UNITREXATES Inj.

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  • Description

Description

UNITREXATES Inj.

(Methotrexate 50mg/2ml)

Visa No: VN2-222-14

 COMPOSITION

Each vial (2 ml) contains:

Methotrexate………………………………………….. 50 mg

Exipients: Sodium chloride, Sodium hydroxide, Hydrocloric acid, Water for injection.

PHARMACODYNAMICS

Methotrexate is a folic acid antagonist with antineoplastic effect. Methotrexate inhibits transformation of folic acid to tetrahydrofolic acid, by having a higher affinity to the enzyme dihydrofolate reductase than endogenous folic acid. DNA synthesis is inhibited, mitosis is arrested, and consequently Methotrexate is S–phase specific in action. Actively proliferating tissues such as rapidly dividing malignant cells, bone–marrow, foetal cells and tissues, skin epithelium, buccal and intestinal mucosal epithelium are the cells which are most sensitive to the effect of Methotrexate.

Methotrexate has an immunosuppressive effect, which is used in treatment of rheumatoid arthritis. The mechanism of action in the management of rheumatoid arthritis includes immunosuppressive and/or antiinflammatory effects. The immune suppressive action is also used to suppress graft–versus–host reactions after bone–marrow transplantation.

PHARMACOKINETICS

Absorption, metabolism

Rapid and complete absorption is achieved following intramuscular administration.

Maximum serum concentrations of Methotrexate are reached 1–2 hours after oral dosage. Large inter- and intra-individual variations are documented, especially during repeated dosage. Saturation of the peroral absorption occurs after doses exceeding 30 mg/m2 approximately 50% of the absorbed dose is bound to plasma proteins through reversible association.

Distribution

Methotrexate easily diffuses into tissues, and the highest concentrations are reached in liver and kidney. Methotrexate also penetrates into the cerebrospinal fluid (CSF).

Elimination

Elimination from plasma follows a triphasic elimination process and the majority of administered Methotrexate is eliminated into urine within 24 hours. Patients with decreased kidney function have prolonged half-life for Methotrexate and may risk accumulation and intoxication unless there is adequate dose adjustment.

INDICATIONS

  • Methotrexate has been used to produce regression in a wide range of neoplastic conditions:
  • Acute leukemias, non-Hodgkin’s lymphoma, soft-tissue and osteogenic sarcomas.
  • Solid cancer particularly breast, head and neck, lung and bladder, trophoblastic disease (choriocarcinoma, chorioadenoma destruens, hydatidiform mole).
  • Methotrexate has also been used in the treatment of severe, uncontrolled psoriasis which is not responsive to other therapy.

DOSAGE & ADMINISTRATION

  • Meningeal leukemia:

Methotrexate is given in following intrathecal doses:

Age Dose
< 1 year

1 year

2 year

> 3 year

adults

6 mg

8 mg

10 mg

12 mg

12 mg

For therapeutic treatment, intrathecal injection is repeated with an interval of at least 7 days. Treatment should continue until the cell count has returned to normal level and after that one extra dose shall be given.

For prothylactic use, the recommended treatment interval varies and relevant recent literature should be consulted.

  • Trophoblastic disease: Intramuscular, 15 – 30 mg daily for 5 five-day course. Such courses are usually repeated for 3 to 5 times at intervals of 7 – 12 days.
  • Breast cancer: Methotrexate is a component in the CMF-regimen (Cylophosphamide, Methotrexate, 5-Fluorouracil) within which the dosage of Methotrexate usually is 40 mg intravenously day 1 and day 8. Treatment is repeated with a 3 week interval.
  • Lung cancer: Methotrexate has a place in treatment of adenocarcinoma, epidermoid cancer and small cellular anaplastic carcinoma. For the two last cancers, Methotrexate is used alone in a dose of 50 mg intravenously every second weeks.
  • Epidermoid cancers of the head and neck: Treatment of patients who can not be treated with surgery and/or radiotherapy, Methotrexate can be used in the dose 200 mg/m2 intravernously every week, followed by leucovorin. In patients responding, the dosage interval can with time be increased to 2 weeks.
  • Bladder cancer: Intravenous infusion or intravenous injection, maximum dose is 100 mg/m2 every 2 weeks.
  • Osteosarcoma: Recommended dose is 600 – 9,000 mg/m² intravenously, followed by Leucovorin rescue.
  • Non-Hodgkin lymphoma: Recommended dose is 90 – 900 mg/m² intravenous infusion or intravenous injection, followed by high-dose Leucovorin rescue.
  • Psoriasis: For the management of psoriasis, a single 5 to 10 mg dose of methotrexate should be given 1 week prior to initiation of methotrexate therapy to detect idiosyncratic reactions. For the treatment of severe psoriasis 10-25 mg orally, once weekly, is recommended. However, intravenously or intramuscularly may be administered: initially 10 mg once week, the dosage being increased as necessary up to 25 mg once week, based on individual requirements and response.

