GENERIC NAME OF THE MEDICINAL PRODUCT:

a) Methotrexate Injection IP 15mg/1ml
b) Methotrexate Injection IP 50mg/2ml
c) Methotrexate Injection IP 1000mg/10ml

QUALITATIVE AND QUANTITATIVE COMPOSITION:

a) Methotrexate Injection IP 15mg/1ml
Each ml contains:
Methotrexate…………………….15mg
Excipient…………………………...q.s.
b) Methotrexate Injection IP 50mg/2ml
Each ml contains:
Methotrexate…………………….25mg
Excipient…………………………...q.s.
c) Methotrexate Injection IP 1000mg/10ml
Each ml contains:
Methotrexate…………………..100mg
Excipient…………………………...q.s.

THERAPEUTIC INDICATIONS:

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 and in severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy.

Methotrexate Injection IP 50mg/2ml (Imutaj) Taj Pharma

  1. Name of the medicinal product

a) Methotrexate Injection IP 15mg/1ml
b) Methotrexate Injection IP 50mg/2ml
c) Methotrexate Injection IP 1000mg/10ml

  1. Qualitative and quantitative composition 

a) Methotrexate Injection IP 15mg/1ml
Each ml contains:
Methotrexate…………………….15mg
Excipient……………………………q.s.
b) Methotrexate Injection IP 50mg/2ml
Each ml contains:
Methotrexate…………………….25mg
Excipient……………………………q.s.
c) Methotrexate Injection IP 1000mg/10ml
Each ml contains:
Methotrexate…………………..100mg
Excipient……………………………q.s.

Excipients with known effect:

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Injection.

Clear, yellow solution.

  1. Clinical particulars

4.1 Therapeutic indications

Acute lymphocytic leukaemia, prophylaxis of meningeal leukaemia, Non-Hodgkin’s lymphomas, osteogenic sarcoma, adjuvant and in advance disease of breast cancer, metastatic or recurrent head and neck cancer, choriocarcinoma and similar trophoblastic diseases, advanced cancer of urinary bladder.

4.2 Posology and method of administration

WARNINGS

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

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

Treatment should be initiated by or occur in consultation with a doctor with significant experience in cytostatic treatment.

Methotrexate can be administered intramuscularly, intravenously, intra-arterial or intrathecally. The dosage is generally calculated per m2 body surface area or body weight. Doses of over 100 mg methotrexate always require subsequent administration of folinic acid (See calcium folinate rescue).

The application and dosage recommendations for the administration of methotrexate for different indications varies considerably. Some common dosages which have been used in different indications are given below. None of these dosages can currently be described as standard therapy. Since the application and dosage recommendations for therapy with methotrexate at high and low dosages vary, only the most commonly used guidelines are given. Current published protocols should be consulted for dosages and the method and sequence of administration.

Methotrexate can be given as convention low dose therapy, intermediate dose therapy, high dose therapy and intrathecal administration.

Conventional low dose therapy: 15-50 mg/m2 body surface area per week intravenously or intramuscularly in one or more doses. 40-60 mg/m2 body surface area (for head and neck cancer) once weekly as intravenous bolus injection.

Intermediate dose therapy: Between 100 mg/m2 to 1000 mg/m2 body surface area in single dose. In advanced squamous epithelial and bladder cancer, intermediate doses of methotrexate up to 100- 200 mg/m2 can be used. (See Calcium folinate rescue).

High dose therapy: In several malignant diseases, including malignant lymphoma, acute lymphatic leukaemia, osteogenic sarcoma and metastatic choriocarcinoma, doses of 1000 mg methotrexate or more per m2 body surface area may be used, administered over a 24-hour period. Administration of folinic acid must begin with 10-15 mg (6-12 mg/m2) to be given 12-24 hours after starting methotrexate treatment (Further refer to therapy protocols, See calcium folinate rescue).

Calcium folinate rescue

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Adults

Acute lymphocytic leukaemias (ALL)

In low doses, methotrexate is applied within the scope of complex therapy protocols for maintaining remission in adults with acute lymphocytic leukaemias. Normal single doses lie within the range of 20-40 mg/m2 methotrexate. The maintenance dose for ALL is 15-30 mg/m2 once or twice weekly.

Other examples:

  • 3.3 mg/m2 in combination with other cytostatic agent once daily for 4-6 week.
  • 2.5 mg/kg every week.
  • High dose regimen between 1 to 12 g/m2 (i.v. 1-6 h) repeated every 1-3 weeks.
  • 20 mg/m2 in combination with other cytostatic agents once week.

Breast cancer

Cyclic combination with cyclophosphamide, methotrexate and fluorouracil has been used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. The dose of methotrexate is 40 mg/m2 intravenously on the first and eighth days of the cycle. The treatment is repeated at 3 week intervals. Methotrexate, in intravenous doses of 10-60 mg/m2, could be included in cyclic combination regimes with other cytotoxic drugs in the treatment of advanced breast cancer.

