Methotrexate (Systemic)


VA CLASSIFICATION
Primary: DE801
Secondary: MS103

Commonly used brand name(s): Folex; Folex PFS; Methotrexate LPF; Rheumatrex.

Another commonly used name is
amethopterin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipsoriatic (systemic)—

antirheumatic (disease-modifying)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


General considerations
Due to the possibility of serious toxic and sometimes fatal reactions, methotrexate should be used only in patients who are not adequately responsive or who are intolerant to other forms of therapy. Caution is also recommended in the long-term use of this agent.{04}{05}

Accepted

Psoriasis (treatment)—Methotrexate is indicated only for treatment of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy, as confirmed by biopsy and/or dermatologic consultation. It is important to rule out that a psoriasis 'flare' is not caused by an undiagnosed disease affecting immune responses.{04}{05}{06}

Arthritis, rheumatoid (treatment)—Methotrexate tablets are indicated [and the parenteral dosage forms are used]1 in the treatment of selected cases of severe or active rheumatoid arthritis not adequately responsive to other forms of therapy. {04}{05}{06}

[Arthritis, psoriatic (treatment)]—Methotrexate is being used in the treatment of selected cases of active severe psoriatic arthritis.{06}

[Dermatomyositis, systemic (treatment) ]1—Methotrexate is used for treatment of systemic dermatomyositis (polymyositis) {03}.

[Seronegative arthritides]—Methotrexate is indicated in the treatment of severe disabling seronegative arthritides.{06}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    454.44

Mechanism of action/Effect:

Methotrexate is an antimetabolite of the folic acid analog type. Methotrexate is cell cycle–specific for the S phase of cell division. Activity is due to inhibition of DNA, RNA, thymidylate, and protein synthesis as a result of relatively irreversible binding with dihydrofolate reductase, which prevents reduction of dihydrofolate to the active tetrahydrofolate. Growth of rapidly proliferating cells (epithelial cells in psoriasis, bone marrow, fetal cells, buccal and intestinal mucosa, cells of the urinary bladder, spermatogonia) is affected more than growth of most normal tissues and skin.


Other actions/effects:

Also has mild immunosuppressant activity.

Absorption:

Widely variable {02}.

Distribution:

Crosses the blood-brain barrier (from blood to central nervous system [CNS]) in only limited amounts (dose-related {02}); however, passes significantly into systemic circulation after intrathecal administration.

Protein binding:

Moderate (approximately 50%), primarily to albumin {02}.

Biotransformation:

Hepatic; intracellular (to polyglutamates, which are retained in the cells).

Half-life:


Terminal:

Low doses: 3 to 10 hours.

High doses: 8 to 15 hours.

Note: There is wide interindividual variation in clearance rates. Small amounts of methotrexate and metabolites are bound and may remain in tissues (kidneys, liver) for weeks to months; the presence of fluids such as ascites or pleural effusion will also delay clearance.



Time to peak serum concentration

Oral—1 to 2 hours.

Intramuscular—30 to 60 minutes.

Elimination:


Single dose—
        Renal (unchanged), 80 to 90% in the first 24 hours; some accumulation of polyglutamates in tissues occurs with repeated doses {1a}.
        Biliary, 10% or less.



Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Antimetabolites have been shown to be carcinogenic in animals, and may be associated with an increased risk of development of secondary carcinomas in humans, although the risk appears to be less than with alkylating agents.

Carcinogenicity studies with methotrexate in animals have been inconclusive. However, there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells.

Pregnancy/Reproduction
Fertility—
Methotrexate appears to have only a slight effect on gonadal function; however, reversible impairment of fertility, defective oogenesis and spermatogenesis, and menstrual function impairment have been reported.

Pregnancy—
Methotrexate crosses the placenta and has been shown to cause adverse effects on the fetus. Methotrexate is a potent abortifacient.

Use as an antipsoriatic or antiarthritic agent is contraindicated in pregnant women.

FDA Pregnancy Category X.

Breast-feeding

Methotrexate is distributed in breast milk in concentration ratio up to 0.08:1 (breast milk to plasma){04}{05}{06}; breast-feeding is not recommended while methotrexate is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Caution should be used in neonates and infants because of reduced renal and hepatic function.


Geriatrics


Although appropriate studies with methotrexate have not been performed in the geriatric population, caution should be used in the elderly because of possible reduced renal and hepatic function and reduced folate stores. Dosage adjustment, especially on the basis of renal function, may be necessary.


