UNITREXATES Tabs.

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  • Description

Description

UNITREXATES Tabs.

Methotrexate 2.5 mg

Visa No.: VN2-191-13

COMPOSITION

Each tablet contains:

Methotrexate……………………………………….. 2.5 mg

Exipients: Lactose monohydrate, corn starch, hydroxypropyl cellulose, magnesium stearate, povidone, sodium lauryl sulfate, sodium starch glycolate, yellow No. 4 (tartrazine).

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 anti-inflammatory effects. The immune suppressive action is also used to suppress graft–versus–host reactions after bone–marrow transplantation.

PHARMACOKINETICS

Absorption: When given in low doses, methotrexate is rapidly absorbed from the gastrointestinal tract, but higher doses are less well absorbed. Peak serum concentrations are achieved in 1 to 2 hours after an oral dose.

Distribution: Methotrexate is distributed to tissues and extracellular fluid with a steady-state volume of distribution of 0.4 to 0.8 litres/kg; it penetrates ascitic fluid and effusions, which may act as a depot and thus enhance toxicity. Clearance from plasma is reported to be triphasic, with a terminal elimination half-life of between 3 and 10 hours after doses less than 30 mg/m2. It is about 50% bound to plasma protein. Methotrexate enters the cells in part by an active transport mechanism and is bound as polyglutamate conjugates: bound drug may remain in the body for several months, particularly in the liver. Only small or insignificant amounts cross the blood-brain barrier and enter the CSF after oral doses although this may be increased by giving higher doses. Methotrexate has been detected in very small amounts in saliva and breast milk. It crosses the placenta.

Metabolism: Methotrexate does not appear to undergo significant metabolism at low doses; after high-dose therapy the 7-hydroxy metabolite has been detected. Methotrexate may be partly metabolised by the intestinal flora after oral doses.

Elimination: It is excreted primarily in the urine, by glomerular filtration and active tubular secretion. Small amounts are excreted in bile and found in faeces; there is some evidence for enterohepatic recirculation. 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 is indicated for the treatment of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, and hydatiform mole), leukemia.

Methotrexate is used in the treatment of rheumatoid arthritis.

And it is also used in the treatment of severe, uncontrolled psoriasis which is not responsive to other therapy.

DOSAGE & ADMINISTRATION

  1. Leukemias

Oral methotrexate dosage of 3.3 mg/m2 daily and prednisone 40-60 mg/m2 daily for 4-6 weeks have been used. The maintenance dosage is 30 mg/m2 per week, divides 2 times, orally or by IM injection or 2.5 mg/kg has been administered IV every 14 days.

  1. Trophoblastic

UNITREXATES is administered orally in dose of 10-30 mg daily for a 5-day course. A repeat course may be given after a rest period of 7-12 days provided all signs of residual toxicity have disappeared.

  1. Rheumatoid arthritis

7.5-20 mg once weekly or every 12 hours in three divided doses, orally.

  1. Psoriasis

7.5-20 mg once weekly or every 12 hours in three divided doses, orally.

CONTRAINDICATIONS

Methotrexate is contradicated in the following patients:

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

CAUTIONS

Methotrexate should be with caution administered in the following patients:

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

GENERAL PRECAUTIONS

  1. 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.
  2. Manifestation or depravation of infection, bleeding tendency should be cautioned.
  3. Use in children or patients who are possible to be pregnant should be considered of the effect on gonad.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Since this drug has immunosuppressive function, it may decrease immune response of vaccine. Concomitant administration with live vaccine may occur serious antigen response.
  9. 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.
  10. Hemopoietin depression even at low-dose may occur suddenly.
  11. In case of radiotherapeutics to central nervous system, concomitantly intraspinal administration of this drug should not recommended.
  12. 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

Protein-bound drugs and weak organic acids

Because methotrexate is partly bound to serum proteins, its toxicity may be increased as a result of displacement by certain drugs such as salicylates, sulfonamides, sulfonylureas, phenytoin, phenylbutazone, tetracyclines, chloramphenicol, and aminobenzoic acid. These drugs should be given cautiously in patients receiving methotrexate. In addition, the possibility that weak organic acids, including salicylates, may delay renal excretion of methotrexate and increase accumulation should be considered.

