Methotrexate

CLINICAL USE

Antineoplastic agent:Severe rheumatoid arthritis Severe uncontrolled psoriasis Crohn’s disease Neoplastic disease

DOSE IN NORMAL RENAL FUNCTION

Rheumatoid arthritis: Oral, SC, IM, IV: 7.5–20 mg once a weekPsoriasis: (Oral) 10–25 mg once weekly, adjusted to responseCrohn’s disease: 15–25 mg weekly Neoplastic disease: Dose by weight or surface area according to specific indication

PHARMACOKINETICS

Molecular weight :454.4

%Protein binding :45–60

%Excreted unchanged in urine : 80–90

Volume of distribution (L/kg) :0.4–0.8

half-life – normal/ESRD (hrs) :2–17/Increased

DOSE IN RENAL IMPAIRMENT

GFR (mL/MIN)

20 to 50 : 50–100% of normal dose

10 to 20 : 50% of normal dose

<10 :

Contraindicated

DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

CAPD :Not dialysed.

Contraindicated

HD :Dialysed. Haemodialysis clearance is 38–40 mL/minute. 50% of normal dose at least 12 hours before next dialysis. Use with caution

HDF/high flux :Dialysed. 50% of normal dose at least 12 hours before next dialysis. Use with caution

CAV/VVHD :Unknown dialysability. Dose as in GFR 10 to 20 mL/min

IMPORTANT DRUG INTERACTIONS

Potentially hazardous interactions with other drugs

Anaesthetics: antifolate effect increased by nitrous oxide – avoid concomitant use

Analgesics: increased risk of toxicity with NSAIDs

Antibacterials: absorption possibly reduced by neomycin; antifolate effect increased with co-trimoxazole and trimethoprim; penicillins and possibly ciprofloxacin reduce excretion of methotrexate (increased risk of toxicity); increased haematological toxicity with doxycycline and tetracycline

Antimalarials: antifolate effect enhanced by pyrimethamine

Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis)

Ciclosporin: methotrexate may inhibit the clearance of ciclosporin or its metabolites; ciclosporin may inhibit methotrexate eliminationCorticosteroids: increased risk of haematological toxicityCytotoxics: increased pulmonary toxicity with cisplatinProbenecid: excretion of methotrexate reduced

Retinoids: concentration increased by acitretin, also increased hepatotoxicity – avoid concomitant use

ADMINISTRATION

Reconstition

Compatible with glucose 5%, sodium chloride 0.9%, compound sodium lactate, or Ringers solution

Route

Oral, IM, IV (bolus injection or infusion), intrathecal, intra-arterial, intraventricular

Rate of Administration

Slow IV injection

Comments

High-dose methotrexate may cause precipitation of methotrexate or its metabolites in renal tubules. A high fluid throughput and alkalinisation of urine, using sodium bicarbonate if necessary, is recommended.470 METhoTrEXATE

OTHER INFORMATION

The dose is well absorbed at doses <30 mg/m2 – bioavailability is decreased by food and milk. Metabolism is via liver and intracellular metabolism to polyglutamated productsExcreted primarily by the kidneys (>90%), although small amounts via the bile. Clearance is higher in children than in adultsCalcium folinate (calcium leucovorin) is a potent agent for neutralising the immediate toxic effects of methotrexate on the haematopoietic systemCalcium folinate rescue may begin 24/32/36 hours post start of methotrexate therapy, according to local protocol. Doses of up to 120 mg may be given over 12–24 hours by IM or IV injection or infusion, followed by 12–15 mg IM, or 15 mg orally every 6 hours for the next 48 hoursRenal function should be closely monitored throughout treatmentAn approximate correction for renal function may be made by reducing the dose in proportion to the reduction in creatinine clearance based on a normal creatinine clearance of 60 mL/minute/m2Alternative dosing regimen: CrCl (mL/min) Dose>80 100%60 65%45 50%<30 AvoidDoses in renal failure from Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.

See how to identify renal failure stages according to GFR calculation

See how to diagnose irreversible renal disease

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