Metoject (Medexus Pharmaceuticals, 7.5 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

METOJECT is indicated as a Disease Modifying Antirheumatic Drug (DMARD) in the following diseases where standard therapeutic interventions fail:

• Severe disabling psoriasis/psoriatic arthritis
• Severe disabling rheumatoid arthritis (RA)
• Severe disabling seronegative arthritides.

In the treatment of psoriasis, METOJECT 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 (≥65 years of age): 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 (<18 years of age): Safety and effectiveness in pediatric patients have not been established. Therefore, METOJECT should not be used as a DMARD in pediatric patients.

CONTRAINDICATIONS

METOJECT is contraindicated:

• In patients who are hypersensitive to this drug or to any ingredient in the formulation or 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).
• In pregnant patients with psoriasis or rheumatoid arthritis.
• In women of childbearing potential until pregnancy is excluded.
• In nursing mothers.
• In patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease.
• In patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes.
• In patients with psoriasis or rheumatoid arthritis who have 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

General

Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. It should be emphasized to the patient that the recommended dose is taken weekly for rheumatoid arthritis and psoriasis, and that daily use of the weekly recommended dose has led to fatal toxicity.

Fatal toxicities related to intravenous dosing miscalculation have been reported. Special attention must be given to dose calculation.

Because of the possibility of serious toxic reactions (which can be fatal), METOJECT should be used only in patients with severe, recalcitrant, disabling psoriasis or rheumatoid arthritis that are not adequately responsive to other forms of therapy. The patient should be informed by the physician of the risks involved and should be under a physician’s constant supervision.

Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on METOJECT 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 METOJECT 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 may induce “tumour lysis syndrome” in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

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.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with non-steroidal anti-inflammatory drugs (NSAIDs) (see DRUG INTERACTIONS, Drug-Drug Interactions).

Bone marrow and mucosal toxicity depend on dose and duration of exposure of high levels (>2x10^-8 mol/L (0.02 micromolar)) of methotrexate. Since the critical time factor has been defined for these organs as being 42 hours in humans, this has the following implications:

• when high doses of methotrexate are employed (>1g/m²), drug levels in serum should be monitored
• when drug levels exceeding 2 x 10^-8 mol/L (0.02 micromolar) for >42 hours may forecast significant toxicity
• when toxicity can be minimized by appropriate administration of Leucovorin Calcium
• when high-dose methotrexate (HDMTX) is employed, it is imperative to alkalinise the urine in order to prevent crystallisation of methotrexate and its 7-hydroxy metabolite in the urine, which may lead to acute renal failure.

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

METOJECT should be used with extreme caution in the presence of debility.

Drug Interactions with Proton Pump Inhibitors (PPI)

Use caution when administering high dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. 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.

Carcinogenesis and Mutagenesis

Malignant lymphomas may occur in patients receiving low-dose methotrexate. These lymphomas may regress following withdrawal of methotrexate without requiring treatment.

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 and human bone marrow cells, the clinical significance remains uncertain. Assessment of the carcinogenic potential of methotrexate is complicated by conflicting evidence of an increased risk of certain tumours in rheumatoid arthritis. Benefit should be weighed against this potential risk before using METOJECT alone or in combination with other drugs, especially in young adults. (See TOXICOLOGY).

Gastrointestinal

If vomiting, diarrhea, or stomatitis occurs, resulting in dehydration, METOJECT should be discontinued until recovery occurs. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. METOJECT should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.

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).

Hematologic

METOJECT should be used with caution in patients with impaired bone marrow function and previous or concomitant wide field radiotherapy. Methotrexate may produce marked bone marrow depression with resultant anemia, aplastic anemia, pancytopenia, leucopenia, neutropenia, and/or thrombocytopenia. In controlled clinical trials in rheumatoid arthritis (n=128), leucopenia (WBC <3000/mm³) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm³) in 6 patients, and pancytopenia in 2 patients.

The nadir of circulating leukocytes, neutrophils and platelets usually occurs between 5 and 13 days after an IV bolus dose (with recovery between 14 to 28 days). Leukocytes and neutrophils may occasionally show two depressions, the first occurring in 4-7 days and a second nadir after 12-21 days, followed by recovery. Clinical sequel such as fever, infections and hemorrhage from various sites may be expected.