Nonsteroidal anti-inflammatory drugs

Severe, sometimes fatal, toxicity (including hematologic and GI toxicity) has occurred following administration of a NSAIDs (e.g., indomethacin, ketoprofen) concomitantly with methotrexate (particularly with high-dose therapy) in patients with various malignant neoplasms, psoriasis, or rheumatoid arthritis. The toxicity was associated with elevated and prolonged serum concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIDs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination.

NSAIDs should be avoided in patients receiving relatively high dosages of methotrexate (e.g., those used in the treatment of neoplastic disease). The risk of concomitant low-dose, intermittent (e.g., 5-15 mg weekly) methotrexate therapy and NSAIDs has not been fully elucidated. However, NSAIDs should be used with caution in patients receiving low-dose methotrexate regimens such as those employed in the management of rheumatoid arthritis, and the possibility of increased and prolonged serum methotrexate concentrations and resultant toxicity should be considered. Although intermittent regimens also are used in the management of psoriasis, methotrexate dosages in such regimens usually are higher than those used in the management of rheumatoid arthritis and therefore are more likely to result in toxicity during concomitant NSAIDs therapy; serious toxicity, including at least one death, has been reported in several patients with psoriasis receiving combined therapy with the drugs.

Penicillins

Concomitant use of penicillins (e.g., amoxicillin, carbenicillin, mezlocillin) may decrease renal clearance of methotrexate, presumably by inhibiting renal tubular secretion of the drug. Increased serum concentrations of methotrexate, resulting in GI or hematologic toxicity, have been reported in patients receiving low- or high-dose methotrexate therapy concomitantly with penicillins, and patients receiving the drugs concomitantly should be carefully monitored.

Other Drugs

Drugs with similar pharmacologic activity such as pyrimethamine should not be given to patients receiving methotrexate.

Co-trimoxazole should be used with caution in patients receiving methotrexate, since sulfonamides can displace methotrexate from plasma protein-binding sites resulting in increased free methotrexate concentrations.

Vaccination with live virus vaccines generally should not be performed in patients receiving methotrexate. Disseminated vaccinia infection has been reported following smallpox vaccination in at least one patient receiving methotrexate. Although the antibody response to killed virus vaccines is not normal, partial or complete protection may still be attained and these vaccines may be used if necessary in patients receiving methotrexate.

It has been suggested that folic acid preparations including vitamin products may decrease the effectiveness of methotrexate therapy and should not be given to patients receiving methotrexate; however, there have been no clinical studies to support or refute this hypothesis.

Concomitant use of other potentially hepatotoxic drugs (e.g., retinoids, azathioprine, sulfasalazine) and methotrexate may increase the risk of hepatotoxicity; patients receiving concomitant administration of these drugs should be closely monitored.

Methotrexate may decrease clearance of theophylline; serum theophylline concentrations should be monitored in patients receiving theophylline concomitantly with methotrexate.

ADVERSE EFFECTS

Adverse drug reactions, type I

Low-dose treatment as anti-rheumatic or antipsoriatic drug. During treatment with low dose methotrexate as antirheumaticum or antipsoraticum, the most frequent reactions are nausea and elevated liver enzymes in plasma.

Common, ADR > 1/100

General: Headache, vertigo.

Gastrointestinal tract: Nausea, stomatisis, diarrhea, vomiting, anorexia.

Skin: Alopecia, skin reactions with effusion.

Liver: Significant elevation of liver enzyme in plasma.

Other: Increase risk of infections.

Less common, 1/1000 < ADR < 1/100

Blood: Nose bleeding, leukopenia, thrombocytopenia.

Skin: Itching.

Airways: Pulmonary fibrosis, pneumonitis.

Urogenital: Vaginal ulcerations.

Rare, ADR < 1/1000

General: Impotence.

CNS: Depression and confusion.

Other: Decrease libido.

Comment about adverse reactions, during low-dose treatment

Risk factors for reacting with liver toxicity is obesity, diabetes mellitus and decreased kidney function. Lung disease caused by methotrexate is a potentially severe complication which can develop at anytime during treatment, and this reaction has been reported after as low dosed as 7.5 mg of methotrexate per week. The lung toxicity is not always reversible. Symptoms from the lung with a dry, non-productive cough, should cause alarm and calls for investigation of lung. Until lung toxicity is excluded, treatment shall be discontinued.

Death has been reported as consequence of methotrexate induced chronic interstitial lung disease. The ling alterations which occur during methotrexate treatment of rheumatoid arthriris can also be manifestations of the disease itself.