Dental

The bone marrow depressant effects of methotrexate may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Methotrexate also commonly causes ulcerative stomatitis, gingivitis, and pharyngitis associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» Hepatotoxic medications, other (See Appendix II )    (concurrent use may increase the risk of hepatotoxicity)


Anticoagulants, coumarin- or indandione-derivative    (methotrexate may increase anticoagulant activity and/or increase the risk of hemorrhage as a result of decreased hepatic synthesis of procoagulant factors and interference with platelet formation)


» Anti-inflammatory analgesics, nonsteroidal (NSAIAs)     (concurrent use of phenylbutazone with methotrexate may increase the risk of agranulocytosis or bone marrow depression and is not recommended; also, phenylbutazone may displace methotrexate from its protein-binding sites and decrease its renal clearance, leading to increased methotrexate plasma concentration and risk of toxicity. If concurrent use with phenylbutazone cannot be avoided, especially careful monitoring of the patient for plasma methotrexate concentrations {02} or signs of methotrexate toxicity and/or adequacy of renal function is recommended)

    (although not well documented, the possibility exists that other NSAIAs may also decrease methotrexate excretion and increase its plasma concentration to potentially toxic levels)

    (severe, sometimes fatal, methotrexate toxicity has also been reported with low to moderate doses in patients receiving diclofenac, indomethacin, naproxen, or phenylbutazone; it is recommended that use of NSAIAs with low to moderate doses of methotrexate be undertaken with caution, with methotrexate dosage being adjusted by monitoring plasma methotrexate concentrations and/or adequacy of renal function)


Blood dyscrasia–causing medications (See Appendix II )    (leukopenic and/or thrombocytopenic effects of methotrexate may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of methotrexate, if necessary, should be based on blood counts)


» Bone marrow depressants, other (See Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Folic acid    (may interfere with the antifolate effects of methotrexate)


Neomycin, oral    (may decrease absorption of oral methotrexate)


Penicillins    (may reduce the renal clearance of methotrexate and increase serum concentration with corresponding hematologic and gastrointestinal toxicity; careful monitoring is recommended{04}{05})


» Probenecid    (concurrent use may inhibit renal excretion of methotrexate and result in toxic plasma concentrations; if used concurrently with probenecid, methotrexate dosage should be decreased, the patient observed for signs of toxicity, and/or plasma methotrexate concentrations monitored)


Pyrimethamine or
Triamterene or
Trimethoprim    (concurrent use may rarely increase the toxic effects of methotrexate because of similar folic acid antagonist actions)


» Salicylates and other weak organic acids    (concurrent use may inhibit renal tubular secretion of methotrexate and result in toxic plasma concentrations; salicylates may also increase plasma concentrations by displacing methotrexate from binding sites; if methotrexate is used concurrently with these medications, the patient should be observed for signs of toxicity and/or methotrexate plasma concentration monitored)


Theophylline    (methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate{04})

{05}
Sulfonamides    (in addition to increased risk of hepatotoxicity that may occur when sulfonamides are used concurrently with other hepatotoxic medications, medications that cause displacement from plasma protein binding may theoretically produce toxic plasma concentrations of methotrexate when used concurrently, although clinical significance has not been established)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by methotrexate therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by methotrexate therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the methotrexate therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Assay for folate    (methotrexate may inhibit the organism used in the assay and interfere with detection of folic acid deficiency)

With physiology/laboratory test values
Isocitric acid dehydrogenase (ICD) concentrations    (may be increased, indicating hepatotoxicity)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Bone marrow depression
» Hepatic function impairment, severe
» Immunodeficiency
» Renal function impairment, severe
Risk-benefit should be considered when the following medical problems exist
» Ascites or
Gastrointestinal obstruction or
» Pleural or peritoneal effusions or
» Renal function impairment    (risk of methotrexate toxicity is increased because elimination of methotrexate may be impaired and accumulation may occur; even small doses may lead to severe myelosuppression and mucositis)

    (a lower dosage of methotrexate and careful monitoring of plasma or serum methotrexate concentrations are recommended for patients with impaired renal function)


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Folate deficiency{04}{05}{06}    (may increase methotrexate toxicity)


