Boxed Warnings
Warnings. Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy, or in the case of non-oncological conditions, by a specialist physician.
Patients should be fully informed of the risk of fatal or severe toxic reactions involved with the administration of methotrexate and should be under constant supervision of the physician.
Deaths have been reported with the use of methotrexate.
In the treatment of psoriasis and rheumatoid arthritis, methotrexate should be restricted to severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after appropriate consultation.
Potential of fatal toxicity from dosing errors. 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 (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose). For the same reason great care should be taken with dispensing to ensure the correct tablet strength of Chexate is given to the patient. Chexate is available as 2.5 mg and 10 mg tablets.
Organ system toxicity. Gastrointestinal. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy; otherwise, haemorrhage enteritis and death from intestinal perforation may occur.
Gastrointestinal toxicity has been reported with concomitant administration of methotrexate (usually in high doses) along with nonsteroidal anti-inflammatory agents (NSAIDs).
Haematological. Methotrexate may produce marked depression of bone marrow, anaemia, aplastic anaemia, leukopenia, neutropenia, thrombocytopenia and bleeding.
Unexpectedly severe (sometimes fatal) marrow suppression and aplastic anaemia have been reported with concomitant administration of methotrexate (usually in high doses) along with NSAIDs.
Hepatic. 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.
Musculoskeletal. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Infection or immunologic states. Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy.
Immunisation. Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections.
Pulmonary. 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 a dry, non-productive cough) may require interruption of treatment and careful investigation. Pulmonary lesions can occur at all dosages. Infections (including pneumonia) needs to be excluded. Patients should be closely monitored for pulmonary symptoms.
Renal. Impaired renal function is usually a contraindication.
Malignant lymphomas. 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.
Fetal toxicity. Use in pregnancy. Pregnancy category D.
Methotrexate has caused fetal death and/or congenital abnormalities. 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 and rheumatoid arthritis 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 fetus should they become pregnant while undergoing treatment.
Use in lactation. Women should be advised not to breastfeed while being treated with methotrexate.
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.
1 Name of Medicine
Methotrexate sodium.
2 Qualitative and Quantitative Composition
Each Chexate 2.5 mg tablet contains 2.5 mg of methotrexate (as sodium).
Each Chexate 10 mg tablet contains 10 mg of methotrexate (as sodium).
Excipient of known effect. Chexate 2.5 mg tablets and 10 mg tablets contain 82 mg and 328 mg of lactose monohydrate, respectively.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Tablet.
Chexate 2.5 mg tablets. Yellow, round, uncoated, flat tablet, with a cosmetic score line and engraved with ORN 57 on one side, diameter 6 mm.
The score line on the 2.5 mg tablet is only cosmetic and must not be used to divide the tablet into equal doses.
Chexate 10 mg tablets. Yellow, capsule-shaped, convex, uncoated tablet, engraved with ORN 59 on one side and score on other side, length of 14 mm and width of 6 mm.
The tablet can be divided into equal doses.
4 Clinical Particulars
4.9 Overdose
Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate have been reported (see Boxed Warnings; see Section 4.2 Dose and Method of Administration).
Signs and symptoms. Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacological doses, particularly haematological and gastrointestinal reactions. These signs and symptoms include leukopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding, anorexia, progressive weight loss and bloody diarrhoea. In some cases of overdose, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure and aplastic anaemia were also reported.
Recommended treatment. Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within 1-hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Folinic acid (calcium folinate) neutralises effectively the immediate toxic effects of methotrexate. After an inadvertent overdosage of methotrexate, calcium folinate should be given as soon as possible and preferably started within 1 hour after the administration of methotrexate. As the time interval between methotrexate administration and folinic acid initiation increases, the effectiveness of folinic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with folinic acid.
Calcium folinate should be given at 10 mg/m2 IV or IM q 6 hours until the serum methotrexate levels are below 10-8 M. In the presence of gastric stasis or obstruction calcium folinate should be administered parenterally. Concomitant hydration (3 L/d) and urinary alkalinisation with sodium bicarbonate should be employed. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater. Serum samples should be assayed for creatinine levels and methotrexate levels at 24 hour intervals. If the 24 hour serum creatinine level has increased 50% over baseline or if the 24 hour methotrexate level is > 5 x 10-6 M or the 48 hour methotrexate level is 9 x 10-7 M or higher, the doses of calcium folinate should be increased to 100 mg/m2 IV q 3 hours until the methotrexate level is < 10-8 M. The infusion rate of calcium folinate should not exceed 16.0 mL (160 mg calcium folinate) per minute. Patients with significant third space accumulations should be considered high-risk and monitored until serum methotrexate levels are < 10-8 M regardless of their 24 hour serum concentration.
The above mentioned statements on calcium folinate dosage do not apply with high-dosage methotrexate therapy. The dosages of calcium folinate have varied in different studies and the published literature on high-dosage methotrexate should be consulted.
In cases of massive overdose, hydration and urinary alkalinisation may be necessary to prevent the precipitation of the drug and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have 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. However, effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high-flux dialysator.
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. No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results.
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.
Assessment of the carcinogenic potential of methotrexate is complicated by conflicting evidence of an increased risk of certain tumours in rheumatoid arthritis. 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 sodium is an orange, brownish or yellow crystalline hygroscopic powder.
Chemical structure.
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSMETSOD.gif CAS number. 7413-34-5.
7 Medicine Schedule (Poisons Standard)
Prescription Only Medicine - S4.
Summary Table of Changes
https://stagingapi.mims.com/au/public/v2/images/fulltablegif/CHEXATST.gif
