Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK
Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia, and the symptomatic treatment of severe recalcitrant disabling psoriasis which is not adequately responsive to other forms of therapy.
Important warning about the dosage of Methotrexate:
In the treatment of psoriasis, Methotrexate must only be taken once a week. Dosage errors in the use of Methotrexate can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.
Methotrexate is active orally and parenterally. Methotrexate Injection may be given by the intramuscular, intravenous, intraarterial or intrathecal routes. Dosage is related to the patient’s body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.
Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for a 5 day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.
The effectiveness of therapy can be evaluated by 24 hours quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.
Hydatidiform mole may precede or be followed by choriocarcinoma, and methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.
Prolonged cyclic combination with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40 mg/m² intravenously on the first and eighth days.
Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.
Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral methotrexate dosage 3.3 mg/m² daily, and prednisolone 40-60 mg/m² daily for 4-6 weeks has been used. After a remission is attained, methotrexate in a maintenance dosage of 20-30 mg/m² orally or by intramuscular injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5 mg/kg has been administered intravenously every 14 days.
Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.
Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. The dose of intrathecal Methotrexate is constant regardless of age or body surface area in patients over the age of 3 years of age, the maximum intrathecal dose should be 12 mg in such patients. Patients under the age of 3 years should be treated in accordance with combination chemotherapy protocols. The administration is at weekly intervals and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.
In Burkitt’s Tumour, stages 1-2, methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days. In stage 3, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin’s disease responds poorly to methotrexate and to most types of chemotherapy.
Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10 mg daily by mouth for weeks or months and dosage should be adjusted according to the patient’s response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg twice weekly.
Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). 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 intersubject pK variability.
Table 1a. Dose adjustments for methotrexate doses <100 mg/m² in patients with renal impairment:
| Creatinine Clearance (ml/min) | % of dose to Administer |
|---|---|
| >60 | 100 |
| 30-59 | 50 |
| <30 | Methotrexate must not be administered. |
Table 1b. Dose adjustments for methotrexate doses >100 mg/m² in patients with renal impairment:
| Creatinine Clearance (ml/min) | % of dose to Administer |
|---|---|
| >80 | 100 |
| = ~80 | 75 |
| = ~60 | 63 |
| <60 | Methotrexate must not be administered. |
Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, intramuscular or intravenous doses of 10-25 mg per week, and adjusted according to the patient’s response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10 mg.
The prescriber should specify the day of intake on the prescription.
An alternative dosage schedule consists of 2.5 to 5 mg of methotrexate administered orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses each week; weekly dosages should not exceed 30 mg.
A daily oral dosage schedule of 2 to 5 mg administered orally for 5 days followed by a rest period of at least 2 days may also be used. The daily dose should not exceed 6.25 mg.
The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.
Methotrexate should be used with extreme caution in elderly patients. A reduction in dosage should be considered.
Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate in these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions
Calcium folinate (calcium leucovorin) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than, the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.
Other supporting therapy such as blood transfusion and renal dialysis may be required. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.
As packaged for sale: 18 months
After dilution: Chemical and physical in-use stability has been demonstrated in dextrose 5% and sodium chloride 0.9% infusion solutions for 30 days at 4°C in PVC containers when protected from light.
From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
As packaged for sale: Do not store above 25°C. Do not freeze. Keep container in the outer carton.
After dilution: see 6.3.
5 mg/2 ml: Conventional or Onco-Tain Type I glass vial with rubber stopper, aluminium seal and plastic ‘flip-off’ top. Packs containing 5 vials.
Not all presentations and pack sizes listed above may be marketed.
Single use only. Discard any unused contents.
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