Methotrexate should be used alone, or concomitantly with radiotherapy, surgical therapy. Determination of dosage should be considered.

WARNINGS

Methotrexate must be prescribed only by physicians experienced in antimetabolite chemotherapy. Because of the possibility of fatal or severe toxic reactions the patient should be fully informed by the doctor of the risks involved and should be under constant supervision.

CONTRAINDICATIONS

Methotrexate contraindicated with the following patients:

  • Patients with a history of hypersensitivity to this drug.
  • Patients with severe kidney failure or liver failure.
  • Patients with hydrothorax and ascites (prolonged retention of hydrothorax and ascites may enhance the toxicity).
  • Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia significant anemia.
  • Patients who have overt or laboratory evidence of immunodeficiency syndromes.
  • Patients with psoriasis or rheumatoid arthritis, contraindications with the following cases: alcoholism, alcoholic liver disease, or other chronic liver disease.
  • Pregnant women or nursing mothers.

PRECAUTIONS

Methotrexat should be used with cautions on the following pateints:

  • Patients with kidney failure (elimination of this drug may delay).
  • Patients with liver impairment.
  • Patients with diarrhea or ulcerative stomatitis (splanchnic perforation may result in hemorrhagic enteritis and death).
  • Patients with gastric ulcer or colitis ulcerativa.
  • Patients with hematologic disorder.
  • Patients with bone marrow depression.
  • Patients with chickenpox (lethal systemic impairment may occur)
  • Patients with complication with infections.
  • Patients with mental disorder.
  • The elderly and children.

GENERAL PRECAUTIONS

  • Since crucial adverse effects such as bone marrow depression, hepatic impairment, renal impairment may occur, a patient’s condition should be monitored and clinical tests (e.g., bleed test, hepatic function test, kidney function test, urine test) performed frequently. If any symptoms occur, appropriate therapy such as reduction or discontinuance of the dosage should be instituted.
  • Manifestation or depravation of infection, bleeding tendency should be cautioned.
  • Use in children or patients who are possible to be pregnant should be considered of the effect on gonad.
  • The renal impairment by the administration of this drug is due primarily to the precipitation of Methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization, and elimination by urine and measurement of serum Methotrexate and creatinine levels are essential for safe administration.
  • Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. When pulmonary disease is suspected, lung function test such as baseline measurement is effective.
  • Since low-dose, long-term therapy of methotrexate may particularly occur liver toxicity, hepatic function tests should be needed regularly. If any symptoms occur, the administration should be discontinued at least for 2 weeks.
  • The effects on spermigenesis, ovogenesis by the administration of this drug may decrease reproductive function reversely, pregnancy should be avoided at least for 6 months after therapy.
  • Since this drug has immunosuppressive function, it may decrease immune response of vaccine. Concomitant administration with live vaccine may occur serious antigen response.
  • When elements counts of bleed are increased, the administration should be discontinued, and supportive therapy such as bleed transfusion or reverse barrier nursing should be instituted.
  • Hemopoietin depression even at low-dose may occur suddenly.
  • In case of radiotherapeutics to central nervous system, concomitantly intraspinal administration of this drug should not recommended.
  • Since the drug contains tartrazine as a coloring agent, patients with hypersensitivity to the drugs or a history of allergy should be with caution administered.

DRUG INTERACTIONS   

The following drug combinations with Methotrexate should be avoided: non steroidal anti inflammatory drugs, such as Azapropazone, Diclophenac, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Naproxen, Probenecid, and salicylic acid derivatives; Pyrimethamine, vaccines.

The following drug combinations with Methotrexate will cause need for dose adjustment: Mercaptopurin, Penicillin, Theophyllin.

Per oral antibacterial drugs, such as Tetracyclin, Cloramphenicol and non-absorbed broad spectrum antibiotics can decrease the absorption and the metabolism of Methotrexate.

Treatment with trimethoprim/ sulfamethoxazole after treatment with Methotrexate has in some cases been known to cause megaloblastic pancytopenia. Vitamin treatment with fonilic acid can decrease the risk of this adverse effect of Methotrexate.

ADVERSE EFFECTS

Shock: Rarely, shock may occur, should be monitored sufficiently. If necessary, the administration should be discontinued and appropriate therapy instituted.

Gastrointestinal: If gastrointestinal tract ulcer, bleeding, stomatitis, abdominal pain, diarrhea, nausea, vomiting occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Anorexia, black vomit.