» Hepatic function impairment
» Infection
» Mucositis, oral
Nausea and vomiting    (inadequate hydration secondary to severe nausea and vomiting may result in increased methotrexate toxicity)


» Peptic ulcer
Sensitivity to methotrexate
» Ulcerative colitis
» Caution should be used also in patients who have had previous cytotoxic drug therapy and radiation therapy, and in cases of general debility.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood urea nitrogen (BUN) concentrations and
Creatinine clearance {03} and/or
Serum creatinine concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Examination of patient's mouth for ulceration    (recommended before administration of each dose)


» Hematocrit or hemoglobin and
» Platelet count and
» Total and, if appropriate, differential leukocyte count     (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Liver biopsy    (may be useful during long-term therapy or if hepatic function test results are abnormal; also recommended in patients who have received a cumulative dose of 1500 mg {1c} {03})


» Serum alanine aminotransferase (ALT [SGPT]) concentrations and
» Serum aspartate aminotransferase (AST [SGOT]) concentrations and
» Serum bilirubin concentrations and
» Serum lactate dehydrogenase (LDH) concentrations    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Incidence and severity of side effects, particularly hepatotoxicity, appear to be related to dosage frequency and duration of methotrexate therapy. Toxicity tends to occur less frequently and be less severe with a total dose administered as intermittent weekly dosage than with prolonged daily dosage.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Gastrointestinal ulceration and bleeding, enteritis, or intestinal perforation, which may be fatal (diarrhea; stomach pain)
    
leukopenia, bacterial infection, or septicemia (usually asymptomatic; rarely, fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
    
severe acute methotrexate toxicity, cutaneous vasculitis, or reactivation of sunburn or increased erythematous response to ultraviolet therapy (reddening of skin)
    
ulcerative stomatitis, gingivitis, or pharyngitis (sores in mouth and on lips )

Note: With leukopenia and thrombocytopenia, the nadir of the leukocyte and platelet counts occurs after 7 to 10 days, with recovery 7 days later.


Incidence rare
—dose-related     
Central nervous system (CNS) effects, increased cerebrospinal fluid pressure, leukoencephalopathy, demyelination, or chemical arachnoiditis ( back pain; blurred vision; convulsions {1a} ; dizziness; drowsiness; fever; headache; unusual tiredness or weakness)
    
hepatotoxicity, including liver atrophy
necrosis
cirrhosis
fatty changes
periportal fibrosis (yellow eyes or skin )
    
pericarditis{04}{06} (chest pain)
    
pneumonitis, potentially fatal {1a} , or pulmonary fibrosis
pneumocystis carinii pneumonia {04}{05}{06}(cough ; shortness of breath; fever)

Incidence rare
—non–dose-related    
Epidermal necrolysis
Stevens-Johnson syndrome
exfoliative dermatitis
skin necrosis
erythema multiforme (dead or loose skin layers, ; red blisters, ulcers on lips, mouth, eye, nasal passages, and genital area,; reddening of skin with or without hair loss){04}{06}
    
plaque erosion, painful (painful peeling of skin patches)— in the treatment of psoriasis{04}
    
Soft tissue and bone necrosis ( sloughing of skin, muscle and bone)— following radiation therapy
{04}


Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Acne
    
boils
    
loss of appetite
    
nausea
    
pale skin
    
skin rash or itching
    
vomiting



Those not indicating need for medical attention
Incidence less frequent or rare
    
Loss of hair





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
Specific treatment—Leucovorin is used to minimize the toxicity and counteract the effect of methotrexate overdose. Leucovorin therapy should begin as soon as possible in order to maximize its effectiveness. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment of leucovorin.{04}{05}{06}

To enhance elimination—Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, acute, intermittent hemodialysis using a high-flux dialyzer has been reported to effectively clear methotrexate.{04}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Methotrexate—For Noncancerous Conditions (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to methotrexate

Pregnancy—Use not recommended because of teratogenic, abortifacient, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects





Use in children—Newborns and other infants may be more sensitive to effects






Use in the elderly—Side/adverse effects may be more frequent
Other medications, especially alcohol or other hepatotoxic medications, nonsteroidal anti-inflammatory drugs (NSAIDs), other bone marrow depressants, probenecid, salicylates, or previous cytotoxic drug therapy or radiation therapy
Other medical problems, especially hepatic function impairment, renal function impairment, chickenpox, herpes zoster, infection, oral mucositis, peptic ulcer, or ulcerative colitis