In psoriasis and rheumatoid arthritis, METOJECT should be stopped immediately if there is a significant drop in blood counts. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.

Hepatic/Biliary/Pancreatic

Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Acutely, liver enzyme elevations are frequently seen after methotrexate administration and are usually not a reason for modification of methotrexate therapy. Liver enzyme elevations are usually transient and asymptomatic, and also do not 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 of at least 1.5 grams. Liver biopsy after sustained use 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 are usually recommended for psoriatic patients who are 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 METOJECT, clinical and laboratory evaluation should be performed to evaluate preexisting hepatitis virus B and hepatitis virus C infection. METOJECT 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. 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 1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to 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 METOJECT 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 METOJECT 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).

If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), METOJECT may be continued and the patient monitored according to the recommendations listed above. METOJECT should be 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

METOJECT should be used with extreme caution in the presence of active infection, and is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes (see CONTRAINDICATIONS).

Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. Hypogammaglobulinemia has been reported rarely.

Neurologic

There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intravenous methotrexate (1 g/m²). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.

Chronic leukoencephalopathy has also been reported in patients with osteosarcoma who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. There are also reports of leukoencephalopathy in patients who received low oral doses (4-8 mg/week) of methotrexate therapy for rheumatoid arthritis or psoriatic arthritis.

Discontinuation of METOJECT does not always result in complete recovery.

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.

Intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.

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 intravenous cytarabine.

Renal

Methotrexate is contraindicated in patients with severe renal impairment including end stage renal disease with and without dialysis (see CONTRAINDICATIONS and 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. Cases of pleural effusion with or without interstitial pneumonitis have also been reported at any time during therapy at low doses. Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific 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.

Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii should be considered.

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.

Sexual Function/Reproduction

Methotrexate causes embryotoxicity, abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy (see TOXICOLOGY). The risk of effects on reproduction should be discussed with both male and female patients taking METOJECT. (See TOXICOLOGY).

Skin

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’s Syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular or intravenous methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic diseases, 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: METOJECT is contraindicated in pregnant patients with psoriasis or rheumatoid arthritis (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS: Serious Warnings and Precautions). Methotrexate has been reported to cause impairment of fertility, oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of therapy. Methotrexate can cause fetal death, embryotoxicity, abortion, or teratogenic effects when administered to a pregnant woman.

METOJECT is contraindicated in women of childbearing potential until pregnancy is excluded and should be fully counselled on the serious risk to the fetus should they become pregnant while undergoing treatment (see CONTRAINDICATIONS). Pregnancy should be avoided if either partner is receiving METOJECT. The optimal time interval between the cessation of methotrexate treatment of either partner and pregnancy has not been clearly established. Published literature recommendations for time intervals vary from 3 months to one year. The risk of effects on reproduction should be discussed with both male and female patients taking METOJECT.

Nursing Women: METOJECT is contraindicated in nursing mothers because of the potential for serious adverse reactions from methotrexate in breast-fed infants.

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

Overdose by intravenous miscalculation of dosage (particularly in juveniles) have occurred. Special attention must be given to dose calculation.

Geriatrics (≥65 years of age): 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. Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. Elderly patients should be closely monitored for early signs of hepatic, bone marrow and renal toxicity.

Renal Impairment: METOJECT is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION-Special populations).

Monitoring and Laboratory Tests

General: Patients undergoing METOJECT therapy should be informed of the early signs and symptoms of toxicity and closely monitored so that toxic effects are detected promptly. Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures. Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: e.g., pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria, and 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).

Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. 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.

During therapy of rheumatoid arthritis and psoriasis, monitor:

• Hematologic: Patients should have their blood tests checked at least monthly.

• Hepatic: Liver biopsies prior to METOJECT therapy are not indicated routinely. Liver function tests should be determined prior to the initiation of therapy with METOJECT and they should be monitored every 1 to 2 months. 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 METOJECT 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.
• Renal: Renal function should be monitored every 1 to 2 months.
• Respiratory: Pulmonary function tests may be useful if methotrexate-induced lung disease (e.g. interstitial pneumonitis) is suspected, especially if baseline measurements are available.

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 under WARNINGS AND PRECAUTIONS section. 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. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.

Adverse Drug Reactions by Organ System

Blood and lymphatic Leucopenia, anemia, aplastic anemia, thrombopenia, pancytopenia, system disorders: agranulocytosis, lymphadenopathy and lymphoproliferative disorders (including reversible), neutropenia and eosinophilia have also been observed.