Respiratory system: Death by interstitial pneumonia has been reported. Occasionally, chronic interstitial occlusive pulmonary disease, pulmonary fibrosis may occur. Pulmonary symptoms (especially a dry, non productive cough) or nonspecific pneumonia may be the symptoms of risk potential impairment, and may occur in, therefore require discontinuance of treatment and carefully investigation.

Psychoneural system: Headache, dizziness, blurred vision, dysphasia, hemiplegia, paralysis, convulsion, coma, tension of neck and head, backache may occur.

Urogenital system: Aspermia, ovarian insufficiency, catamenia insufficiency, infertility, abortion, fetal abnormality may occur.

Hematologic: Anemia, leukopenia, thrombocytopenia, bleeding, hypogammaglobulinemia, ichoremia may occur. If granulocytopenia and flush occur, should be examined immediately and appropriate therapy such as parenteral extensive antibiotic agents should be instituted.

Hepatic: Hepatic impairments (increases of GOT, GPT, AL-P), jaundice, fatty liver, sphacelism of liver tissue, fibrosis of liver tissue, hepatocirrhosis may occur. When crucial fibrosis of liver tissue and hepatocirrhosis occur, the administration should be discontinued.

Renal: Ureteral necrobiosis, crucial nephropathy, hematuria, increases of BUN or creatinine value may occur. High-dose methotrexate for the treatment of osteosarcoma may occur acute kidney failure.

Hypersensitivity: Disorder of consciousness, hypotension, tachycarida, paralysis, sneeze, dyspnea, anxiety of the breast, cold, sweating may occur. If these occur, appropriate therapy should be instituted.

Skin: Photohypersensitivity, rash, urticaria, pruritus, erythematous rash, erythema, pigmentation, decoloration, subcutaneous ecchymosis, acne, calvities, telangiectasia, incised wound may occur.

Other: Malaise, parotiditis, blennophthalmia, cystitis, arthralgia, myalgia, diabetes, osteoporosis, accidental death may occur.

Inform your doctor in case of any adverse reactions related to drug use.

USE IN PREGNANCY AND NURSING MOTHERS

In animal study, Methotrexate have been reported teratogenic effects, therefore the drug is not used in pregnant women or women of childbearing potential.

Since safety use in breast feeding has not been established, methotrexate is not used in nursing mothers. If the administration is necessary, breast feeding should be discontinued.

USE IN THE ELDERLY AND CHILDREN

Clinical pharmacology in elderly has not been studied, the elderly have reservation of folic acid and low hepatic and renal function, therefore they should be administered by low-dose and monitored initial signs of toxicity.

Safety in prematures, neonates, infants (not more than 1 year) have not been established (Use-experience is not enough).

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Side effects on central nervous system, such as fatigue and dizziness, can occur during treatment with methotrexate which may have influence on the ability to drive and use machines.

OVERDOSAGE

Manifestions: Ulcerations of oral mucosa are usually the earliest signs of toxicity, but in some patients bone marrow depression coincides with or precedes the appearance of mouth lesions.

Treatment: Leucovorin calcium should be administered as soon as possible, preferably within the first hour, should not be administered intrathecally. Use of leucovorin after an hour ‘s delay is much less effective. In  general, the dose of leucovorin shoud be equal to or greater than that of methotrexate. When large doses or overdoses of methotrexate are given, leucovorin may be administered by I.V infusion in doses up to 75 mg within 12 hours, followed by 12 mg IM every 6 hours for 4 doses. If accidental overdosage of intrathecal occurs, intensive systemic supportive therapy (including administration of high dose leucovorin, alkaline diuresis, rapid CFS drainage, ventriculolumbar perfusion) may be required.

STABILITY OF DILUTED SOLUTION

If stored for 24 hours at a temperature of 21 to 25ºC, a diluted solution of methotrexate injection maintains 90% its label potency. However preservative free solutions should be diluted immediately prior to use and any unused portion discarded.

INCOMPATIBILITY

Methotrexate injection may be further diluted with an approriate preservative free-medium such as 0.9% sodium chloride injection or 5% dextrose injection. Methotrexate sodium has been reported to be incompatible with Cytarabine, Flurouracil, Prednisolone and Sodium phosphate.

SHELF LIFE

36 months from manufacturing date.

Do not exceed the expired date for use printed on the box.

STORAGE

Preserve in tight containers, protected from light.

Store at room temperature not exceeding 300C.

SPECIFICATION

BP 2012.

PACKAGE

10 Vials/ Box.

 Read Dosage & Administration carefully before using.

Keep out of reach of children.

This drug should be used only under prescription.

For any more information, please consult your doctor.

Manufactured by

KOREA UNITED PHARM. INC.

107, Gongdan-ro, Yeonseo-myeon, Sejong-si, Korea.