1. Name of the medicinal product

Methotrexate Tablets USP 2.5mg?Taj Pharma
Methotrexate Tablets USP 5mg?Taj Pharma
Methotrexate Tablets USP 7.5mg?Taj Pharma
Methotrexate Tablets USP 10mg?Taj Pharma

2. Qualitative and quantitative composition

a) Each uncoated tablet contains:
Methotrexate USP?????????????????????????????????? 2.5mg
Excipients???????????????????????????????????????????????? q.s

b) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?5mg
Excipients???????????????????????????????????????????????? q.s

c) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?7.5mg
Excipients???????????????????????????????????????????????? q.s

d) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?10mg
Excipients???????????????????????????????????????????????? q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

4. Clinical particulars

4.1 Therapeutic indications

Methotrexate is a folic acid antagonist and is classified as an antimetabolite cytotoxic agent.

Methotrexate is used in the treatment of adults with severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy.

Methotrexate has also been used in the treatment of severe, uncontrolled psoriasis, which is not responsive to other therapy.

Methotrexate has been used to produce regression in a wide range of neoplastic conditions including acute leukaemias, non-Hodgkin’s lymphoma, soft-tissue and osteogenic sarcomas, and solid tumours particularly breast, lung, head and neck, bladder, cervical, ovarian, and testicular carcinoma.

4.2 Posology and method of administration

Posology

Methotrexate should only be prescribed by physicians with experience in the various properties of the medicinal product and its mode of action.

Dosage for Cancer Treatment

Warning The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of neoplastic diseases.

Fatal cases of intoxication have been reported after administration of incorrectly calculated doses. Health care professionals and patients should be fully informed about toxic effects.

Oral administration

A test dose of 5 – 10 mg parenterally is recommended, one week prior to therapy to detect idiosyncratic adverse events. Low doses not exceeding 30 mg/m²?on five successive days. Thereafter an interval of at least two weeks is recommended to allow the bone marrow to recover.

Doses in excess of 100 mg are usually given parenterally, when the injectable preparation should be used. Doses in excess of 70 mg/m²?should not be administered without leucovorin rescue (folinic acid rescue) or assay of serum methotrexate levels 24 – 48 hours after dosing.

If methotrexate is administered in combination chemotherapy regimens, the dosage should be reduced, taking into consideration any overlapping toxicity of the other drug components.

Dosage for Psoriasis and Rheumatoid arthritis

Important warning about the dosage of Methotrexate Tablets (methotrexate) In the treatment of psoriasis and Rheumatoid arthritis, 2.5mg requiring dosing once a week e.g. rheumatologic and dermatological diseases, Methotrexate?must only be taken once a week. Dosage errors in the use of Methotrexate Tablets (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

The prescriber should specify the day of intake on the prescription.

Psoriasis

Before starting treatment it is advisable to give the patient a test dose of 2.5?5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated.

The usual dose is 7.5 ? 15 mg once a week. Weekly dose may also be administered in three divided doses over 24 hours. For the treatment of severe psoriasis, the total weekly dosage can be raised to 20 – 25 mg administered orally as necessary. Dosage should be adjusted according to the patient’s response and the haematological toxicity.

Rheumatoid Arthritis

In adults with severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy, Methotrexate should be taken as 7.5-15 mg once a week. The planned weekly dose may also be administered in three divided doses over 24 ? 36 hours. The total weekly dosage can be raised to 20-25 mg as necessary. Dosage should be adjusted according to the patient’s response and the haematological toxicity.

Paediatric population

Treatment should follow currently valid protocols for children. Safety and effectiveness in children have not been established, other than in cancer chemotherapy.

Use in Elderly:

Methotrexate should be used with extreme caution in elderly patients. A reduction in dosage should be considered due to reduced liver and kidney function as well as lower folate reserves, which occur with increased age.

Use in patients with renal impairment ? dose adjustments:

Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide intersubject pK variability.

Table 3 a. Dose adjustments for methotrexate doses <100 mg/m2?in patients with renal impairment
Creatinine Clearance (ml/min)	% of dose to Administer
>60	100
30-59	50
<30	Methotrexate must not be administered.

Table 3?b. Dose adjustments?for methotrexate doses >100 mg/m²?in patients with renal impairment

Creatinine Clearance (ml/min)	%?of?dose to Administer
>80	100
= ~80	75
= ~60	63
<60	Methotrexate must not be administered.

Patients with hepatic impairment

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol (see sections 4.3 and 4.4).

Use in a patient with a third distribution space (pleural effusions, ascites)

As the half-life of Methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required.

Special note

If changing the oral application to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration.

Method of Administration

Oral.

4.3 Contraindications

• Significantly impaired hepatic function
• Significantly impaired renal function (creatinine clearance less than 30 ml/min) for methotrexate doses <100 mg/m2, and moderate renal impairment (creatinine clearance less than 60 ml/min) for methotrexate doses >100 mg/m2 (see section 4.2)
• Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia
• Alcoholism
• Severe acute or chronic infections and immunodeficiency syndrome
• Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease
• Pregnancy and breast-feeding (see section 4.6)
• Hypersensitivity to methotrexate or to any of the excipients listed in section 6.1
• During methotrexate therapy concurrent vaccination with live vaccines must not be carried out
• Methotrexate should not be used concomitantly with drugs with antifolate properties (e.g. co-trimoxazole) (see section 4.5).