Cardiac disorders: Pericarditis and pericardial effusion (damage to heart, rarely).

Eye disorders: Conjunctivitis, blurred vision, serious visual changes of unknown etiology, and transient blindness/vision loss.

Gastrointestinal Gingivitis, stomatitis, enteritis, anorexia, nausea, vomiting, diarrhea, disorders: hematemesis, melena, gastrointestinal ulceration and bleeding, pancreatitis, intestinal perforation, non-infectious peritonitis, glossitis.

General disorders and Anaphylactoid reactions, vasculitis, fever, conjunctivitis, infection, administration site sepsis, nodulosis, hypogammaglobulinaemia, and sudden death.

conditions:

Hepatobiliary disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations, hepatic failure.

Infection: Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, and disseminated H. simplex, cytomegalovirus infection, including cytomegaloviral pneumonia.

Metabolism and Diabetes mellitus.

nutrition disorders:

Musculoskeletal, Stress fractures, soft tissue necrosis, osteonecrosis, arthralgia, connective tissue myalgia and osteoporosis.

and bone disorders:

Neoplasms benign, Tumour lysis syndrome. Malignant lymphomas, which may regress malignant and following withdrawal of methotrexate, may occur in patients unspecified (including receiving low-dose methotrexate, and thus may not require cytotoxic cysts and polyps): treatment. Discontinue METOJECT first and, if the lymphoma does not regress, appropriate treatment should be instituted.

Nervous system: Cerebrospinal fluid pressure increased, neurotoxicity, arachnoiditis, paresthesia, headache, dizziness, drowsiness, speech impediment including dysarthria and aphasia; hemiparesis, paresis and convulsions. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal and urinary Renal failure, severe nephropathy or renal failure, azotemia, dysuria, disorders: cystitis, hematuria, urogenital dysfunction. Proteinuria has also been observed.

Reproductive system Defective oogenesis or spermatogenesis, transient oligospermia, and breast disorders: menstrual dysfunction, vaginal discharge and gynecomastia; infertility, abortion, fetal defects, loss of libido/impotence.

Respiratory, thoracic Pneumonia, interstitial alveolitis/pneumonitis often associated with and mediastinal eosinophilia, pulmonary fibrosis, Pneumocystis carinii pneumonia, disorders: pleural effusion. Dyspnea, chest pain, hypoxia, respiratory fibrosis, pharyngitis, and chronic interstitial obstructive pulmonary disease, alveolitis and pulmonary alveolar haemorrhage have occasionally occurred.

Skin disorders: Erythema, pruritus, photosensitisation, petechiae, loss of hair, skin necrosis, exfoliative dermatitis, painful erosion of psoriatic plaques, herpes zoster, vasculitis, urticaria, pigmentary changes, acne, ecchymosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), furunculosis and telangiectasia. Drug reaction with eosinophilia and systemic symptoms.

Vascular disorders: Hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), vasculitis.

Adverse Reactions Reported in Rheumatoid Arthritis:

• Alopecia (common)
• Diarrhea (common)
• Dizziness (common)
• Elevated liver enzymes (very common)
• Leucopenia (common)
• Nausea/vomiting (very common)
• Pancytopenia (common)
• Rash/pruritus/dermatitis (common)
• Stomatitis (common)
• Thrombocytopenia (common)

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

See WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests section.

Post-Market 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:

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.

Drug-Drug Interactions

Non-steroidal 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 of METOJECT. In treating rheumatoid arthritis with methotrexate, the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs without apparent problems. It should be appreciated however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to toxicity.

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.

Amiodarone

Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.

L-asparaginase

The administration of L-asparaginase has been reported to antagonize the effect of methotrexate.

Diuretics

Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.

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 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.

Packed Red Blood Cells

Care should be exercised whenever packed red blood cells and METOJECT are given concurrently. Patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum-Methotrexate concentrations.

Probenecid

Renal tubular transport is also diminished by probenecid; use of METOJECT with this drug should be carefully monitored.

Proton Pump Inhibitors

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.

Psoralen Plus Ultraviolet Light (PUVA) Therapy

Skin cancer has been reported in patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy.

Nephrotoxic Drugs

Methotrexate clearance is decreased by cisplatinum.

