOTREXATE

SUBCUTANEOUS, contact your doctor or pharmacist.

HOW TO STORE IT

Store

METHOTREXATE

SUBCUTANEOUS

between 15- 25°C. Any unused solution should be

discarded.

Keep out of the reach and sight of children.

Store it at room temperature and away from heat and

direct light. Avoid freezing.

Do not keep outdated medicine or medicine no

longer needed. Be sure that any discarded medicine

is out of the reach and sight of children.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting

page

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: Should you require information related to the

management

of

side

effects,

contact

your

health

professional. The Canada Vigilance Program does

not provide medical advice.

. MORE INFORMATION

If you want more information about METHOTREXATE

SUBCUTANEOUS:

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://www.canada.ca/en/health-

canada/services/drugs-health-products/drug-

products/drug-product-database.html

calling the sponsor Accord Healthcare Inc. at 1-866-

296-0354.

This leaflet was prepared by:

Accord Healthcare Inc.

3535 boul. St. Charles, Suite 704

Kirkland, QC, H9H 5B9

Canada

Date prepared: August 2, 2019

Similar products

Search alerts related to this product

View documents history

Share this information