4.4 Special warnings and precautions for use

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Patients must be appropriately monitored during treatment so that signs of possible toxic effects or adverse reactions can be detected and evaluated with minimal delay.

Especially strict monitoring of the patient is indicated following prior radiotherapy (especially of the pelvis), functional impairment of the haematopoietic system (e.g., following prior radio- or chemotherapy), impaired general condition as well as advanced age and in very young children.

Because of the possibility of severe or even fatal toxic reactions, patients should be extensively informed by the treating doctor of the risks involved (including early signs and symptoms of toxicity) and the recommended safety measures. Patients should be informed that they must notify the doctor immediately if any symptoms of an overdose occur and that the symptoms of the overdose need to be monitored (including regular laboratory tests).

Doses exceeding 20 mg week can be associated with a substantial increase in toxicity, especially bone marrow depression.

Because of the delayed excretion of methotrexate in patients with impaired kidney function, they should be treated with particular caution and only with low doses of methotrexate (see sections 4.2 and 4.3).

Methotrexate should be used only with great caution, if at all, in patients who have a significant liver disease, particularly if this is/was alcohol-related (see sections 4.2 and 4.3).

Skin and mucosal contact with methotrexate injection solution is to be avoided.

Concomitant use of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drugs, e.g. leflunomide) is not advisable.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest X-ray) undertaken to exclude infection and tumours. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Methotrexate-induced lung diseases such as pneumonitis can occur acutely and at any time during treatment, are not always completely reversible and have already been observed at all doses (including low doses of 7.5 mg/week).

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when diagnosis has been established by biopsy and/or after dermatological consultation.

Deaths have been reported in association with the use of methotrexate in the treatment of psoriasis.

Methotrexate should be used with extreme caution in the presence/history of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. Use in patients with active gastrointestinal ulcer disease is contraindicated. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression blood or platelet transfusions may be necessary.

Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Following the occurrence of haematemesis, black coloured stools or blood in the stools, treatment must be discontinued.

In addition other conditions leading to dehydration such as emesis, can increase the toxicity of methotrexate due to elevated levels of the active substance. In these cases use of methotrexate should be interrupted until symptoms cease. It is important to determine any increase in active substance levels within 48 hours of therapy, otherwise irreversible methotrexate toxicity may occur.

Because of the possibility of severe and even life-threatening toxic reactions the patient should be fully informed by the attending physician of the risks involved before onset of methotrexate treatment. The patient should be closely monitored throughout the treatment.

Patients should be informed of the signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including regular laboratory tests for monitoring toxicity.

It should be emphasized to the patient treated for psoriasis that the recommended dose must be taken only once a week. The prescriber should specify the day of intake on the prescription. Patients should be instructed on the importance of adhering to the once-weekly intakes, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Sections 4.2 and 4.9).

Most adverse reactions are reversible if detected early. When adverse reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this includes the use of calcium folinate and/or acute, intermittent haemodialysis with high-flux dialyzer.

Methotrexate should be used with extreme caution in patients with psychiatric disorders. Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy or treatment should be withdrawn.

Before beginning Methotrexate therapy or reinstituting Methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.

Patients receiving low-dose methotrexate should:

• Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.
• Patients should report all symptoms and signs suggestive of infection, especially sore throat. Any infections should be attended to, before initiation of methotrexate therapy.

Haematopoietic suppression caused by Methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see section 4.8). Patients should be advised to report all symptoms or signs suggestive of infection. Any infections should be attended before initiation of methotrexate therapy.

Methotrexate may be hepatotoxic, particularly at high doses or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Risk factors for severe liver damage are e.g. previous liver disease, repeatedly abnormal liver function tests and alcohol consumption. Additional hepatotoxic medicinal products should not be taken during the treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or clearly reduced (see section 4.5).

Diabetic patients who are treated with insulin have increased risk for liver toxicity.

Liver function tests

Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.

Check of liver-related enzymes in serum

Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13?20 %. In the case of a constant increase in liver-related enzyme, a reduction of the dose or discontinuation of therapy should be taken into consideration. Closer monitoring of liver enzymes is necessary especially in patients taking other liver- or haematotoxic medicinal products (e.g. leflunomide). Further research is needed to establish whether serial liver function tests or determinations of propeptide of type III collagen are appropriate for detecting hepatotoxicity.

Patients with risk factors

These primarily include

– anamnestic alcohol abuse

– persistent increase in liver enzymes

– anamnestic hepatopathy including chronic hepatitis B or C

– familial anamnesis with hereditary hepatopathy

and secondarily (with possibly lower relevance):

– diabetes mellitus

– adiposity

– anamnestic exposure to hepatotoxic medicines or chemicals.

The need of liver biopsy should be evaluated case by case and national recommendations should be followed.

Kidneys

Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination. Impaired renal function may result in methotrexate accumulation in toxic amount or even in additional renal damage. In patients with renal impairment the dose of methotrexate should be reduced.

Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given. If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m2 not be given (see section 4.2 and 4.3).

Treatment with methotrexate doses of >100 mg/m2 should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.

Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization by oral or intravenous administration of sodium bicarbonate (5 x 625mg tablets every three hours) or acetazolamide (500 mg orally four times a day), and measurement of serum methotrexate and renal function are recommended.

As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.

If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.

If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.

Immune system

Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. Vaccination with live vaccines is contra-indicated during the therapy.

The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential activation.

Methotrexate may trigger tumour lysis syndrome in patients with rapidly growing tumour.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Since cases of encephalopathy/ leukoencephalopathy have occurred in cancer patients treated with methotrexate, this cannot be ruled out either for patients with non-cancer indications.

The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

In the treatment of rheumatoid arthritis, acetylsalicylic acid, nonsteroidal anti-inflammatory (NSAID) agents, and/or low dose steroids can be continued, although concomitant use of NSAIDs and methotrexate may be associated with an increased risk of toxicity. Steroids may be gradually reduced in patients responsive to methotrexate.

The interactions of methotrexate and other antirheumatic drugs such as gold, penicillamine, hydroxychloroquine, sulfasalazine or cytotoxic agents have not been studied comprehensively, and concurrent use may increase the incidence of adverse reactions.

Concomitant administration of folate antagonists such as trimethoprim/sulfamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid. In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid supplementation may reduce methotrexate toxicity, such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes.

It is recommended to check levels of vitamin B12 prior to initiating folic acid supplementation, particularly in adults aged over 50 years, as folic acid intake may mask a vitamin B12 deficiency.

Methotrexate may cause adverse urinary tract reactions, such as cystitis and haematuria.

Methotrexate has been shown to be teratogenic ? reproductive risk; it causes embryotoxicity, abortion and foetal malformations in humans.

Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age (see section 4.6).

In non-oncologic indications, the absence of pregnancy must be confirmed before Methotrexate tablet is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.

For contraception advice for men see section 4.6.

If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of treatment, affecting spermatogenesis and oogenesis during the period of its administration – effects that appear to be reversible on discontinuing therapy.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’s syndrome) or Stevens-Johnson syndrome have been reported after single or multiple doses of methotrexate.

Methotrexate 2.5mg Tablets contain lactose and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as diphenylhydantoins, acidic anti-inflammatory agents, salicylates, phenylbutazone, phenytoin, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, p-aminobenzoic acid, thiazide diuretics, oral hypoglycaemics, doxorubicin,, tetracyclines, probenicid or sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity.

Since probenecid and weak organic acids, such as ?loop-diuretics? as well as pyrazols reduce tubular secretion, great caution should be exercised when these medicinal products are coadministered with methotrexate.

Concurrent use of other, potentially nephro- hemato or hepatotoxic agents (e.g. sulphasalazine, leflunomide and alcohol) should be avoided. Special caution should be exercised when observing patients receiving methotrexate therapy in combination with azathioprine or retinoids.

Methotrexate in combination with leflunomide can increase the risk for pancytopenia.

Enhancement of nephrotoxicity may be seen if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).

Antibiotics, like penicillin, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal methotrexate absorption or interfere with the enterohepatic circulation, due to inhibition of the intestinal flora or suppression of bacterial metabolism.

Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indomethacin (NSAID’s) is commenced, as concomitant use of NSAID’s has been associated with fatal methotrexate toxicity.

Hepatic, hematotoxic and nephrotoxic drugs should be avoided.

Vitamin preparations or other products containing folic acid or its derivatives may impair methotrexate efficacy.

Under (pre-) treatment with substances that may have adverse effects on the bone marrow (e.g. sulfonamides, trimethoprim-sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of marked haematopoietic disorders should be considered.

Co-administration of medicinal products which cause folate deficiency (e.g. sulfonamides, trimethoprim-sulfamethoxazole) can lead to increased methotrexate toxicity. Particular caution should therefore also be exercised in the presence of existing folic acid deficiency.

Acitretin (a treatment for psoriasis) is metabolised to eretinate. Methotrexate levels may be increased by eretinate and severe hepatitis has been reported following concomitant use.

Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.

Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematoxic effects of methotrexate.

There is evidence that co-administration of methotrexate and omeprazole prolongs the elimination of methotrexate via kidneys. Co-administration of proton pump inhibitors such as omeprazole or pantoprazole can cause interactions. In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Excessive consumption of beverages containing caffeine or theophylline (coffee, soft drinks containing caffeine, black tea) should be avoided during methotrexate therapy since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors.

One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsant medicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t? of 5–fluorouracil).

The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. While this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided (see section 4.2).

Colestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation.

Delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products.

The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment or renal function.

Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.

Methotrexate increases plasma levels of mercaptopurine. Combinations of methotrexate and mercaptopurine may therefore require dose adjustment.

Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections (see section 4.3). On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out (see sections 4.3 and 4.4).

Cytotoxic agents may impair absorption of phenytoin, which may decrease efficacy of phenytoin and increase the risk for exacerbation of convulsions. Risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin is possible.

Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used.

Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution.

Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

4.6 Fertility, pregnancy and lactation

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases.

In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate.

Pregnancy

Methotrexate is contra-indicated during pregnancy in non-oncological indications (see section 4.3).

If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications.

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate, the patient should be informed of the potential risk to the foetus.

Breast-feeding

Patients should not breast feed whilst taking methotrexate.