Although not documented, other nephrotoxic drugs such as aminoglycosides, Amphotericin B and Cyclosporin could theoretically increase methotrexate toxicity by decreasing its elimination.

Nitrous Oxide

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis, neurotoxicity (with intrathecal administration of methotrexate) and 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.

Penicillins and Sulfonamides

Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity have been observed in combination with methotrexate. Use of METOJECT with penicillins should be carefully monitored.

Ciprofloxacin

Renal tubular transport is diminished by ciprofloxacin; use of METOJECT with this drug should be carefully monitored.

Oral Antibiotics

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate 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. Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive antifolate effect.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with METOJECT.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. Combination of METOJECT and mercaptopurine may therefore require dose adjustment.

Vitamins

Vitamin preparations containing folic acid or its derivatives may decrease responses to methotrexate.

In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes.

Before taking a folate supplement, it is advisable to check B₁₂ levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B₁₂ deficiency.

Folate deficiency states may increase methotrexate toxicity.

Radiotherapy

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

Hepatoxins

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with METOJECT and other potential hepatotoxic agents (e.g., leflunomide, azathioprine, sulfasalazine, retinoids) should be closely monitored for possible increased risk of hepatotoxicity.

Cytarabine and other cytotoxic agents

Methotrexate given concomitantly with IV cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke-like episodes (see WARNINGS AND PRECAUTIONS: Neurologic).

Combined use of methotrexate with other cytotoxic agents has not been studied and may increase the incidence of adverse effects.

Drug-Herb Interactions

The effects of herbal products on the pharmacokinetics of methotrexate have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Use of alcohol with METOJECT is contraindicated (see CONTRAINDICATIONS). The effects of smoking, on the pharmacokinetics of methotrexate have not been specifically studied.

Some of the effects (e.g., dizziness and fatigue) may have an influence on the ability to drive or operate machinery.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Psoriasis and Rheumatoid Arthritis:

• The patient should be fully informed of the risks involved and should be under constant supervision of the physician (see WARNINGS AND PRECAUTIONS).
• All dosage schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see ADVERSE REACTIONS). Maximal myelosuppression usually occurs in seven to ten days.
• Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity.

Recommended Dose and Dosage Adjustments

Psoriasis:

Recommended starting dose schedule:

• Weekly single intramuscular or intravenous dose schedule: 10 to 25 mg per week until adequate response is achieved.

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 effective dose and to the longest possible rest period.

Rheumatoid Arthritis:

Recommended starting dosage schedule:

Dosages may be gradually adjusted to achieve optimal clinical response, but not ordinarily to exceed a total weekly dose of 20 mg.

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, dosage should be reduced gradually to the lowest possible effective maintenance dose. The optimal duration of therapy is unknown; limited data from long-term studies indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy.

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. METOJECT is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS).

Table 1: Dose Adjustments in Patients with Renal Insufficiency

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 1 for reduced doses in patients with renal impairment.

Missed Dose

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

OVERDOSAGE

Overdose with methotrexate has occurred with intrathecal administration, although intravenous and intramuscular overdose have also been reported.

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 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 standard hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Methotrexate is a folate antagonist.

Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated via the DHFR-catalyzed reaction in order to maintain the intracellular pool of tetrahydrofolate one-carbon derivatives for both thymidylate and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines and thus in a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication.

Methotrexate is most active against rapidly multiplying cells, because its cytotoxic effects occur primarily during the S phase of the cell cycle. Since cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. As a result, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to DHFR inhibition effects of methotrexate.

The cytotoxicity of methotrexate results from three important actions: inhibition of DHFR, inhibition of thymidylate synthase, and alteration of the transport of reduced folates. The affinity of DHFR to methotrexate is far greater than its affinity for folic acid or dihydrofolic acid, therefore, large doses of folic acid given simultaneously will not reverse the effects of methotrexate. However, Leucovorin calcium, a derivative of tetrahydrofolic acid may block the effects of methotrexate if given shortly after the antineoplastic agent. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma.

The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamination of methotrexate. The actual mechanism of action is unknown.

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 are 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 is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver and skin. 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 parenterally.

Metabolism: At low doses, methotrexate does not appear to undergo significant metabolism following high-dose therapy, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that 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. 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.