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Frequency of nausea; importance of continuing medication despite stomach upset; checking with physician if vomiting occurs

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Not taking at all; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding alcoholic beverages, which may increase hepatotoxicity

Possible photosensitivity reactions; avoiding too much unprotected exposure to sun or overuse of sunlamp

» Avoiding salicylate-containing products and NSAIDs, which may increase toxicity

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problems; stomach, kidney, or liver problems; loss of hair; or cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially gastrointestinal ulceration and bleeding, enteritis, intestinal perforation, leukopenia, bacterial infection, septicemia, thrombocytopenia, severe acute methotrexate toxicity, cutaneous vasculitis, reactivation of sunburn or reaction to ultraviolet light, ulcerative stomatitis, gingivitis, pharyngitis, CNS effects, hepatotoxicity, pericarditis, pneumonitis, pulmonary fibrosis , and pneumocystis carinii pneumonia

Epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, and soft tissue and bone necrosis following radiation therapy are reported in patients regardless of their dose or indication. Painful plaque erosion is reported in the treatment of psoriasis regardless of the dose.

Physician or nurse can help in dealing with side effects

Possibility of hair loss; should return after treatment has ended


General Dosing Information
Patients receiving methotrexate should be under supervision of a physician experienced in antimetabolite chemotherapy.

In general, use of intermittent courses of methotrexate is associated with less risk of serious toxicity than prolonged daily dosage.

It is recommended that methotrexate therapy be interrupted if diarrhea or ulcerative stomatitis occurs, because of the risk of hemorrhagic enteritis and fatal intestinal perforation {04}{05}{06}.

It is recommended that methotrexate therapy be interrupted if pulmonary symptoms (especially a dry, unproductive cough) occur, because of the risk of potentially irreversible pulmonary toxicity {04}{05}{06}.

If bone marrow depression occurs, withdrawal of methotrexate is recommended {1a}. The following precautions may also be useful:    • Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of methotrexate. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
   • Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.



For use as an antipsoriatic
After a favorable response is obtained, it is recommended that the dosage be decreased gradually to the lowest dosage and longest rest period that will maintain an adequate clinical response. To reduce the methotrexate requirement, it is recommended that an attempt be made to return to conventional therapy or to concomitant topical conventional therapy as soon as possible.{04}{05}{06}

For use as an antirheumatic
Methotrexate appears to be effective by the oral, intramuscular, or intravenous route; however, oral administration is associated with less toxicity.

For parenteral use
Methotrexate may be administered intramuscularly or intravenously (rapid or continuous infusion).


Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral cytotoxic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:
   • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

METHOTREXATE TABLETS USP

Usual adult dose
Psoriasis or
[ Psoriatic arthritis]


Initial weekly dose schedule:
Oral, initially 10 to 25 mg once weekly until adequate response is achieved.{04}{05}{06} The dose may be increased as necessary in increments of 2.5 mg per week{03} up to 30 mg{04}{05}{06} to [ 50 mg] {07}{08}per week.



Initial divided dose schedule:
Oral, initially 2.5 to 5 mg every twelve hours for three doses {02} once a week. The dose may be increased as necessary in increments of 2.5 mg per week{03} up to a maximum of 30 mg per week.{04}{05}{06}{08}


Rheumatoid arthritis


Initial weekly dose schedule:
Oral, initially 7.5 mg once weekly.{04}{05}{06} The dose may be increased as necessary in increments of 2.5 mg per week{03} up to 20 mg per week.{04}{05}{06}{08}



Divided dose schedule:
Oral, initially 2.5 to 5 mg every twelve hours for three doses {02} once a week. The dose may be increased as necessary in increments of 2.5 mg per week{03} up to a maximum of 20 mg per week.{04}{05}{06}{08}



Note: Some clinicians recommend an initial test dose at the lowest dosage level because of interindividual variation in sensitivity to methotrexate {03}.


Usual adult prescribing limits
Psoriasis— 30 mg{04}{05}{06}{07} to [50 mg]{07}{08} per week should not ordinarily be exceeded.
Rheumatoid arthritis—20 mg per week should not ordinarily be exceeded. A significant increase in the incidence and severity of toxic effects, especially bone marrow suppression, was seen at doses greater than 20 mg per week{04}{05}{06}{07}{08}

Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Rheumatrex{04}][Generic]

Canada—


2.5 mg (Rx) [Rheumatrex (dye and tartrazine-free){06}][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container and protect from light.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • Do not take other medicines without advice from your doctor.
   • Avoid overexposure to sun.



