METHOTREXATE INJECTION BP 1000mg in 10ml

INJECTION

**4.2 Dose and method of administration** **Dosage** 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. **_Antineoplastic Chemotherapy_** _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 only the first and eighth days. _Choriocarcinoma and Similar Trophoblastic Diseases_ Methotrexate is administered intramuscularly in doses of 15 mg to 30 mg daily for a five day course. Such courses are usually repeated three to five times as required with a rest period of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin hormone (β-hCG), which should return to normal or less than 50 units/24 hour usually after the 3rd or 4th course and usually followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalisation of β-hCG is usually recommended. Before each course of the drug, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumour 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 choriocarcinoma. _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 alone or in combination with steroids was used initially for induction of remission of lymphoblastic leukaemias. More recently, corticosteroid therapy in combination with other antileukaemic drugs or in cyclic combination therapy including methotrexate, has produced rapid and effective remissions. When used for induction, in doses of 3.3 mg/m2 in combination with prednisolone 60 mg/m2 given daily, remission occurred in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate alone, or in combination with other agents, appears to be the drug of choice for securing maintenance of drug induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, by administering methotrexate 2 times weekly intramuscularly in doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. _Meningeal Leukaemia_ Patients with leukaemia are subject to leukaemic invasion of the central nervous system (CNS). This may manifest characteristic signs or symptoms or may 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 cerebrospinal fluid is minimal, for adequate therapy the drug is administered intrathecally. It is now common practice to administer methotrexate intrathecally as prophylaxis in all cases of lymphocytic leukaemia. By intrathecal injection the distribution of methotrexate is in the CSF, the volume of which is dependent on 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:  There is some indication that infants less than 4 months and adults ≥70 years may have increased acute toxicity with doses recommended and dose reduction may be indicated. The solution is made in a strength of 1 mg/mL with an appropriate, sterile, preservative-free medium such as 0.9% Sodium Chloride Injection BP. Remove a volume of cerebrospinal fluid equivalent to the volume of methotrexate being administered. 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. Do not exceed the maximum recommended single dose of 15 mg. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point, one additional dose is advisable. 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 intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukaemic therapy with drug should be appropriately adjusted, reduced or discontinued. Focal leukaemic involvement of the CNS may not respond to intrathecal chemotherapy and is best treated with radiotherapy. _Lymphomas_ In Burkitt’s tumour, stages I–II, methotrexate has produced prolonged remission in some cases. Recommended dosage is 10 to 25 mg per day orally for 4 to 8 days. In stage III, 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. 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. Hodgkin’s Disease responds poorly to methotrexate and to most types of chemotherapy. _Mycosis Fungoides_ As an alternative to oral therapy, methotrexate 50 mg intramuscularly weekly or 25 mg intramuscularly twice weekly may be given. _High dose 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_ _)_ Dosage regimens have varied considerably in different studies, the nature and severity of the disease and the previous experience of the investigator are some of the factors influencing the choice of dosage and the duration of therapy. It must be emphasised that high dosages should be used only by qualified specialists and in hospitals where the necessary facilities are available. **_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 full blood count, 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 during and for at least 6 months following methotrexate therapy. The commonly used injectable dosage schedule is by weekly parenteral intermittent large doses. All schedules should be continually tailored to the individual patient. Dose schedules cited below pertain to an average 70 kg adult. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5 mg to 10 mg parenterally. _Recommended Starting Dose Schedules_ Weekly single IM or IV dose schedule: 10 mg to 25 mg per week until adequate response is achieved. With this dosage schedule, 50 mg per week should ordinarily not be exceeded. Dosage may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated for each schedule. Once optimal clinical response has been achieved the dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged. **Dosage Adjustment** _**Renal Impairment**_ Methotrexate is excreted primarily by the kidneys. In patients with renal impairment the dose may need to be adjusted to prevent accumulation of drug (see section 4.4 Special warnings and precautions for use, Use in Renal Impairment – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Method of Administration** **Methotrexate Injection (BP) products suitable for IV, IM or intrathecal use:** Methotrexate Injection BP 50 mg/2 mL Methotrexate Injection BP 500 mg/20 mL **Methotrexate Injection (BP) products suitable for IV use only. Not for intrathecal use as the solution is hypertonic:** Methotrexate Injection BP 1000 mg/10 mL (Hypertonic) For intrathecal injection, Methotrexate Injection should be diluted to a strength of 1 mg/mL with an appropriate preservative-free medium such as 0.9% Sodium Chloride Injection. For conversion of mg/kg bodyweight to mg/m2 of body surface area or the reverse, a ratio of 1:30 is given as a guideline. The conversion factor varies between 1:20 and 1:40 depending on age and body build. **Instructions for Handling** As with all antineoplastic agents, trained personnel should prepare Methotrexate Injection BP. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling methotrexate. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as methotrexate. Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation. Items used to prepare Methotrexate Injection BP, or articles associated with body waste, should be disposed of by placing in a double sealed polythene bag and incinerating at 1100°C. **Spills and Disposal** If spills occur, restrict access to the affected area. Wear two pairs of gloves (latex rubber), a respirator mask, a protective gown and safety glasses. Limit the spread of the spill by covering with absorbent material such as absorbent towel or adsorbent granules. Collect up the towel of absorbent/adsorbent material and other debris from spill and place in a leak proof plastic container and label accordingly. Cytotoxic waste should be regarded as hazardous or toxic and clearly labelled ‘CYTOTOXIC WASTE FOR INCINERATION AT 1100°C’. Waste material should be incinerated at 1100°C for at least 1 second. Cleanse the remaining spill area with copious amounts of water. Single use only. Discard unused portion.