METHOTREXATE REMEDICA FILM-COATED TABLET 2.5MG [SIN17136P]

Product Info

METHOTREXATE REMEDICA FILM-COATED TABLET 2.5MG

[SIN17136P]

Indications

Antineoplastic chemotherapy
Methotrexate has a broad spectrum of antineoplastic activity. It is indicated for the treatment of breast cancer, gestational choriocarcinoma, and in patients with chorioadenoma destruens and hydatidiform mole.

Methotrexate may be used in combination with other chemotherapeutic agents for the palliative treatment of acute leukaemias, particularly acute lymphoblastic leukaemia. It may also be used in the treatment of Burkitt's lymphoma, advanced stages (III and IV, Peters Staging System) of lymphosarcoma, especially in children, and in advanced cases of mycosis fungoides.

High dose therapy
In high-dose schedules, methotrexate may be effective alone or in combination therapy, in the treatment of epidermoid cancers of the head and neck, osteogenic sarcoma and bronchogenic carcinoma.

Calcium folinate (leucovorin calcium) must be used in conjunction with high dose methotrexate therapy.

Psoriasis chemotherapy
Methotrexate may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of treatment. However, due to the high risk associated with its use, methotrexate should be used after the diagnosis has been definitely established, as by biopsy and/or after dermatologic consultation.

Rheumatoid arthritis chemotherapy
Management of severe, recalcitrant, active rheumatoid arthritis in adults not responding to, or intolerant of, an adequate trial of NSAIDs and one or more disease modifying drugs.

Aspirin, NSAIDs and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylate has not been fully explored.

Steroids may be reduced gradually in patients who respond to methotrexate.

Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine or cytotoxic agents has not been studied and may increase the incidence of adverse effects.

Rest and physiotherapy as indicated should be continued.

Dosage and method of administration

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.

Anti-neoplastic chemotherapy
Oral administration in tablet form is often preferred since absorption is rapid and effective serum levels are obtained. It is recommended that oral methotrexate should be taken on an empty stomach.

A guideline of a ratio of 1:30 is given for the con-version of mg/kg body weight to mg/m² body surface area. The conversion factor varies between 1:20 and 1:40 depending on age and body build.

Trophoblastic diseases: The usual dosage is 15 to 30 mg daily for a 5-day course. A repeat course may be given after a period of one or more weeks provided all signs of toxicity have disappeared. Three to five courses of therapy are usually employed. The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary chorionic gonadotropin hormone (CGH), which should return to normal or less than 50 international units/24 h, usually after the 3^rd or 4^th course. Complete resolution of measurable lesion usually occurs 4 to 6 weeks later. One to two courses of methotrexate after normalization of CGH is usually recommended. Before each course of the drug careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

Since hydatidiform mole may precede or be followed by choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for trophoblastic neoplasms.

Leukemia: Acute lymphatic (lymphoblastic) leukemia in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. In chronic lymphatic leukemia, the prognosis for adequate response is less encouraging.

Methotrexate in doses of 3.3 mg/m² orally in combination with prednisolone 60 mg/m² daily has been given for induction of remission of lymphoblastic leukemias.

When remission and general clinical improvement have been attained, a maintenance dosage of methotrexate 30 mg/m² orally twice weekly may be given. This treatment is expected to produce remission in 50% of patients treated, usually within 4 to 6 weeks.

Acute granulocytic leukemia is rare in children but common in adults. This form of leukemia responds poorly to chemotherapy and remissions are short with relapses common, and resistance to therapy develops rapidly.

Lymphomas: The usual dosage of methotrexate for the treatment of stage I or II of Burkitt’s lymphoma, is 10 to 25 mg per day orally for 4 to 8 days. In Stage III, methotrexate is commonly given concomitantly with other antineoplastic agents. In all stages courses of drug therapy are usually administered interposed with 7 to 10 days rest periods. Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily.

Methotrexate is of no value in the treatment of Hodgkin’s Disease.

Mycosis fungoides: Dosage of methotrexate for the treatment of mycosis fungoides is usually 2.5 to 10 mg orally each day for weeks or months. Initial dosage and dosage adjustment are determined by patient response and hematologic monitoring.

High-dosage therapy: Recent published literature should be consulted for details; dosage regimens have varied considerably in different studies depending upon the nature and severity of the disease, the experience of the investigator etc. It must be emphasised that high dosages should be only used by qualified specialists and in hospitals where the necessary facilities are available.