Parenteral Dosage Forms

METHOTREXATE SODIUM INJECTION USP

Usual adult dose
Psoriasis or

[Rheumatoid arthritis]1—Intramuscular or intravenous, initially 10 mg (base) once a week, the dosage being increased as necessary up to 25 mg (base) once a week.

Note: Some clinicians recommend an initial test dose of 10 mg because of interindividual variation in sensitivity to methotrexate {03}.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


2.5 mg (base) per mL (Rx)[Generic] (with preservative)


25 mg (base) per mL (Rx) [Folex PFS (without preservative)] [Methotrexate LPF (preservative free)][Generic] ( with and without preservative)

Canada—


2.5 mg (base) per mL (Rx)[Generic] (with and without preservative)


10 mg (base) per mL (Rx)[Generic] (without preservative)


25 mg (base) per mL (Rx)[Generic] (with and without preservative)

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
Methotrexate Sodium Injection USP may be further diluted with an appropriate preservative-free medium such as 0.9% sodium chloride injection or 5% dextrose injection.

Stability:
If stored for 24 hours at a temperature of 21 to 25 °C (70 to 77 °F), a diluted solution of methotrexate sodium injection maintains 90% of its labeled potency. However, preservative-free solutions should be diluted immediately prior to use and any unused portion discarded {1a}.


METHOTREXATE SODIUM FOR INJECTION USP

Usual adult dose
Psoriasis or

[Rheumatoid arthritis]1—Intramuscular or intravenous, initially 10 mg (base) once a week, the dosage being increased as necessary up to 25 mg (base) once a week.

Note: Some clinicians recommend an initial test dose of 10 mg because of interindividual variation in sensitivity to methotrexate {03}.


Usual pediatric dose
Dosage has not been established.

Size(s) usually available:
U.S.—


20 mg (base) (Rx)[Generic] (without preservative)


25 mg (base) (Rx) [Folex (without preservative)]


50 mg (base) (Rx) [Folex (without preservative)][Generic] ( without preservative)


100 mg (base) (Rx) [Folex (without preservative)][Generic] ( without preservative)


250 mg (base) (Rx) [Folex (without preservative)][Generic] ( without preservative)


1 gram (base)[Generic] (without preservative)

Canada—


20 mg (base) (Rx)[Generic] (without preservative)

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Preparation of dosage form:
For intravenous or intramuscular use, methotrexate sodium for injection is diluted with 2 to 25 mL (depending on route of administration) of 0.9% sodium chloride injection (for Folex).Methotrexate sodium for injection may be further diluted with an appropriate sterile, preservative-free medium.{04}{09}

Stability:
Solutions without preservative should be freshly reconstituted immediately prior to each dose; any unused portion should be discarded.



Revised: 01/27/00



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Folex PFS package insert, Adria, 2/86.
  1. Methotrexate package insert, Lederle, 3/88.
  1. Reviewer comment, 1988 revision (used for 1989).
  1. Panel comments, 1989 revision.
  1. Product Information: Methotrexate sodium tablets, methotrexate sodium for injection, methotrexate LPF sodium (methotrexate sodium injection) and methotrexate sodium injection. ESI Lederle Inc., Philadelphia, PA, USA, rev 2/99, rec. 11/99.
  1. Product Information: Methotrexate tablets, USP. Barr Laboratories, Inc., Pomona, NY, USA, rev.6/98, rec. 11/99.
  1. Product Information: Methotrexate sodium in solution, methotrexate sodium powder, methotrexate tablets (Wyeth-Ayerst). In: Gillis, MC, (ed): CPS Compendium of pharmaceuticals and specialties, 34th ed. Canadian Pharmacists Association, Ottawa, Ontario, Canada; 1999:1030–1034.
  1. Product Information: Methotrexate tablets (Faulding). In: Gillis, MC, (ed): CPS Compendium of pharmaceuticals and specialties, 34th ed. Canadian Pharmacists Association, Ottawa, Ontario, Canada; 1999:1036–1039.
  1. Panel comment, 2000 revision.
  1. Manufacturer comment, (Wyeth–Ayerst Laboratories—US), 2000 revision.
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