A test dose of 2.5 mg should be given before initiating full maintenance therapy, in order to test patient for eventual idiosyncrative reaction.

Full control of blood picture should be performed before treatment and repeatedly after on week of treatment and from then on preferentially once per month.

Lung X-ray should be performed before treatment and in case of suspected lung toxicity.

Liver biosy has been recommended in many cases, after the patient has reached a cummulative dose of 2 g and new biopsy after the patient has reached the next 2 g or every 6-18 months.

Adverse drug reaction, type II

Concentional antineoplastic high-dose treatment. The frequency of adverse reactions and severity depends on dose, treatment duration and administration route. Treatment with folinic acid during high dose thepary can counteract or minimize several adverse reactions. In case of leukopenia it is recommended that methotrexate is discontinued of sometime.

Antidote: Folinic acid 10 mg/m2 intravenous or orally every 6 hours until methotrexate concentrations have dropped below 5 x 10-8 mol/litre plasma.

Common, ADR> 1/100

Blood: Bone marrow suppression causing leukopenia, thrombocytopenia and anemia, also at low dose.

Gastrointestinal tract: Stomatitis, especially after high-dose treatment, nausea, vomiting and diarrhea, anorexia.

Skin: Erythematous rask, prutitus, urticaria.

Liver: Hepatitis after high-dose treatment for long time; transient reversible transaminase elevation after single injection.

Urogenital: Decreased kidney function, especially after high-dose treament.

Less common, 1/1000 < ADR < 1/100

General: Allergic reactions, immunosuppression.

Gastrointestinal tract: Gastrointestinal bleedings and ulcerations, enteritis.

Skin: Erythema, pruritus and urticaria, alopecia especially after high dose and long term treatment, reactivation of phototoxicity.

Liver: Fibrosis and cirrhosis also at low-dose given more frequently than 12 days per month, long lasting transaminase elevation without live toxicity at low-dose given less often than 12 days per month.

Musculoskeletal: Osteoporosis.

Neurology: Epileptic seizures and headache after high-dose treatment.

Urogenital: Decreased fertility and reproduction toxicity in the form of defectogenesis and inhibited spermatogenesis, transient oligospermia, menstrual disturbances and infertility. Decreased kidney function after conventional doses.

Eye: Conjunctivitis.

Others: Aggravating toxic effects of radiotherapy.

Rare, ADR < 1/1000

General: Vertigo.

Circulation: Vasculitis in hands and feet.

CNS: Depression and confusion.

Airways: Interstitial pneumonitis with non-productive cough, respiratory difficulties and fever also after long-lasting low dose treatment.

Neurology: Epileptic seizure, headache, encephalopathy after high dose treatment.

Other: Impotency.

Lung disease caused by methotrexate is a potentially life-threatening complication which can debute at any time during treatment. A lasting or sudden non-productive dry cough should always lead to the suspicion of lung toxicity, and then treatment should be discontinued, and the patient examined.

Instructions about how to manage adverse and side effects

Stomatitis can be counteracted and controlled to some degree by repeated mouth wash containing folic acid. The neurological adverse effects are usually reversible after dose-reduction or discontinuation.

In order to avoid renal precipitations it is recommended to alkaline, the urine and adequate hydration of the patients with at least 3 litres per 24 hours. Renal function can deteriorate after high dose therapy so much that the methotrexate elimination is decreased, which can lead to elevated methotrexate concentrations, and intoxication.

In patient with decreased liver function, adverse effects of methotrexate, above all stomatisis is aggraveted.

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.

Methotrexate reaches measureable concentration in breast milk and ther is risk for effects in the child if the mother is breast feeding during treatment with methotrexate. Breast feeding shall be therefore stop if methotrexate is needed.

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.

In case of severe overdosage of methotrexate, hydration and urinary alkalinization may be needed to prevent precipitation of the drug and/or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis generally have been ineffective in improving the elimination of methotrexate.

STORAGE

Preserve in tight containers. Store at room temperature not exceeding 300C.

SHELF LIFE

36 months from manufacturing date.

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

SPECIFICATION

USP 35.

PACKAGE

10 Tablets/ Blister x 10 Blisters/ Box.

This drug should be used only under prescription.

Read Dosage and Administration carefully before using.

Keep out of reach of children.

For any more information, please consult your doctor.

Manufactured by

KOREA UNITED PHARM. INC.

25-23, Nojanggongdan-gil, Jeondong-myeon, Sejong-si, Korea.