Methotrexate Sodium Injection USP

METHOTREXATE SODIUM INJECTION USP

Faulding

Antimetabolite

Action And Clinical Pharmacology: Methotrexate is an antimetabolite which competitively inhibits the enzyme folic acid reductase. During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, methotrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of methotrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, methotrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues.

The basis for the use of methotrexate in psoriasis lies in the fact that the rate of production of the epithelial cells in this skin condition are greatly increased over normal and thus methotrexate affects the psoriatic tissues which are reproducing at a greater rate than the normal skin cells.

Indications And Clinical Uses: Antineoplastic Chemotherapy: For the treatment of gestational choriocarcinoma, and in patients with chorioadenoma destruens and hydatidiform mole.

For the palliation of acute and subacute lymphocytic and meningeal leukemia. The greatest effect of methotrexate is in the palliation of acute lymphoblastic (stem-cell) leukemia.

Methotrexate is also effective in the treatment of the advanced stages (III and IV, Peters’ Staging System) of lymphosarcoma, especially in children, and in advanced stages of mycosis fungoides.

Psoriasis Chemotherapy: Because of the high risk attending its use, methotrexate is only indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established and the need for therapy has been confirmed by dermatologic consultation.

Contra-Indications: Pregnancy: Methotrexate has caused fetal deaths and congenital abnormalities.

Methotrexate is contraindicated in the presence of pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia and anemia. Kidney disease. Liver disease including fibrosis, cirrhosis, recent or active hepatitis. Active infectious disease. Active peptic ulcer. Ulcerative colitis.

Manufacturers’ Warnings In Clinical States: Methotrexate is a potent and potentially fatal drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Renal and hepatic function must be assessed prior to therapy and frequently during therapy. Blood counts should be taken once or twice weekly.

Methotrexate should be used only by physicians who are experienced in providing antimetabolite chemotherapy.

Methotrexate, preservative-free is recommended for intrathecal administration to eliminate the possibility of preservative toxicity.

Patients should be fully informed by the physician of the risk of fatal or severe toxic reactions involved with the administration of methotrexate and they should be under the physician’s constant supervision.

It is recommended that a liver biopsy be taken prior to methotrexate therapy and periodically thereafter during methotrexate therapy.

Methotrexate therapy is not recommended in patients who are known to ingest excessive quantities of alcohol. The concomitant use of hepatotoxic drugs and alcohol should be avoided.

During the treatment of psoriasis with methotrexate, deaths have been reported. Although the reasons for the sudden deaths have not been completely explained, it appears that they may be due to hypersensitivity reactions.

Methotrexate should be restricted to severe recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of therapy and only when the diagnosis of psoriasis has been established following dermatologic consultation.

Methotrexate is toxic to the hematopoietic system and may produce depression of the bone marrow, anemia, leukopenia, thrombocytopenia and bleeding.

At high or prolonged doses, methotrexate may be hepatotoxic. Liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Hepatic function should be determined prior to initiation of methotrexate treatment, as changes may occur without previous signs of gastrointestinal or hematologic toxicity. Furthermore, hepatic function should be monitored regularly throughout each course of therapy.

The concomitant use of steroidal anti-inflammatory drugs may potentiate methotrexate toxicity.

In men and women of fertile age, steps should be taken to avoid conception during methotrexate therapy. The risk of genetic abnormalities may persist after discontinuing methotrexate therapy. Thus, it is advised that both men and women avoid intercourse leading to conception for an indefinite period (at least 8 weeks) after taking methotrexate to ensure the re-establishment of normal germinal cells.

Interruption of methotrexate therapy as a result of toxicity is indicated in the following situations: ulcerative stomatitis, severe diarrhea, hemorrhagic enteritis, hepatic fibrosis or cirrhosis, impaired liver function, impaired renal function, suppression of the hematopoietic system.

Precautions: Methotrexate has a high potential for toxicity which is usually dose-related.

Before using methotrexate the physician should be familiar with the various characteristics and established clinical usage of methotrexate.

Methotrexate patients should be kept under appropriate supervision so that signs and symptoms of toxicity or adverse effects may be detected and evaluated as early as possible.

The use of methotrexate in chemotherapy requires pretreatment and periodic hematologic evaluations as a result of its hematopoietic suppressive effects.

Methotrexate administration should be discontinued if an unexpected large drop in white blood cell count occurs and appropriate therapy instituted.

The drug should be used with caution, if at all, in patients with malignant disease in which there is pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anemia.

Because methotrexate is excreted primarily by the kidneys, impaired renal function can lead to drug accumulation with resultant toxicity or even additional renal damage. Therefore, pre-existing kidney disease is considered a contraindication to methotrexate therapy. It is recommended that the renal status of the patients proposed for methotrexate therapy be determined prior to beginning therapy and at appropriate intervals during therapy. Caution should be taken if significant renal damage is present, and drug dosage should be reduced or discontinued until renal function is improved or restored.

