TREXOL 50 MG INJECTION

Indications

• Severe active rheumatoid arthritis
• Moderate to severe Crohn's disease
• Maintenance of remission of Crohn's disease
• Ulcerative colitis
• Acute lymphoblastic leukemia
• Chronic myeloid leukemia
• Psoriasis
• Certain solid tumors

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Initially 7.5 mg once weekly, adjusted according to response; maximum 20 mg per week.

Mechanism of action

Methotrexate enters tissues and is converted into methotrexate polyglutamate, which inhibits enzymes responsible for nucleotide synthesis, including dihydrofolate reductase, thymidylate synthase, and aminoimidazole carboxamide ribonucleotide transformylase (AICART). This inhibition prevents DNA synthesis and cell division. In rheumatoid arthritis, the polyglutamate metabolites preferentially inhibit AICART, leading to an accumulation of ribonucleotide that enhances anti-inflammatory effects through adenosine receptor stimulation.

Pharmacodynamics

Methotrexate's inhibition of nucleotide synthesis leads to a decrease in cell proliferation and an anti-inflammatory response. It has a long duration of action and is typically dosed once weekly, demonstrating a narrow therapeutic index. Care must be taken to monitor for toxicity, particularly in the context of its immunosuppressive effects.

Pharmacokinetics

Methotrexate is absorbed well from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 2 hours after oral administration. It is widely distributed in body tissues and has a plasma half-life of approximately 6 to 7 hours, although this can vary based on dose and patient factors. The drug undergoes hepatic metabolism and is primarily eliminated via renal excretion. Dose adjustments may be necessary in patients with renal impairment.

Contra-indications

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Active infection
• Hypersensitivity to methotrexate or any component of the formulation
• Absence of thiopurine methyltransferase activity

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Mouth ulcers
• Hepatotoxicity
• Bone marrow suppression
• Leucopenia
• Thrombocytopenia
• Increased risk of infection
• Pulmonary toxicity
• Rash
• Alopecia
• Fatigue
• Anemia
• Fever
• Arthralgia

Interactions

• Nitrous oxide - severe (increases risk of methotrexate toxicity)
• Tedizolid - severe (increases exposure)
• Acitretin - severe (increases concentration)
• Sulfonamides - moderate (increases exposure)
• Aspirin - unknown (increases risk of toxicity)
• Pyrimethamine - unknown (increases risk of adverse effects)
• Asparaginase - unknown (affects efficacy)

Precautions

• Monitor liver function regularly
• Monitor blood counts due to risk of myelosuppression
• Use with caution in patients with liver disease
• Consider dose adjustments in renal impairment
• Patients with reduced thiopurine methyltransferase activity should be treated under specialist supervision

Pregnancy

Methotrexate is contraindicated in pregnancy due to its teratogenic effects.

Breast-feeding

Methotrexate is excreted in breast milk; breastfeeding is not recommended during treatment.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Intramuscular injection
• Subcutaneous injection
• Intravenous injection

Mechanism of action

Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase. Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate. This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action. Methotrexate and its polyglutanate metabolites reversibly inhibits dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments necessary for synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The affinity of dihydrofolate reductase for methotrexate is far greater than its affinity for folic acid or dihydrofolic acid. and, therefore, even very large doses of folic acid given simultaneously will not reverse the effects of methotrexate. Leucovorin calcium, a derivative of tetrahydrofolic acid, may block the effects of methotrexate if given shortly after the antineoplastic agent. Results of one study indicate that methotrexate also causes an increase in intracellular deoxyadenosine triphosphate, which is thought to inhibit ribonucleotide reduction, and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair. Tissues with high rates of cellular proliferation such as neoplasms, psoriatic epidermis, bone marrow, the lining of the GI tract, hair matrix, and fetal cells are most sensitive to the effects of methotrexate. Methotrexate ... has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or antiinflammatory effects.

Pharmacodynamics

Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily.