The highest concentrations of methotrexate are observed in liver and kidneys. Methotrexate slowly penetrates the peritoneal and pleural cavities. Methotrexate in the blood is approximately 50% protein bound, mainly to serum albumin.

Penetration of Blood Brain Barrier :

Methotrexate slowly penetrates into the central nervous systems. High methotrexate concentrations in (>106 mol) are however, only observed when high doses of methotrexate (>500mg/m2) are applied.

Placental Barrier : Methotrexate crosses the placental barrier.

Biotransformation :

In liver and tumor tissue methotrexate oligoglutamates are formed. When methotrexate is administered at low doses (<50mg/m2) hardly any conversion takes place. At higher dosages 7-30% of the administered dose is reduced to 7 – hydroxymethotrexate in the liver. While in the gut, methotrexate is converted into 2,4-diamino-N-10 methyl-piezidinic acid.

Elimination :

Following intravenous administration of methotrexate plasma elimination progresses triphasically With half lives of 45 min, 3-4 hours and 23-31 hours. Methotrexate is mainly excreted in urine; more than 90 the administered dose is excreted unchanged in urine within 24 hours. At dosages of 50-200 mg/kg less than 60% is excreted as unchanged drug in urine within 72 hours. Alkalisation of urine accelerates methotrexate elimination. Following the intravenous administration of the methotrexate 1-2 % of the dosage applied is excreted in feaces as unchanged drug and metabolities. 1-6% of the dose is excreted vis bile. To a minor extent methotrexate is excreted in tears. In case of renal failure the plasma eliminationhalf life increases and serious toxicity may result.

The dose of methotrexate to be given, the frequency of dosing, the total dose and the combination with other cytostatic drugs and/or folinic acid are subject to frequent modification as our knowledge improves. Methotrexate should be only applied by Physician’s experience in the area.

Head and Neck Cancer :

Methotrexate at a dose of 40mg/m2 body surface area is given at weekly intervals, until progression. This dosage is used without folinic acid therapy.

Trophoblastic Toumours :

The treatment of trophoblastic tumors has to be strictly supervised by as assigned committee of exports, In patients with non-metastatic and low risk metastatic trophoblastic tumors a methotrexate dose of 15 to 30 mg daily isadministared orally or intramuscularly for 5 days. A repeat course may be given after a period of one or more weeks. Three to five courses are usually employed. Patients with high risk trophoblastic tumours are often trated with a combination therapy, including 300 mg methotrexate/m2 body surface. followed by folinic acid therapy the therapy has to be evaluated on the basis of hCG (Human Chorinic gonadotropin) plasma concentrations.

Leukemia :

Methotrexate is used as part of the maintenance therap, in acute lymphoblastic leukemia at a dose of 15-30 mg/m2 orally, intramuscularly or intravenously once a week.

Psoriasis :

The treatment of psoriasis in women should start immediately following a menstrual period. Once week prior rointiation of methotrexate therapy a testdose of 5-10 mg is given parenterally to detect idiosyncratic reactions of the patients. In adults weekly dosage schedule of 10-25 mg orally intramus- cularly or intravenously is used. In most patients an improvement occurs usually within 4 week and an optimal results is reached in 2-3 months. Discontinuation of the methotrexate treatment gives relapse symptoms within 2 weeks to 6 months. After optional clinical result has been reached the dose should be reduced to the lowest possible with the longest intermediate time span possible. Conventational topical therapy should be restarted as soon as possible.

RheunmatoidArthritis :

A single test dose of methotrexate may be given prior to initiation of therapy to detect possible sensitivity to adverse effect to the drugs. A weekly regimen is used. The recommended starting dosage schedule, is either a) single oral dosage of 7.5 mg once weekly or b) an oral dose of 2.5 mg at 12 hours intervals for three dosages given as a course once weekly. Althrough an upward gradual modification in either the single or divided dosage schedule may be done foroptimisation of response, the total dosage usually should not exceed beyond 20 mg per week so as to avoid severe toxicity particularly bone marrow suppression associated with. After the optimum response is achived the dose in each schedule should be preferably reduced to the lowest possible effective dose. The response, whicj is apparent by between 3-6 weeks may continue for three months or more. The optimal duration of therapy is not known. However limited response for at least 2 years with continued therapy. On discontimuation of therapy arthritis usually worsens within a span of 3-6 weeks.

or Intrathecal Use :

LEUKEMIA MENINGENEAL

IMPORTANT NOTE : Only preservative free methotrexate dilute with preservative free 0.9% Sodium Chloride Injection, USP or other suitable medium to a concentration of 1 mg / ml should be used for intrathecal administration.

Following intrathecal dosing regiments based on patient age

n the treatment of menigeal leukemia, intrathecal (IT) methotrexate may be administered at intervals of 2 to 5 days. Caution should be excercised as IT methorexate administered at intervals of less than once week may increase subacute toxicity. IT methotrexate should be given until the cell count of the CSF returns to normal, and then one additional dose. IT methotrexate adds significantly to the systemic methotrexate drug level. therefore, concurrent systemic antileukemic therapy should be appropriately adjusted.