4.7 Effects on ability to drive and use machines

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with methotrexate which may have minor or moderate influence on the ability to drive and use machines.

4.8 Undesirable effects

In general, the incidence and severity of side effects are considered to be related to the dose, the dosing frequency, the method of administration and the duration of exposure.

Most adverse reactions are reversible if detected early. When adverse reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. This includes the use of calcium folinate (see sections 4.2 and 4.4). Methotrexate therapy should only be resumed with particular caution, after careful consideration of the need for treatment and with increased vigilance for the possible recurrence of toxicity.

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome.

Most frequently observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently occurring adverse reactions are leukopenia, anaemia, thrombocytopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.

The most relevant adverse reaction is suppression of the haematopoietic system and gastrointestinal disorders.

In the antineoplastic treatment, myelosuppression and mucositis are the predominant dose-limiting toxic effects of methotrexate. The severity of these reactions depends on the dose, mode and duration of application of methotrexate. Mucositis generally appears about 3 to 7 days after methotrexate application, leucopenia and thrombocytopenia follow a few days later. In patients with unimpaired elimination mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28 days.

Adverse reactions for the various systems are as follows:

Skin and subcutaneous tissue disorders:

Exanthema, Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, erythema multiforme, onycholysis, increased pigmentation, petechia, allergic vasculitis, hidradenitis, alopecia, depigmentation, ecchymosis, telangiectasia, acne, furunculosis, painful damage to psoriatic lesions, skin ulceration, herpetiform eruptions of the skin, hyperpigmentation of the nails and acute paronychia.

The recall phenomenon has been reported in both radiation and solar damaged skin. Lesions of psoriasis may worsen with concomitant UV therapy. Radiation dermatitis and sunburn may be ?recalled?.

Blood and the lymphatic system disorders:

Megaloblastic anaemia, hematopoietic disorders, eosinophilia, lymphoproliferative disorder (partly reversible), lymphadenopathy, bone marrow depression (especially at high-dose of methotrexate) is most frequently manifested by thrombocytopenia (which are usually reversible), neutropenia, leukopenia, pancytopenia, agranulocytosis, anaemia, aplastic anaemia, immunosuppression, lymphoproliferative disorders (frequency very rare) or any combination may occur. Infection or hypogammaglobulinaemia, haemorrhage from various sites. Bone marrow depression may lead to decreased resistance to infection and sepsis.

Gastrointestinal disorder:

Mucositis, stomatitis, gingivitis, hematemesis, melena, pancreatitis, enteritis, gastrointestinal ulceration (including oral ulcers) and bleeding, malabsorption, toxic mega-colon, dyspepsia, abdominal pain, anorexia, nausea, vomiting, diarrhoea.

Gastrointestinal disorders frequently require dosage adjustment. Ulcerative stomatitis and diarrhoea require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.

Hepatobiliary disorders:

Hepatic toxicity resulting in increase of transaminases (ASAT, ALAT), alkaline phosphatase and bilirubin, decrease in serum albumin, acute hepatitis, periportal fibrosis or hepatic cirrhosis, hepatic failure, fatty degeneration of liver, reactivation of chronic hepatitis or death.

Renal and urinary disorders:

Renal failure, uraemia, ulceration of the urinary bladder, disturbed micturition, oliguria, haematuria, dysuria, anuria, proteinuria, electrolyte disturbance, nephropathy.

Respiratory, thoracic and mediastinal disorders:

Pneumonia, acute or chronic interstitial alveolitis/pneumonia which can be fatal and is often associated with eosinophilia, acute pulmonary oedema, interstitial/pulmonary fibrosis, chronic interstitial obstructive pulmonary disease, pharyngitis, pleurisy, non-productive cough, thoracic pain, dyspnoea, pleural effusion, bronchial asthma, respiratory paralysis.

In the treatment of rheumatoid arthritis, Methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible

Epistaxis (frequency not known) has been reported. Pulmonary alveolar haemorrhage (frequency not known) has been reported for methotrexate used in rheumatologic and related indications.

Nervous system disorders:

Headaches, fatigue, drowsiness, dizziness, vertigo, lethargy, aphasia, irritability, hemiparesis, paresis, convulsions, encephalopathy/leukoencephalopathy.

Leukoencephalopathy has been reported especially following intravenous Methotrexate in high doses, or low doses following cranial-spinal radiation.

Cerebral oedema, transient subtle cognitive dysfunction, dysarthria, unusual cranial sensations.

Pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), meningism, acute aseptic meningitis, paralysis.

Psychiatric disorders:

Depression, confusion, mood alterations, insomnia, psychoses.

Cardiac disorder:

Percardial effusion, pericarditis, pericardial tamponade.

Vascular disorders:

Thromboembolic events (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolus), vasculitis, hypotension.

Eye disorders:

Conjunctivitis, blurred/impaired vision, retinopathy.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Lymphoma, which can be reversible, Methotrexate may trigger tumour lysis syndrome in patients with rapidly growing tumour.

Reproductive system and breast disorder:

Gynecomastia, decreased libido/impotence, defective oogenesis or spermatogenesis, transient oligospermia, infertility, menstrual dysfunction, vaginal bleeding, vaginal ulceration, inflammation of the vagina, vaginal discharge.