In order to prevent precipitation of methotrexate in the renal tubules, the patients should maintain an adequate urine flow by drinking plenty of fluids for 2 days after a high dose injection (greater than 200 mg) and keep the urine alkaline by using sodium bicarbonate continuously for at least 24 hours afterwards.

Psoriasis chemotherapy
The patient should be fully informed of the risks involved and should be under constant supervision of the physician.

Assessment of renal function, liver function, and blood elements should be made by history, physical examination, and laboratory tests (such as haemogram, urinalysis, serum creatinine, liver function studies and liver biopsy if indicated) before beginning Methotrexate, periodically during methotrexate therapy, and before reinstituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception for at least 12 weeks following methotrexate therapy.

There are three commonly used general types of dosing schedules:

• weekly oral intermittent large doses;

• divided dose intermittent oral schedule over a 36-hour period;

• daily oral with a rest period.

All schedules should be continually tailored to the individual patient. A single test dose of 5 to 10 mg parenterally one week prior to initiation of therapy is recommended to detect any idiosyncratic reaction.

Recommended dose schedules for a 70kg adult are:

• Weekly single oral dose schedule: 10 to 25 mg per week until adequate response is achieved. Weekly dosage should not exceed 50 mg.

• Divided oral dose schedule: 2.5 mg orally at 12-hour intervals for three doses or at 8-hour intervals for four doses each week. Weekly dosage should not exceed 30 mg.

• Daily dose schedule: 2.5 mg orally daily for five days followed by a rest period of at least 2 days. Daily dosage should not exceed 6.25 mg.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated. After optimal response is achieved, each dosage schedule should be reduced to the lowest possible dose with the largest possible rest period. Conventional topical therapy should be resumed as soon as possible.

Rheumatoid arthritis chemotherapy
The patient should be fully informed of the risks involved and should be under constant supervision of the doctor.

Assessment of haematological, hepatic, renal and pulmonary function should be made by history, physical examination and laboratory tests before beginning, periodically during and before reinstituting methotrexate therapy. Appropriate steps should be taken in men and women to avoid conception during methotrexate therapy.

Both the doctor and the pharmacist should emphasise to the patient the importance of the weekly dosage regimens: mistaken daily use may cause serious and sometimes life threatening or fatal toxicity.

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Complete blood count with platelets should be evaluated seven to ten days later.

Recommended starting dosage schedules are single oral doses of 7.5 mg once weekly or divided oral doses of 2.5 mg at twelve-hour intervals for three doses given as a course once weekly.

Therapeutic response usually begins within three to six weeks and the patient may continue to improve for another twelve weeks or more. The dosage in each schedule may be increased to 15 mg/week after six weeks in non-responsive patients. If necessary, dosage may be gradually increased further to achieve optimal response, but not ordinarily to exceed a total weekly dosage of 20 mg. Once response has been achieved, each schedule should be reduced, if possible, to the lowest possible amount of drug and with the longest rest period.

The optimal duration of therapy is unknown. Limited data available from long-term studies indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within three to six weeks.

Use in elderly
Due to diminished hepatic and renal function as well as decreased folate states in elderly patients, relatively low doses should be considered and these patients should be closely monitored.

Instructions for handling
The following protective recommendations are given due to the toxic nature of this substance:

• Personnel should be trained in good handling technique.

• Pregnant staff should be excluded from working with this drug.

• A designated area should be assigned for preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper.

• All items used for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration accidental contact with the skin or eyes should be treated immediately by copious.

• Lavage with water or sodium bicarbonate solution; medical attention should be sought.

Contraindications

• Methotrexate is contraindicated in patients with severe renal impairment.

• In the treatment of psoriasis and rheumatoid arthritis, methotrexate is contraindicated in pregnant women and in patients with poor nutritional status, bone marrow depression, hepatic disorders or in those with pre-existing blood dyscrasias such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anaemia.

• Methotrexate is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndrome(s).

• Breast-feeding is contraindicated in women taking methotrexate. Methotrexate is contraindicated in rheumatoid arthritis patients with active, infectious disease or psoriasis patients with serious infections, and in psoriasis and rheumatoid arthritis patients with peptic ulcer disease or ulcerative colitis. Methotrexate is contraindicated in psoriatic and rheumatoid arthritis patients suffering severe renal disorders, alcoholism or hepatic disorders including alcoholic liver disease or other chronic liver disease.

• Methotrexate is contraindicated in patients with a known hypersensitivity to it or any excipients in the formulation.

• Radiotherapy to the central nervous system should not be given concurrently with intrathecal methotrexate.

• An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Therefore, the combination of methotrexate and acitretin is also contraindicated.