Excretion: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. Total clearance averages 12 L/h, but there is wide interindividual variation. 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 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.

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 (especially in RA and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity.

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 METOJECT between 15-25°C. Protect from light. It is recommended that the syringe remains in the carton until time of use.

SPECIAL HANDLING INSTRUCTIONS

General: Individuals who have contact with this drug, or work in areas where these drugs are used, may be exposed to these agents in air or through direct contact with contaminated objects.

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 cytotoxic drugs should avoid contact with skin and inhalation of airborne particles.

DOSAGE FORMS, COMPOSITION AND PACKAGING

METOJECT (methotrexate sodium) 10 mg/mL solution for injection is available in single-use pre-filled syringes. Non-medicinal ingredients include sodium chloride, sodium hydroxide and water.

METOJECT is available as follows;

* 1 mL syringe with 0.75 mL solution for injection, equivalent to 7.5 mg methotrexate

All syringes are available in cartons of 1, 5 or 10 single-use pre-filled syringes. Each carton of one syringe will also contain a single needle for use with METOJECT. The sterile hypodermic needle is a Sterican^® and is for single use only.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Methotrexate

Chemical name: N-[4-[[(2,4-diamino-6-pteridinyl)methylamino]benzoyl]-L-glutamic acid

Molecular formula and molecular mass: C₂₀H₂₂N₈O₅ (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 C₂₀ H₂₂ N₈ O₅ 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.

DETAILED PHARMACOLOGY

Human Pharmacokinetics

Absorption:

Methotrexate is generally completely absorbed from parenteral routes of injection. 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 can be achieved Methotrexate in serum is approximately 50% protein-bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by 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. 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.

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 by glomerular filtration and active tubular secretion. Non-linear 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 high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing.

TOXICOLOGY

The acute toxicity (LD₅₀) of methotrexate in mice ranges from 65 to 70 mg/kg intravenously and 45 to 90 mg/kg intraperitoneally. In dogs, the intravenous dose of 50 mg/kg was lethal. The main targets after a single dose were the hemolymphopoietic system and gastrointestinal (GI) tract.

The acute oral toxicity (LD₅₀) in rats is 180 mg/kg; subcutaneously, it is 58 mg/kg and intraperitoneally it ranges from 80 to 464 mg/kg. The tolerance to methotrexate in mice increased with age. The toxic effects after repeated administration of methotrexate were investigated in mice and rats. The main targets of methotrexate in the above animal species were the hemolymphopoietic system, GI tract, lung, liver, kidney, testes, and skin. The tolerance of mice to chronic methotrexate doses increased with age.

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^-8M. Both factors must be exceeded for toxicity to occur to these organs.

Doses of methotrexate resulting in plasma levels in excess of 2xl0^-8M 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.