Infections and infestations:

Respiratory or cutaneous bacterial infections, herpes zoster infections, opportunistic infections,?Pneumocystis carinii/jiroveci?pneumonia and other lung infection, reactivation of inactive chronic infection.

Musculoskeletal, connective tissue and bone disorders:

Osteoporosis, stress fractures, arthralgia/myalgia, increased rheumatic nodules.

Osteonecrosis of jaw (frequency not known) (secondary to lymphoproliferative disorders).

Endocrine disorders:

Diabetes mellitus.

Immune system disorders:

Allergic reaction, anaphylactic reaction, anaphylactic shock.

Ear and labyrinth disorders:

Tinnitus.

General disorders:

Fever, chills, wound healing impairment, asthenia.

Other

Increased risk of toxic reactions in radiotherapy (soft tissue necrosis, osteonecrosis).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate have been reported. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions.

The toxicity of methotrexate affects mainly the haematopoietic organs. Calcium folinate neutralises effectively the immediate toxic effects of methotrexate. Parenteral calcium folinate therapy should be started within one hour after the administration of methotrexate. The dose of calcium folinate should be at least as high as the dose of methotrexate received by the patient.

Symptoms of an overdose are mainly the same as the undesirable effects, but stronger.

Leucovorin is a specific antidote for methotrexate and, following accidental overdosage, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary.

In post-marketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported.

Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following chronic overdose in the self-administered dosage for rheumatoid arthritis and psoriasis (see Sections 4.2 and 4.4). In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialysator. Observation of serum methotrexate concentrations is relevant in determining the right dose of calcium folinate and the duration of the therapy.

Treatment measures for methotrexate overdosage can be discontinued when the serum methotrexate level has fallen below the level of 5×10^-8?M (10) (see section 4.4).

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressive agents

Mechanism of action

Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division.

The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.

5.2 Pharmacokinetic properties

Absorption

Orally administered, the absorption of methotrexate seems to be dose-dependent. Peak serum levels are reached within 1 to 2 hours. Generally, at doses of 30 mg/m²?or less, methotrexate is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80?100 %) at doses of 30 mg/m²?or less. Saturation of the absorption starts at doses above 30 mg/m²?and absorption of doses exceeding 80 mg/m^2?is incomplete. After parenteral injection, peak serum levels are seen in about one half this period. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes.

About one half of absorbed methotrexate is reversibly bound to serum protein but is readily distributed in tissues. Excretion takes place mainly via the kidneys. Approximately 41 % of the dose is excreted unchanged in the urine within the first six hours, 90 % within 24 hours. A minor part of the dose is excreted in the bile of which there is pronounced enterohepatic circulation.

The half-life is approximately 3?10 hours following low dose treatment and 8?15 hours following high dose treatment. If the renal function is impaired, the concentration of methotrexate in serum and in tissues may increase rapidly.

Methotrexate does not enter the cerebrospinal fluid at oral or parenteral therapeutic doses. However, cytotoxic concentrations (>10^-7?M) can be achieved in the CSF with high doses (>500 mg/m²). When high drug concentrations are indicated, direct intrathecal administration should be used.

5.3 Preclinical safety data

Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Animal studies show that methotrexate impairs fertility and is embryo- and foetotoxic. Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys no malformations occurred. Methotrexate is mutagenic?in vivo?and?in vitro. There is evidence that methotrexate causes chromosomal aberrations in animal cells and in human bone marrow cells, but the clinical significance of these findings has not been established. Rodent carcinogenicity studies do not indicate an increased incidence of tumours.

6. Pharmaceutical particulars

6.1 List of excipients

Maize starch, Lactose, Pregelatinised starch, Polysorbate 80, Microcrystalline cellulose, Magnesium stearate.

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Keep the blister in the outer carton in order to protect from light.

6.5 Nature and contents of container

White high density polyethylene container with high density polyethylene screw closure. Pack size: 100 tablets.

Polyvinylchloride (PVC)/Aluminium foil blisters containing 2 blisters with 12 tablets in each.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Women who are pregnant, planning to be or breast-feeding should not handle methotrexate.

Parents, care givers and patients should be advised to keep methotrexate out of the reach of children, preferably in a locked cupboard.

Accidental ingestion can be lethal for children.

Anyone handling methotrexate should wash their hands after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling methotrexate.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Methotrexate Tablets USP 2.5 mg/5mg/7.5mg/10mg Taj Pharma
(Methotrexate)

Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have any further questions, ask your doctor, pharmacist or
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet

1. What Methotrexate Tablets are and what they are used for
2. What you need to know before you take Methotrexate Tablets
3. How to take Methotrexate Tablets
4. Possible side effects
5. How to store Methotrexate Tablets
6. Contents of the pack and other information

 

1. What Methotrexate Tablets are and what they are used for

Methotrexate Tablets contain the active ingredient methotrexate. Methotrexate is referred to as a cytotoxic medicine. It is most commonly used to kill cells in tumours.

Methotrexate Tablets can be used to treat rheumatoid arthritis. It is usually used for patients who have tried other treatments but their illness has not improved. In the treatment of rheumatoid arthritis, methotrexate is thought to stop or reduce inflammation by altering the body?s defences.

Methotrexate Tablets can also be used to treat severe, uncontrolled psoriasis. It is usually used for patients who have tried other treatments but their condition has not improved.

