- Approval Id
- ff452e87d268cfee
- Drug Name
- DBL METHOTREXATE INJECTION BP 50 mg/2 ml (WITHOUT PRESERVATIVE)
- Product Name
- DBL METHOTREXATE INJECTION BP 50 mg/2 ml (WITHOUT PRESERVATIVE)
- Approval Number
- SIN00758P
- Approval Date
- 1988-05-04
- Registrant
- PFIZER PRIVATE LIMITED
- Licence Holder
- PFIZER PRIVATE LIMITED
- Drug Type
- Therapeutic
- Forensic Classification
- Prescription Only
- Dosage Form
- INJECTION
- Dosage
- **4.2 Dose 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.
**Dosage**
1. **Antineoplastic chemotherapy**
**_Trophoblastic neoplasms_**
Methotrexate is administered intramuscularly in doses of 15 mg to 30 mg daily for a five 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 hours, usually after the 3rd or 4th course. Complete resolution of measurable lesions usually occur 4 to 6 weeks later. One to two courses of methotrexate after normalization of CGH are usually recommended. Before each course of methotrexate, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antineoplastic drugs has been reported as being useful.
Since hydatidiform mole may precede 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.
**_Breast carcinoma_**
Prolonged cyclic combination chemotherapy 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.
**_Leukaemia_**
Acute lymphatic (lymphoblastic) leukaemia 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 leukaemia, 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 leukaemia. When remission and general clinical improvement have been attained, a maintenance dosage of methotrexate 30 mg/m2 IM (intramuscular) twice weekly may be given. This treatment is expected to produce remission in 50% of patients treated, usually within 4 to 6 weeks.
Alternatively, 2.5 mg/kg IV (intravenous) every 14 days may be given. Should relapse occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and antifolic agents have recently been introduced. Multiple drug therapy with several agents, including methotrexate given concomitantly, appears to be gaining increasing support in both the acute and chronic forms of leukaemia.
Acute granulocytic leukaemia is rare in children but common in adults. This form of leukaemia responds poorly to chemotherapy and remissions are short with relapses common. Resistance to therapy also develops rapidly.
**_Meningeal leukaemia_**
Patients with leukaemia are subject to leukaemic invasion of the central nervous system. This may manifest characteristic signs or symptoms or remain silent and be diagnosed only by examination of the cerebrospinal fluid (CSF), which contains leukaemic cells in such cases. Therefore, the CSF should be examined in all leukaemic patients. Since passage of methotrexate from blood serum to the CSF is minimal, for adequate therapy the drug is administered intrathecally. Only preservative-free methotrexate should be used for intrathecal administration.
It is now common practice to administer methotrexate intrathecally as prophylaxis in all cases of acute lymphocytic leukaemia.
By intrathecal injection the distribution of methotrexate is in the CSF, the volume of which is dependent upon age and not body surface area. The CSF is at 40% of adult volume at birth and reaches adult volume in several years. The recommended dose by age is:
**Age (yrs)**less than 1123+ older**Dose (mg)**681012
There is some indication that infants less than 4 months and adults 70 years of age or older may have increased acute toxicity with the doses recommended and dose reduction may be indicated.
For the treatment of meningeal leukaemia, intrathecal methotrexate may be given at intervals of 2 to 5 days, however there is some indication that doses given at intervals of less than one week may result in increased toxicity.
Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal, then one additional dose of the drug is administered.
For prophylaxis against meningeal leukaemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.
Large doses may cause convulsions. Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.
Methotrexate given by the intrathecal route appears in significant concentrations in the systemic circulation and may cause systemic methotrexate toxicity. Therefore systemic antileukaemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukaemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.
**_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, several courses of drug therapy are usually administered interposed with 7 to 10 day 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_**
Methotrexate has been given IM in doses of 50 mg once weekly or 25 mg twice weekly. Initial dosage and dosage adjustment are determined by patient response and haematologic monitoring.
Methotrexate appears to produce clinical remissions in 50% of the cases treated.
2. **High-dosage therapy (see section 4.4 Special warnings and precautions for use** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_ **)**
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.
3. **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.
The commonly used injectable dosage schedule is weekly parenteral intermittent large doses.
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 70 kg adult_**
Weekly single dose schedule: 10 to 25 mg IM or IV per week until adequate response is achieved. Weekly dosage should not exceed 50 mg.
Dosage may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated. After optimal response has been 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.
4. **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.
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.
**Method of administration**
**DBL Methotrexate Injection products suitable for IV, IM, intra-arterial or intrathecal use:**
DBL Methotrexate Injection 5 mg/2 mL
DBL Methotrexate Injection 50 mg/2 mL
DBL Methotrexate Injection 500 mg/20 mL
**DBL Methotrexate Injection products suitable for IV use only. Not for intrathecal use as the solution is hypertonic:**
DBL Methotrexate Injection 1 g/10 mL (Hypertonic)
A guideline of a ratio of 1:30 is given for the conversion 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.
**_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
- personnel handling injectable methotrexate should wear protective clothing including goggles, gowns and disposable gloves and masks
- 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.
- Route Of Administration
- INTRAVENOUS, INTRAMUSCULAR, INTRA-ARTERIAL
- Indication Info
- **4.1 Therapeutic 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 (see WARNINGS box** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_ **)**
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 (see WARNINGS box** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_ **)**
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.
- Contraindications
- **4.3 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, leukopenia, 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 to any of the excipients.
During methotrexate therapy concurrent vaccination with live vaccines must not be carried out.
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.
- Atc Code
- L01BA01
- Atc Item Name
- methotrexate
- Pharma Manufacturer Name
- PFIZER PRIVATE LIMITED
- Company Detail Path
- /organization/pfizer-private-limited
