INDICATIONS AND USAGE Neoplastic Diseases Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.

In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents.

Methotrexate is also indicated in the treatment of meningeal leukemia.

Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types.

Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.

Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor.

Psoriasis: Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by a biopsy and/or after dermatologic consultation .

It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis: Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non- steroidal anti-inflammatory agents (NSAIDs).

Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored.

(See PRECAUTIONS, Drug Interactions .) Steroids may be reduced gradually in patients who respond to methotrexate.

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.

Rest and physiotherapy as indicated should be continued.

WARNINGS WARNINGS – SEE BOXED WARNINGS .

For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate.

Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol.

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 doses), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, 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.

ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION.

THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTIONS SECTION.

THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress.

Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Other adverse reactions that have been reported with methotrexate are listed below by organ system.

In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.

Alimentary System - gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.

Blood and Lymphatic System Disorders - suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible).

Hypogammaglobulinemia has been reported rarely.

Cardiovascular - pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).

Central Nervous System - headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.

Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Hepatobiliary Disorders - hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations.

Infection - There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases.

Pneumocystis carinii pneumonia was the most common opportunistic infection.

There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H.

simplex hepatitis, and disseminated H.

simplex .

Musculoskeletal System - stress fracture.

Ophthalmic - conjunctivitis, serious visual changes of unknown etiology.

Pulmonary System – respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.

Skin - erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.

Urogenital System - severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects.

Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, lymphoma, including reversible lymphomas, tumor lysis syndrome, soft tissue necrosis, and osteonecrosis.

Anaphylactoid reactions have been reported.

Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below.

Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids.

Hepatic histology was not examined in these short-term studies.

(See PRECAUTIONS ) .

Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to 10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ).

Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm 3 ), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.

(See PRECAUTIONS .) Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.

Adverse Reactions in Psoriasis There are no recent placebo-controlled trials in patients with psoriasis.

There are two literature reports (Roenigk, 1969, and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate.

Dosages ranged up to 25 mg per week and treatment was administered for up to four years.

With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies.

Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996).

Adverse Reactions in JRA Studies The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m 2 /wk or 0.1 to0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%.

Although there is experience with dosing up to 30 mg/m 2 /wk in JRA, the published data for doses above 20 mg/m 2 /wk are too limited to provide reliable estimates of adverse reaction rates.