Methotrexate helps patients with psoriasis by killing the cells in the skin, which are growing too quickly. It is these fast growing cells, which cause the raised patches of skin in psoriasis.

Methotrexate is used to treat a wide range of tumours, in particular:

• acute leukaemias,
• Non-Hodgkin?s lymphoma,
• soft tissue and bone sarcomas,
• solid tumours like breast, lung, head and neck, bladder, cervical, ovarian and testicular

Methotrexate can be given alone or in combination with other medicines.

You should consult your doctor if you are unsure why you have been given Methotrexate 2.5mg Tablets. You must talk to a doctor if you do not feel better or if you feel worse.

2. What you need to know before you take Methotrexate Tablets

Your doctor may perform several tests such as blood tests, x-rays and physical examinations before treatment with Methotrexate tablets is started, and at regular intervals during treatment.

Do not take Methotrexate Tablets if you:

• are allergic to methotrexate, or any of the other ingredients of this medicine (listed in section 6).
• are pregnant, trying to become pregnant or breast-feeding. Methotrexate may harm your baby (see section on Pregnancy). You and your partner should avoid conception (becoming pregnant or fathering children) for at least three months after your treatment with methotrexate has
• have severe liver problems, including fibrosis, cirrhosis and recent or active
• have severe kidney problems, including conditions requiring kidney
• have any serious blood problems including severe anaemia and clotting
• have an alcohol dependency.
• have a medical condition or are receiving medication which lowers your resistance to
• are taking antibiotics which prevent the production of folic acid (vitamin B9) such as co- trimoxazole, which are used to treat bacterial
• have an active infectious disease (e.g. fever, chills, joint pain).
• are being treated with live
• ulcer of the oral cavity and
• inflammation of mouth or

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Methotrexate Tablets if you have any of the following conditions. This will help them decide if Methotrexate Tablets are suitable for you:

• have any mild or moderate kidney disease
• have a stomach ulcer or ulcerative colitis (inflammation and ulceration of the gut)
• have any blood disorders or anaemia
• have diarrhoea
• have gastro-intestinal (digestive) problems
• have severe mouth ulcers
• have or have ever suffered from mental illness
• received or you are receiving radiotherapy (x-ray treatment) or UV radiation
• have received any vaccinations recently or you are due to have any, as methotrexate can reduce their effect
• have any symptoms or signs of infection
• have excess fluid, between the lungs and chest wall (pleural effusion) or abdominal swelling (ascites) causing breathlessness
• develop a persistent cough or develop shortness of breath as it may be associated with serious lung disease
• special care is also needed in children, the elderly and in those who are in poor physical condition
• have or have ever had liver damage, dependence on alcohol or abnormal liver function tests,
• have diabetes and are being treated with insulin,
• have an inactive chronic infection, such as herpes zoster, tuberculosis, hepatitis B or C
• methotrexate temporarily affects sperm and egg production. Methotrexate can cause miscarriage and severe birth defects. You and your partner should avoid having a baby if you are being given methotrexate at the time and for at least 6 months after the end of your treatment with

methotrexate. See also section ?Pregnancy, breast-feeding and fertility?.

Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood you should contact your doctor immediately.

Regular Check?ups

Whilst being treated with this medicine your doctor will want to monitor your progress on a weekly basis until your therapy is stable. Thereafter, you will be monitored every 2 to 3 months, whilst taking the medicine.

These checks may include taking blood and urine samples to check your blood cells and to make sure that your liver and kidneys are working properly. It is important that you do not miss any blood tests.

There may also be a chest x-ray and a physical examination to check for swelling of your lymph nodes (glands in your neck, armpits and groin). Any unusual swellings should also be reported to your doctor.

If the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal.

Other medicines and Methotrexate Tablets

Tell your doctor or pharmacists if you are taking, have recently taken, or might take any other medicines. This includes the following medicines, as the effect of Maxtex Tablets may be altered when they are taken at the same time:

• vaccinations / live virus vaccines
• ibuprofen, indomethacin (NSAID?s, non-steroidal anti-inflammatory drugs) which are used for pain or inflammation
• aspirin or similar medicines (known as salicylates)
• diuretics (water tablets)
• medicines used/taken for diabetes
• antibiotics (used to treat bacterial infections e.g. chloramphenicol, penicillin, sulfonamides, co- trimoxazole, trimethoprim / sulfamethoxazole, ciprofloxacin and tetracyclines)
• thiazides (a group of diuretics used for the treatment of fluid retention e.g. bendroflumethiazide)
• hypoglycaemics (used for lowering blood sugar levels e.g. metformin)
• p-aminobenzoic acid, acitretin (used to treat psoriasis or skin disorders)
• diphenylhydantoins, phenytoin (used to treat epilepsy)
• probenicid, sulfinpyrazone (used to treat gout)
• acitretin (a medicine used to treat psoriasis)
• radiotherapy
• vitamin preparations containing folic acid or similar products
• nitrous oxide (a gas used in general anaesthesia)
• levetiracetam (a medicine used to treat seizures in epilepsy)
• loop diuretics (used to treat hypertension and oedema)
• sulfasalazine, leflunomide (used to treat arthritis)
• cisplatin (used in chemotherapy)

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Methotrexate Tablets with food, drink and alcohol

Alcohol should be avoided while receiving methotrexate as it increases the risk of liver damage.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Do not use Methotrexate during pregnancy except if your doctor has prescribed it for oncology treatment. Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. It is therefore very important that methotrexate is not given to pregnant women or to women who are planning to become pregnant unless used for oncology treatment.