DOSE MODIFICATIONS :

When the leukocyte count or thrombocyte count is decreased on the first day of treatment the dose of methotrexate, in case of a standard therapy with 40mg/m2 body surface, should be adapted according to the following scheme, the lowest value determines the reduction. %of Normal doseeucocuytes count / mm3hrombocytes

If the number of leukocytes is 2500-35000/mm3 and or the number of thrombocytes is 75000-125000 it is preferred to discontinue the treatment for once week. If the blood count has shown a recovery, the treatment can be continued. If the blood count is not recovered, a dose reductions can be applied .

Methotrexate should not be given to patients with a creatinine clearance less than 60ml./min. Therapy with high dose methotrexate should be postponed in case of in case of liver toxicity.

ROUTE OF ADMINISTRATION

For intramuscular, intravenous & intrathecal use.

The cytostatic drug may only be used under constant supervision of a physician who is experienced in oncology. Treatment should take place in hospital experienced in cancer chemotherapy. During the use of methotrexate the following laboratory tests are generally advised : Hernograms and heman tocrit. renal function test and urine analysis, measurements of liver encymes : chest X-ray is recommended. The tests have to be performed prior to, during and after methotrexate treatment. Live biopsy and bone marrow aspiration studies are advisable, especially in patients receiving high dose or prolonged treatment in patients with psoriasis it should be taken under consideration to perform liver biopsies every 6-12 months or whenever liver function disorder is suspected, in order to prevent serious liver toxicity. Methotrexate should be used with extreme care in patients with infection. Peptic ulcer, ulcerative colitis, debility and in the very young or aged. In the event of serve  set in. When Infection occurs. discontinuation of methotrexate and adequate antibacterial therapy is indicated. In case of severe bone marrow depression blood or thrombocytes transfusion may be necessary.

During methotrexatetherapy and until at least three months after treatment with methothotrexate contraceptive precautions should be taken by female as well as male patients. While in general a low dose of methogerxate is applied in the treatment of psoriasis, as compared to the doses used in antineoplastic therapy, intoxication and death may occur. Patients should be fully informed on the risks of methotrexate therapy and should be instructed to report any manifestation of toxicity immediately. The simultaneous use of methotrexate and other potentially hepatotoxic drugs or alcohol should be avoided.

Non-steroidal anti inflammatory drugs should not be administrated prior to or concomitantly with the high doses of methotrexate. NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong seru methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Oral antibiotics such as tetracycline, chloramphenicol and non absorbable broad spectrum antibiotics may increase intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

Hematotoxicity often occurs. Following a single intravenous of methotrexate the nadir of hemoglobin concentration occured in 6-13 days, followed by recovery. Reticulocytes reached a nadir in 2-7 days, followed by recovery in 9-19 days. Leukocytes generally showed two periods of depression : the first occured in 4-7 days with recovery in 7-13 days and the second in 12-21 days with recovery in 15-29 days.

Thrombocytes reached a nadir in 5-12 days and recovered in 15-27 days. Gastrointestinal toxicity occurs in patients treated with methotrexate : stomatitis, anorexia, nausea vomiting and diarrhoea. Ulcerative stomatitis is often the earliest symptom of toxicity. Methotrexate therapy should be interrupted to prevent intestinal perforation.

Liver toxicity may occur in patients receiving high dose or prolonged therapy atrophy, necrosis, fatty degeneraton, fibrosis and cirrhosis. Dermatological toxicity occurs infrequently : dermatitis, alopecia, irregular formation of nails, depigmentation, pruuitus, urticaria, foliculitis, vasculitis, conjunctivitis and acne. Photosensitivity has been observed. Methotrexate and its metabolite 7-hydroxymethotrextae are nephrotoxic. Serious nephropathy, renal insufficinecy, azotemia, cystitis and hematturia may occur. To prevent renal damage methotrexate should be administered exactly following the instructions. Occasionally

methotrexate can cause a characteristic pneumonitis.

Rarely anaphylactoid reactions occur following methotrexate administration. Other reported adverse reactions include headache, somnolence, chills, fatigue, dizziness and osteoporosis. Infrequently eye irritation has been observed. Methotrexate causes defective oogenesis or spermatogenesis, transient oligos permia, menstrual dysfunction and infertility. Mutagenic effects of methotrexate causes defective oogeneisis or spermatogenesis. transientoligospermia, menstrual dysfunction and infertility, Mutagenic effects of methotrexate cannot be excluded, while contradictory results from mutagenecity tests have been reported. From carcinogenecity tests it can be concluded that methotrexcate has no carcinogenic properties.

Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.

Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.

In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin).

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored.

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.

Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect.

Zuvitrex Inj 50 mg :    Pack of 2ml vial.

Zuvitrex Inj 100 mg :  Pack of 4ml vial.

Zuvitrex Inj 15 mg :    Pack of 3ml vial.