The following laboratory tests should be carried out as part of the clinical evaluation and monitoring of patients on methotrexate therapy: complete hemogram, hematocrit, urinalysis and renal function tests. A liver biopsy is mandatory. A chest x-ray is recommended.

The reason for the above tests is to determine any pre-existing organ function or system impairment. Tests should be performed prior to, during and after termination of therapy. If high-dose long-term therapy is used, it is imperative that liver biopsy and bone marrow aspiration studies be completed.

Drug Interactions: Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs, such as salicylates, sulfonamides, diphenylhydantoin and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulfonamides, whether antibacterial, hypoglycemic or diuretic, should not be given concurrently until the significance of these findings is established.

Because of the potential for drug interaction, corticosteroids should not be given concurrently with methotrexate.

Vitamin preparations containing folic acid or its derivatives may alter responses to methotrexate.

Use methotrexate with extreme caution when infection is present and in patients with peptic ulcer, ulcerative colitis or general debilitation. Also exercise caution with the use of methotrexate in young children and in the elderly.

Bacterial infection may be a threat or may occur if profound leukemia occurs during therapy. In this instance the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.

The possible immunosuppressant action of methotrexate should be taken into consideration when considering the use of the drug in patients where immune responses are important or essential.

When considering the use of methotrexate for chemotherapy, clinicians must evaluate the need and potential value of the drug against the risks, adverse reactions or toxic effects.

Most adverse effects are reversible if detected early. When adverse reactions occur, the dosage should be reduced or the drug discontinued and appropriate corrective action taken according to the clinical judgment of the physician. Caution should be taken when reinstituting methotrexate therapy and adequate consideration given to the need for further drug administration as well as being alert to the possible recurrence of toxicity.

Adverse Reactions: The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin: erythematous rashes, pruritus, urticaria, photosensitivity, depigmentation, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.

Blood: bone marrow depression, leukopenia, thrombocytopenia, anemia, hypogammaglobulinemia, hemorrhage from various sites, septicemia.

Alimentary: gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or hepatic cirrhosis.

Urogenital: renal failure, azotemia, cystitis, hematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal defects, severe nephropathy.

CNS: headaches, drowsiness, blurred vision. Aphasia, hemiparesis, paresis and convulsions have occurred, possibly related to hemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis and Guillain-Barré syndrome, increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to or attributed to the use of methotrexate, such as pneumonitis, metabolic changes, precipitating diabetes, osteoporotic effects, abnormal tissue cell changes and even sudden death have been reported. Although not completely explained as yet, the sudden death would appear to point to the possibility of hypersensitivity reactions.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Discontinue or reduce dosage at the first sign of ulceration or bleeding, diarrhea or marked depression of hematopoietic system.

Leucovorin (citrovorum factor) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the hematopoietic system. When large doses or overdoses are given, calcium leucovorin may be administered by i.v. infusion in doses up to 75 mg within 12 hours, followed by 12 mg i.m. every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of leucovorin calcium may be given i.m. every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of leucovorin should be equal to or higher than the dose of methotrexate and is best administered within the first hour. Use of leucovorin calcium after an hour’s delay is much less effective.

Dosage And Administration: Antineoplastic Chemotherapy: Sodium methotrexate for injection may be given by i.m., i.v. or intra-arterial routes. The preparation without preservatives could also be used for intrathecal administration. It is recommended that initial treatment takes place with the patient under hospital supervision.

Administration of methotrexate tablets is often preferred over the parenteral route. Absorption is rapid and effective serum levels are obtained in 1 to 2 hours. Methotrexate sodium parenteral may be given by i.m., i.v., intra-arterial or intrathecal route. Initial treatment is usually undertaken with the patient under hospital care.

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

Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered in doses of 15 to 30 mg daily for a 5 day course. Such courses are usually repeated 3 to 5 times, as required, with rest periods of 1 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 (CGH), which should return to normal or less than 50 IU/24 hours, usually after the third or fourth course, with a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of CGH are 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 choriocarcinoma.

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 alone or in combination with steroids was used initially for induction of remission of lymphoblastic leukemias. More recently, corticosteroid therapy in combination with other antileukemic drugs or in cyclic combinations with methotrexate appears to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/min combination with prednisone 60 mg/m given daily, produced remission 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 as follows: methotrexate is administered 2 times weekly in doses of 30 mg/m It has also been given in doses of 2.5 mg/kg i.v. every 14 days. If and when relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regime. A variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and anti-folic agents have been proposed. Multiple drug therapy with several agents, including methotrexate, given concomitantly is gaining increasing support in both the acute and chronic forms of leukemia. The physician should become familiar with the new advances in antileukemia therapy.

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.

Meningeal leukemia: Some patients with leukemia are subject to leukemic invasion of the CNS. This may result in characteristic signs or symptoms or may remain silent and be diagnosed only by examination of the CSF, which contains leukemic cells. The CSF should be examined in all leukemic patients. Since the penetration of methotrexate into the CSF is minimal, adequate therapy requires intrathecal administration. Some clinicians have given such chemotherapy in a prophylactic regime, but such a procedure is of doubtful value, and the more common approach is to treat such patients who manifest leukemic involvement by direct intrathecal instillation of methotrexate.