For non-oncological indications, in women of child-bearing age the possibility of a pregnancy must be ruled out, e.g. by pregnancy tests, before treatment is started.

Do not use Methotrexate if you are trying to become pregnant. You must avoid becoming pregnant during treatment with methotrexate and for at least 6 months after the end of treatment. Therefore, you must ensure that you are taking effective contraception for the whole of this period (see also section “Warnings and precautions”).

If you become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment.

If you want to become pregnant, you should speak with your doctor, who may refer you for specialist advice before the planned start of treatment.

Methotrexate can cause birth defects, harm unborn babies or cause miscarriages and so it is very important that it is not given to pregnant patients or patients planning to become pregnant. It may also affect women?s periods; they may become less frequent or stop completely. Methotrexate can affect sperm and egg production with the potential to cause birth defects. You and your partner should avoid conception (becoming pregnant or fathering children) for at least six months after your treatment with methotrexate has stopped.

As methotrexate may cause genetic mutations, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible already prior to therapy, and men should seek advice about the possibility of sperm preservation before starting therapy.

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded and there is no information regarding higher methotrexate doses. Methotrexate can have a genotoxic effect. This means that the medicine can cause genetic mutations. Methotrexate can affect the production of sperm, which is associated with the possibility of birth defects.

You should avoid fathering a child or to donate semen during treatment with methotrexate and for at least 6 months after the end of treatment. As treatment with methotrexate at higher doses commonly used in cancer treatment can cause infertility and genetic mutations, it may be advisable for male patients treated with methotrexate doses higher than 30 mg/week to consider sperm preservation before the beginning of treatment (see also section “Warnings and precautions”).

Breast-feeding

Methotrexate passes into breast milk. You should not take Methotrexate Tablets if you are breast-feeding.

Driving and using machines

Methotrexate Tablets may cause some side effects which could affect your ability to drive or use machinery for example drowsiness, loss of co-ordination or blurred vision. If you experience these symptoms, do not drive or use any tools or machinery. The full list of side effects are listed in section 4.

Methotrexate Tablets contains lactose

These tablets contain Lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Methotrexate Tablets

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Alcohol should be avoided while receiving methotrexate. The recommended dose is:

Dosage for rheumatoid arthritis:

Take Methotrexate only once a week.

Adults

You will usually take your tablets once a week on the same day each week. The dose usually starts at 7.5

• 15 mg per week but may rise to 25 mg per week. The dose may be given all at once, or it can be split into 3 doses at 12 hourly intervals over 36 hours. The dose may be changed depending upon your response to

Elderly

Elderly patients may need smaller doses of methotrexate.

Children

Not recommended for use in children.

Dosage for psoriasis:

Take Methotrexate only once a week. Adults

You will usually take your tablets once a week on the same day each week. Patients may be given a test dose of 2.5-5mg by their doctor first to exclude unexpected toxicities. For severe psoriasis, the dose usually starts at 7.5 – 15 mg per week but may rise to 25 mg per week. The dose may be given all at once, or it can be split into 3 doses over 24 hours. The dose should be adjusted according to your response to treatment and side effects.

Elderly

Elderly patients may need smaller doses of methotrexate.

Children:

Not recommended for use in children.

Dosage for treatment of cancer:

Adults, the Elderly and Children

• Your doctor should give you a test dose of 5 to 10mg by injection one week before starting treatment.
• The doctor will calculate the dosage required from your body surface area (m ), and the dose expressed as mg/m .
• Methotrexate Tablets are usually given as single doses, not exceeding 30mg/m , for up to five
• A rest period of at least two weeks is advised between treatments, to allow recovery from any side
• Doses in excess of 100mg are usually given by injection by your doctor or
• Doses of more than 70mg/m should not be administered without calcium folinate rescue therapy or blood levels of methotrexate being checked 24 to 48 hours after taking your medicine.
• These doses may be reduced if you are receiving other medication. Your doctor will decide the correct dose for you, if you want more information you should ask your

If you have the impression that the effect of Methotrexate Tablets is too strong or too weak, talk to your doctor or pharmacist.

If you take more Methotrexate Tablets than you should

If you accidentally take too many Methotrexate Tablets contact your doctor at once or go to the nearest hospital casualty department. Always take the labelled medicine package with you, whether there are any Methotrexate Tablets left or not.

Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating.

Inappropriate intake resulting in overdose can sometimes lead to death. The antidote in case of an overdose is calcium folinate.

If you forget to take Methotrexate Tablets

If you forget to take a dose, take it as soon as you remember if this is within two days. However, if you have missed a dose by more than two days, please contact your doctor for advice. Do not take a double dose to make up for a forgotten dose.

If you stop taking Methotrexate Tablets

Do not stop taking Methotrexate Tablets unless your doctor tells you to. Should you need to stop taking Methotrexate Tablets, your doctor will have decided which is the best method for you.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. However, Methotrexate is a very toxic medicine and some patients have died or become very ill whilst being treated with it.