REFERENCES

Anti-neoplastic Chemotherapy

1. 1. Cannon GW. Pulmonary Toxicity of Methotrexate. In: William S. Wilke eds. Methotrexate Therapy in Rheumatic Disease. Marcel Dekker, Inc. 270 Madison Ave., New York, N.Y. 10016. 1989; 243-260.
2. 2. Martindale: The Extra Pharmacopoeia. 29th Edition. James E.F. Reynolds ed. London Pharmaceutical Press 1989.
3. 3. Evans AE, D'Angelo GJ, and Mitus A. Central Nervous System Complications of Children with Acute Leukemia. An Evaluation of Treatment Methods. J Pediat. 1964; 6:94-96.
4. 4. Hertz R, Lewis J Jr., and Lipsett MB. Five Years' Experience with the Chemotherapy of Metastatic Choriocarcinoma and Related Trophoblastic Tumours in Women. Amer J Ob Gyn. 1961; 82:631-640.
5. 5. Li MC. Trophoblastic Disease: Natural History, Diagnosis and Treatment. Ann. Int. Med. 1971; 74:102-112.
6. 6. Krivit W, et al. Induction of Remission in Acute Leukemia of Childhood by Combination of Prednisone and either 6-mercaptopurine or Methotrexate. J Pediat. 1966; 68:965-968.
7. 7. Acute Leukemia Group B.: Acute Lymphocytic Leukemia in Children. JAMA. 1969; 207:923-928.
8. 8. Burchenal JH. Chemotherapy for Leukemia. Postgrad. Med. 1970; 48:164-168.
9. 9. Ziegler JL, et al. Treatment of Burkitt's Tumour with Cyclophosphamide. Cancer. 1970; 26:474-484.
10. 10. Hryniuk WM and Bertino JR. Treatment of Leukemia with Large Doses of Methotrexate and Folinic Acid: Clinical Biochemical Correlates. J Clin Invest. 1969; 48:2140-2155.
11. 11. Hersh EM, Wong VG, Henderson ES, and Freireich EJ. Hepatotoxic Effects of Methotrexate. Cancer. 1966; 19:600-606.
12. 12. Dixon RL, Henderson ES, and Rall DP. Plasma Protein Binding of Methotrexate and its Displacement by Various Drugs. Fed. Proc. 1965; 24:454.
13. 13. Pitman SW and Frei E. Weekly Methotrexate-Calcium Leucovorin rescue: Effect of alkalinization on nephrotoxicity: Pharmacokinetics in the CNS; and use in CNS Non-Hodgkin's lymphoma. Cancer Treat Reps. 1977; 61(4):695-701.
14. 14. Rooney TW, Furst De. Comparison of toxicity in Methotrexate (MTX) treated rheumatoid arthritis (RA) patients also taking aspirin (ASA) or other NSAID. Abstract. Arthritis Rheum 29 Suppl 4:S76.
15. 15. Aherne et al. Br Med J. 1978; 1: 1097-1099.
16. 16. Freisheim JH, Matthews DA. Dihydrofolate Reductases. Folate Antagonists as Therapeutic Agents. Academic Press Inc. 1984; 1:70-73.
17. 17. DeVita Jr. LVT, Hellman S, Rosenberg SA. Clinical features of low-grade T-cell lymphomas. Cancer. Principles and Practice of Oncology. 4th. Ed. J.B. Lippincott Co., Philadelphia. pp. 1930-1935.
18. 18. Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, Ayala AG, Shuster JJ, Abelson HT, Simone JV, Vietti TJ. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Eng J Med. 1986; 314(25):1600-1606.
19. 19. Stark AN, Jackson G, Carey PJ, Arfeen S, Proctor SJ. Severe renal toxicity due to intermediate-dose Methotrexate. Department of Haematology, Royal Victoria Infirmary, Newcastle-upon-Tyne.
20. 20. Evans WE, Christensen ML. Drug interactions with Methotrexate. J Rheumatol (Canada). 1985; Suppl 12 12:15-20.
21. 21. Chabner BA, Collins JM. Cancer chemotherapy principles and practice. Philadelphia: Lippincott, 1990; 449-464.
22. 22. Nyfors A. Benefits and adverse drug experiences during long-term Methotrexate treatment of 248 psoriatics.

Psoriasis Chemotherapy

1. 23. Roenigk HH Jr, Maibach HI, and Weinstein GD. Use of Methotrexate in Psoriasis. Arch Derm. 1972; 105:363-365.
2. 24. Roenigk HH Jr, Bergfeld WF, and Curits GH. Methotrexate for Psoriasis in Weekly Oral Doses. Arch Derm. 1969; 99:86-93.
3. 25. Rees RB, Bennett JH, Maibach HI, and Arnold HL. Methotrexate for Psoriasis. Arch Derm. 1971; 103:33-38.
4. 26. Roenigk HH Jr, Maibach HI, and Weinstein GD. Methotrexate Therapy for Psoriasis. Arch Derm. 1973; 108:35.
5. 27. Weinstein GD. Methotrexate for Psoriasis. JAMA. 1973; 225:412.
6. 28. McDonald CJ and Bertino JR. Parenteral Methotrexate in Psoriasis. Arch Derm. 1969; 100:655-668.
7. 29. Weinstein GD. Methotrexate for Psoriasis. Dermatology Digest. 1973; 12:49-53.
8. 30. Weinstein GD and Velasco J. Selective Action of Methotrexate on Psoriatic Epidermal Cells. J of Investigative Dermatology. 1972; 59:121-127.
9. 31. Coe RO and Bull FE. Cirrhosis Associated with Methotrexate Treatment of Psoriasis. JAMA. 1968; 206:1515-1520.
10. 32. Weinstein CD, et al. Cooperative Study. Psoriasis-Liver Methotrexate Interactions. Arch Derm. 1973; 108:36-42.
11. 33. Pearce HP and Wilson BB. Erosion of psoriatic plaques: An early sign of Methotrexate toxicity. Am Acad Dermatol. 1996;35:835-838.

