Boxed Warnings
Warning. Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy, or in the case of non-oncological conditions, by a specialist physician.
Because of the possibility of fatal or severe toxic reactions the patient should be fully informed by the physician of the risks involved and should be under constant supervision of the physician.
Deaths have been reported with the use of methotrexate.
In the treatment of psoriasis methotrexate should be restricted to severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy and only when the diagnosis has been established, by biopsy and/or after consultation.
1. Methotrexate may produce marked depression of the bone marrow, anaemia, aplastic anaemia, leucopenia, neutropenia, thrombocytopenia and bleeding.
2. Methotrexate may be hepatotoxic particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.
3. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
4. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
5. Use in pregnancy. Category D. This category specifies drugs, which have caused an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Methotrexate has caused foetal death and/or congenital anomalies. Therefore, it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive methotrexate.
Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counselled on the serious risk to the foetus should they become pregnant while undergoing treatment.
Pregnancy should be avoided if either partner is receiving methotrexate, during and for a minimum of 6 months after therapy has ceased, although the optimal time interval between the cessation of methotrexate treatment of either partner, and pregnancy, has not been clearly established.
6. Methotrexate is usually contraindicated in patients with impaired renal function.
7. Unexpectedly severe (sometimes fatal) marrow suppression, aplastic anaemia, gastrointestinal toxicity and death have been reported with concomitant administration of methotrexate (usually in high doses) with some nonsteroidal anti-inflammatory drugs (NSAIDs).
8. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
9. Methotrexate induced lung disease, including acute or chronic interstitial pneumonitis and pleural effusion is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially dry, nonproductive cough) may require interruption of treatment and careful investigation. Pulmonary lesions can occur at all dosages. Infection (including pneumonia) needs to be excluded. Patients should be closely monitored for pulmonary symptoms.
10. Methotrexate has been used in very high dosage followed by calcium folinate (leucovorin calcium) rescue in the experimental treatment of certain neoplastic diseases. This procedure is investigational and hazardous. It should not be attempted except by highly experienced teams following carefully designed protocols. The recent published literature should always be consulted.
11. Use in children. Aside from its established use in cancer chemotherapy; the safety and efficacy of using methotrexate in children has not been fully elucidated.
12. Use only isotonic and preservative-free methotrexate for intrathecal administration. For more information, see Section 4.2 Dose and Method of Administration, Method of administration.
13. Both the physician and the pharmacist should emphasise to the patient the importance of the weekly dosing regimen: mistaken daily use may cause serious and sometimes life threatening or fatal toxicity.
14. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
15. Use in lactation. Women should be advised not to breastfeed while being treated with methotrexate.
16. Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections.
Because of its potential to cause severe toxicity, methotrexate therapy requires close supervision with particular caution to distinguish between daily and weekly dosage regimens. Weekly dosage prescriptions should specify a particular day of the week.
1 Name of Medicine
Methotrexate.
2 Qualitative and Quantitative Composition
1 mL contains 25 mg methotrexate,
1 vial of 2 mL solution for injection contains 50 mg methotrexate; or
1 mL contains 100 mg methotrexate,
1 vial of 10 mL solution for injection contains 1000 mg methotrexate.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Methotrexate Accord is a sterile yellow to orange solution for injection.
4 Clinical Particulars
4.9 Overdose
Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms following injectable overdosage would be expected to produce effects, which are an extension of the pharmacological effects. The toxic reactions expected would include those listed under Section 4.8 Adverse Effects (Undesirable Effects).
Calcium folinate (leucovorin calcium) is a potent agent for neutralising the immediate toxic effects of methotrexate on the haematopoietic system. In general, when overdosage is suspected, the dose of calcium folinate should be equal to or higher than the offending dose of methotrexate, and should be given as soon as possible, preferably within the first hour after which it is much less effective. Calcium folinate may be administered by IV infusion in doses of up to 75 mg within 12 hours, followed by 12 mg IM every 6 hours for 4 doses. When average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of calcium folinate may be given IM every 6 hours for 4 doses.
Concomitant hydration and alkalinisation of the urine with sodium bicarbonate is recommended to prevent precipitation of methotrexate or its metabolite in the renal tubules. Patients undergoing methotrexate therapy should be advised to increase fluid intake. Neither standard haemodialysis nor peritoneal dialysis has been shown to significantly improve methotrexate elimination. Some clearance of methotrexate may be obtained by haemodialysis if the patient is totally anuric and no other therapeutic options are available. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high-flux dialyzer.
Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinisation, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent haemodialysis with a high-flux dialyzer may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.3 Preclinical Safety Data
Genotoxicity. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells. In vitro, methotrexate caused chromosomal aberrations in Chinese hamster A(T1) C1-3 cells, induced morphological transformation in mouse C3H/10T1/2 clone 8 cells and was associated with an increased incidence of large colony mutants at the tk locus in L5178Y/tk± mouse lymphoma cells. In vivo, it caused an increased incidence of polychromatic erythrocytes in mice and a transient and reversible increase in chromosomal aberrations in human bone marrow cells. The clinical significance of these findings is uncertain.
Carcinogenicity. Methotrexate is considered to be carcinogenic. However, extensive epidemiologic studies are required to determine its carcinogenicity potential.
Cytotoxic drugs have been reported to be associated with an increased risk of development of secondary tumours in humans. Reports of lymphoma, including reversible lymphomas and tumour lysis syndrome have been documented in patients treated with methotrexate.
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires initiation of cytotoxic therapy.
Benefit should be weighed against this potential risk before using methotrexate alone or in combination with other drugs, especially in children or young adults.
Reproductive and developmental toxicity. There is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Methotrexate is (S)-2-[4-[[(2,4-diaminopteridin-6-yl)methyl]methylamino]benzoylamino] pentanedioic acid. It is a yellow or orange, crystalline powder, practically insoluble in water, in alcohol, in ether and in ethylene chloride. It dissolves in dilute solutions of mineral acids and in dilute solutions of alkali hydroxides and carbonates.
Molecular formula: C20H22N8O5.
Molecular weight: 454.4.
Chemical structure. The structural formula is represented below.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSMETREX.gif CAS number. 59-05-2.
7 Medicine Schedule (Poisons Standard)
S4 - Prescription Only Medicine.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/METHACST.gif