Tell your doctor immediately if you experience any of the following symptoms after taking this medicine. Although they are very rare, these symptoms can be serious.

• Severe skin rash that causes blistering, (this can affect the mouth and tongue). These may be signs of a condition known as Stevens Johnson Syndrome. Your doctor will stop your treatment in these cases.
• Persistent cough, pain or difficulty breathing or become breathless; methotrexate can cause diseases of the lungs e.g. fluid in
• Spitting or coughing blood; this has been reported for methotrexate used in patients with underlying rheumatologic
• Skin rash and fever with swollen glands, particularly in the first two months of treatment, as these may be signs of a hypersensitivity
• Sore throat, fever, chills or achiness; methotrexate can make you more likely to catch infections.
• Severe allergic reaction (anaphylactic reaction) ? although very rare you may experience a sudden itchy skin rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), wheeze, and you may feel you are going to faint. If this happens you should seek medical attention

Other side effects that may occur are:

• Severe mouth ulcers and ulcers of the gut
• Reduction in red blood cells which can make the skin pale and cause weakness or breathlessness
• Reduction in blood platelets which increases risk of bleeding or bruising
• Lung infection (Pneumonia)
• Drowsiness
• Severe skin reaction
• Inflammation of vessels, often with skin rash
• Itchy skin
• Shingles (Herpes Zoster)
• Ringing in the ears
• Abdominal pain
• Indigestion
• Convulsions
• Loss of coordination
• Asthma
• Confusion
• Liver damage (seen as yellowing of the skin and whites of the eye)
• Liver failure
• Kidney damage
• Low levels of white cell count (leukopenia) and red blood cells and cells that clot blood
• Infection, reduced resistance to infection
• Abnormal red blood cell function
• Lung damage/scarred
• Build-up of excess fluid in the lung
• Build-up of fluid or excess fluid in the double layer around the heart
• Abnormal low blood pressure
• Inability to move
• Inability to move in one half of the body
• Dizziness
• Headaches, Blurred vision
• Difficulty sleeping
• Raised blood sugar levels (diabetes mellitus)
• Change in sense of taste
• Loss of ability to speak or understand speech
• Impaired vision
• Brittle bones
• Muscular pain
• Slow thought process
• Mood alteration
• Black or tarry stools
• Skin ulcers and erosions of inflamed areas, in psoriasis patients
• Damaged skin becomes inflamed on re-exposure to radiation and sunlight
• Reduced ability to become pregnant and reduced ability to father children
• Inflammation of the vagina
• Vaginal bleeding
• Menstrual disorders
• Blood in the urine
• Raised liver enzymes
• Weakening or softening of bones
• Unusual sensations in the head
• Anorexia (eating disorders)
• Loss of interest in, or inability to have sex
• Stomach pains and soreness of the mouth, throat and lips
• Inflamed blood vessels
• Feeling sick, being sick and/or diarrhoea, decreased absorption from intestines
• Irritation or swelling of the vaginal tissues
• Vaginal ulcers
• Pain or difficulty in passing urine
• The need to pass urine more often than usual
• Ulcers in urinary bladder
• Joint and muscle pain
• Chills and fever
• Changes in skin and nail colouration
• Bacteria or fungal infection of hand and feet
• Hair loss
• Red spots on the skin, skin lesions, acne, boils
• Flaking skin, redness
• Itchiness and rash
• Sensitivity to light
• Eye infection
• Tiredness and lack of energy
• General feeling of illness
• Other metabolic changes
• Nose bleed (frequency not known)
• Bleeding from the lungs (frequency not known) ? this has been reported for methotrexate used in patients with underlying rheumatologic disease
• Lymphoproliferative disorders (excessive growth of white blood cells) (frequency very rare)
• Bone damage in the jaw (secondary to excessive growth of white blood cells) (frequency not known).

Methotrexate may lead to problems with your blood, liver and kidneys. Your doctor will take blood samples to check for these problems and may ask you to have a small sample of your liver taken for testing (liver biopsy).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5. How to store Methotrexate Tablets

Keep this medicine out of the sight and reach of children. Accidental ingestion can be lethal for children. Keep the blister in the outer carton in order to protect from light.

Do not use this medicine after the expiry date which is printed on the carton and label after EXP. The expiry date refers to the last day of that month.

Anyone handling methotrexate should wash their hands after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling methotrexate.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information What Methotrexate Tablets contains

The active substance is methotrexate.

a) Each uncoated tablet contains:
Methotrexate USP?????????????????????????????????? 2.5mg
Excipients???????????????????????????????????????????????? q.s

b) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?5mg
Excipients???????????????????????????????????????????????? q.s

c) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?7.5mg
Excipients???????????????????????????????????????????????? q.s

d) Each uncoated tablet contains:
Methotrexate USP? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?10mg
Excipients???????????????????????????????????????????????? q.s

The other ingredients are maize starch, lactose (see section 2 ?Methotrexate Tablets contains lactose?), pregelatinised starch, polysorbate 80, microcrystalline cellulose, magnesium stearate and purified water.

What Methotrexate Tablets looks like and contents of the pack

Methotrexate 2.5mg Tablets are available in plastic bottles containing 100 tablets or carton containing 2 blisters with 12 tablets in each blister. Not all pack sizes may be marketed.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).