NSAID Interactions

1. 34. Adams JD and Hunter GA. Drug interaction in psoriasis. Aust J Derm. 1976; 17:3940.
2. 35. 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.
3. 36. Daly H. et al. Interaction between Methotrexate and non-steroidal anti-inflammatory drugs. Lancet. 1986; 557.
4. 37. Daly H, et al. Methotrexate toxicity precipitated by azapropazone. Br J Derm. 1986; 114:733-735.
5. 38. 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.
6. 39. 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.
7. 40. Gabrielli A, et al. Methotrexate and non-steroidal anti-inflammatory drugs. Letter, Br Med J. 1987; 294:776.
8. 41. Maiche AI. Acute renal failure due to concomitant action of Methotrexate and Indomethacin. Letter, Lancet. 1986; 1390.
9. 42. Mandel MA. The synergistic effect of salicylates on Methotrexate toxicity. Plastic and Reconstructive Surg. 1976; 733-737.
10. 43. Singh RR, et al. Fatal interaction between Methotrexate and Naproxen. Letter, Lancet. 1986; 1390.
11. 44. Thyss A, et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between Methotrexate and Ketoprofen. Lancet. 1986; 256-258.

Interaction with Radiotherapy

1. 45. 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

1. 46. Wall SM, et al. Effective clearance of Methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis. 1996; 28(6):846-854.

General

1. 47. Kremer JM, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis & Rheumatol. 1994; 37(3):316-328.
2. 48. Goodman TA, et al. Methotrexate: adverse reactions and major toxicities. Rheumatic Disease Clinics of North America. 1994; 20(2):513-28.
3. 49. Tett SE, et al. Use of Methotrexate in older patients. A risk-benefit assessment. Drugs & Aging. 1996; 9(6):458-71.
4. 50. Said S, et al. Systemic treatment: Methotrexate. Clinics in Dermatology. 1997; 15(5):781-97.
5. 51. Evans WE, et al. Applied Pharmacokinetics: Principles of therapeutic drug monitoring, 3rd ed. Applied Therapeutics, Inc. Vancouver WA, 1992.
6. 52. Green JA, et al. Drug interactions with cytotoxic agents. Cancer Topics. 1990; 7(11); 126-128.
7. 53. 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.
8. 54. 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).
9. 55. Glynn Barnhart AM, et al. Effect of low-dose Methotrexate on the deposition of glucocorticoids and theophylline. J Allergy Clin Immunol. 1991; 88(2):180-86.
10. 56. Glynn Barnhart AM, et al. Effect of Methotrexate on prednisolone and theophylline pharmacokinetics. Pharmacotherapy. 1990; 10(3):255.
11. 57. Yokoo H, Nakazato Y, Harigaya Y, et.al. Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotrexate for rheumatoid arthritis: an autopsy report. Acta Neuropathol. 2007;114:425-430.
12. 58. Worthley S, McNeil J. Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid arthritis. J Rheumatol. 1995;22:335-337.
13. 59. Renard D, Westhovens R, Vandenbussche E, et.al. Reversible posterior leucoencephalopathy during oral treatment with methotrexate. J Neurol. 2004;251:226-228.
14. 60. Raghavendra S, Nair MD, Chemmanam T, et.al. Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate. Eur J Neurol. 2007;14:309-314.
15. 61. Electronic communication from Yasuo Sugano, Labeling Group, PV Dept. Medical Affairs, WKK; 01 August 2008.
16. 62. Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systemic review of the literature. Ann Rheum Dis. 2009;68:1094-1099.
17. 63. ^PrMethotrexate (Methotrexate Tablets USP, Methotrexate Injection USP) Product Monograph. ^®T.M. Wyeth, Pfizer Canada Inc., Licensee. Date of Revision: December 13, 2016. Submission Control Number: 198792.
18. 64. ^Prpms-Methotrexate (Methotrexate Tablets USP) Product Monograph. Date of Revision: August 24, 2017. Submission Control Number: 205553.
19. 65. ^PrMethotrexate Injection USP 10 mg/mL and 25 mg/mL Product Monograph. Pfizer Canada ULC. Date of Revision: July 8, 2019. Submission Control Number: 224776.