Methotrexate is administered by intrathecal injection of the sodium salt in solution in doses of 0.2 to 0.5 mg/kg body weight. Administration is at intervals of 2 to 5 days and is usually repeated until the cell count of the CSF returns to normal. At this point, 1 additional dose is advised. A second common course of administration is methotrexate 12 mg/monce weekly for 2 weeks then once monthly. 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 toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukemic involvement of the CNS may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas: In Burkitt’s tumor, stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In stage III, methotrexate is commonly given concomitantly with other antitumor 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: Therapy with methotrexate appears to produce clinical remission in one-half of the cases treated. Dosage is usually 2.5 to 10 mg daily by mouth for weeks or months. Dose levels of drug and adjustment to dose regimen with reduction or cessation of drug are guided by patient response and hematologic monitoring.

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

Methotrexate therapy should be restricted to patients whose psoriasis is so extensive or severe that it seriously interferes with physical, emotional or economic well-being and is not adequately controlled by standard, topically applied anti-psoriatic therapy. Methotrexate therapy has been widely used for patients and has provided effective therapy. Most studies indicate that about three-quarters of patients benefit from the treatment.

Either oral or parenteral methotrexate may be used for the treatment of psoriasis. With the use of methotrexate for injection, the following dosage schedule is recommended: weekly intermittent i.v. large doses; divided oral doses, intermittent over 36 hours.

These schedules should be continually tailored to the individual patient. Dose schedules cited below pertain to an average 70 kg adult. An initial test dose 1 week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5 to 10 mg parenterally.

Recommended Starting Dose Schedules: Weekly single oral, i.m. or i.v. dose schedule: 10 to 25 mg per week until adequate response is achieved. With this dosage schedule, 50 mg per week should ordinarily not be exceeded.

Divided oral dose schedule: 2.5 mg at 12-hour intervals for 3 doses or at 8-hour intervals for 4 doses each week. With this dosage schedule, 30 mg per week should 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 should be reduced to the lowest amount of the drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

Assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests (such as CBC, urinalysis, serum creatinine, liver function studies and liver biopsy) before beginning methotrexate therapy and before re-instituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception during and for at least 8 weeks following methotrexate therapy.

Dilution: Methotrexate Sodium Injection USP may be diluted with any of the solutions for i.v. infusion listed below in a concentration range of 0.4 mg/mL to 2 mg/mL. Dilutions should be used within 24 hours if kept at room temperature. Unused solution should be discarded after this time in order to avoid risk of microbial contamination.

Solutions: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 4% Dextrose and 0.18% Sodium Chloride Injection and Ringer’s Injection.

Pharmacy Bulk Vials: The availability of Pharmacy Bulk Vials is restricted to hospitals with a recognized i.v. admixture program only.

Pharmacy Bulk Vials are intended for multiple dispensing for i.v. use only employing a single puncture (see Special Instructions, Handling and Disposal of Cytotoxic Drugs).

The Pharmacy Bulk Vial content should be dispensed within 8 hours. Any unused solution should be discarded within 8 hours. The diluted solutions prepared from the Pharmacy Bulk Vial should be used within 24 hours, when kept at room temperature, from the time of initial puncture of the Pharmacy Bulk Vial.

Pharmacy Bulk Vials contain no preservatives. Care must be taken to minimize the potential for inadvertent introduction of micro-organism during manipulation in the hospital environment.

Special Instructions – Handling and Disposal of Cytotoxic Drugs: Preparation of all antineoplastic agents should be done in a vertical laminar flow hood. Personnel preparing parenteral antineoplastic agents should wear PVC gloves, safety glasses, disposable gowns and masks. All needles, syringes, vials, ampuls and other materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more. Sealed containers may explode. Intact and unopened vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. If incineration is not available, the material should be neutralized usually with 5% sodium hypochlorite and/or 5% sodium thiosulfate, placed in sealed containers and deposited in land fill sites, according to local regulations. Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.

Availability And Storage: Pharmacy Bulk Vials: 25 mg/mL: Each mL of sterile, unpreserved, isotonic solution contains: methotrexate (as methotrexate sodium USP) 25 mg. Vials of 20, 40 and 200 mL.

Vials: 10 mg/mL: Each mL of sterile, unpreserved, isotonic solution contains: methotrexate (as methotrexate sodium USP) 10 mg. Vials of 2 mL.

25 mg/mL: Each mL of sterile, unpreserved, isotonic solution contains: methotrexate (as methotrexate sodium USP) 25 mg. Vials of 2 mL.

Each mL of sterile, preserved, isotonic solution contains: methotrexate (as methotrexate sodium USP) 25 mg. Vials of 2 and 20 mL.

Store below 25°C. Protect from light.

METHOTREXATE SODIUM INJECTION USP Faulding Antimetabolite

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