Osteosarcoma

Effective adjuvant chemotherapy requires the administration of several cytotoxic chemotherapeutic drugs. In addition to high dose methotrexate with calcium folinate rescue, doxorubicin, cisplatin and a combination of bleomycin, cyclophosphamide and dactinomycin (BCD) can be given. Methotrexate is used in high doses (8,000-12,000 mg/m2) once weekly. If dose is insufficient to reach real serum concentration of 10-3 mol/L at the end of infusion, dose can be increased to 15 g/m2 for subsequent treatment. Calcium folinate rescue is necessary. Methotrexate has also been used as the sole treatment in metastatic cases of osteosarcoma.

Older people

Dose reduction should be considered in elderly patient due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Patient with impaired renal function

Methotrexate should be used with caution in patients having impaired renal function. The dose regimens must be adjusted according to the creatinine clearance and serum methotrexate concentrations

  • If creatinine clearance (ml/min) is >50, 100% MTX dose can be given
  • If creatinine clearance (ml/min) is 20-50, 50% of MTX dose can be given
  • If creatinine clearance (ml/min) is <20, MTX should not be given

Patients with impaired hepatic function:

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated if bilirubin values are >5 mg/dl (85.5 μmol/L).

Paediatric population

Methotrexate should be used with caution in paediatric patients. Treatment should follow currently published therapy protocols for children (see section 4.4).

4.3 Contraindications

Hypersensitivity to the active substance methotrexate or to any of the excipients listed in section 6.1.

Sever liver impairment (See Section 4.2).

Alcohol abuse.

Severe renal impairment (Creatinine clearance les than 20 ml/min, see section 4.2).

Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia.

Serious, acute or chronic infections such as tuberculosis and HIV.

Ulcers of the oral cavity and known active gastrointestinal ulcer disease.

Pregnancy, breast-feeding (see section 4.6).

Concurrent vaccination with live vaccines.

4.4 Special warnings and precautions for use

Fatal toxicity in association with intravenous and intrathecal administration due to dose miscalculation has been reported. Particular caution should be exercised when calculating the dose ( see 4.2. posology and administration).

Because of the risk of severe toxic reactions (which can be fatal), methotrexate must only be used in life-threatening neoplastic diseases. Deaths have been reported during treatment of malignancies with methotrexate. The doctor should inform the patient of the risks of treatment and the patient should be monitored constantly by the doctor.

Fertility

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.

Teratogenicity – Reproductive risk

Methotrexate 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 Methotrexate15mg/1ml 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.

Tumor lysis syndrome

Like other cytotoxic agents, methotrexate can induce tumour lysis syndrome in patients with rapidly growing tumours. Appropriate supportive treatment and pharmacological measures can prevent or alleviate such complications.

Methotrexate and NSAIDs

Unexpected severe (including fatal) myelosuppression, aplastic anaemia and gastrointestinal toxicity have been reported in connection with concomitant treatment with methotrexate (usually at a high dose) and non-steroidal anti-inflammatory agents (NSAIDs) (see 4.5 interaction with other medicinal products and other forms of interaction).

Concomitant methotrexate treatment and radiotherapy can increase the risk of soft tissue necrosis and osteonecrosis.

Intrathecal and intravenous administration of methotrexate can result in acute encephalitis and acute encephalopathy, possibly with a fatal outcome. Patients with periventricular CNS lymphoma who are given methotrexate intrathecally have reportedly developed cerebral herniation.

Methotrexate and pleural effusion/ascites

Methotrexate is eliminated slowly from collections of fluid (e.g. pleural effusion, ascites). This results in a prolonged terminal half-life and unexpected toxicity. In patients with significant collections of fluid, drainage of the fluid before treatment is started and monitoring of plasma methotrexate levels are recommended.

If stomatitis, diarrhoea, haematemesis or black stool occurs, therapy with methotrexate should be discontinued due to the danger of haemorrhagic enteritis or death from intestinal perforation or dehydration (see section 4.8 undesirable side effects).

Conditions in which there is folic acid deficiency can increase the risk of methotrexate toxicity.

In association with intrathecal administration or in high dose treatment, methotrexate must not be mixed with solutions which contain preservatives (see also 6.6).

Solutions of methotrexate which contain the preservative benzyl alcohol are not recommended for use in infants. Gasping syndrome with fatal outcome has been reported in infants following intravenous treatment with solutions containing the preservative benzyl alcohol. Symptoms include rapid onset of respiratory problems, hypotension, bradycardia and cardiovascular collapse.

Infection or immunological conditions

Methotrexate must be used with great care in connection with active infection and is usually contraindicated in patients with manifest suppression of the immune response or where immunodeficiency is demonstrated by laboratory tests.

Pneumonia (which in certain cases can lead to respiratory failure) can occur. Potentially fatal opportunistic infections including Pneumocystis carinii pneumonia can occur in association with methotrexate treatment. When a patient exhibits pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered (see section 4.8).

Immunisation

Methotrexate may interfere with results of immunological tests Immunisation after a vaccination may be less effective in association with methotrexate treatment. Particularly caution should be exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) due to possible activation. Immunisation with live viruses is not normally recommended.

Skin toxicity: Due to the risk of phototoxicity, the patient must avoid sunlight and solarium.

Monitoring treatment

Patients on methotrexate treatment must be closely monitored so that toxic effects can be detected immediately. Analyses before treatment must include a full blood count with differential and platelet counts, liver enzymes, testing for hepatitis B and C infections, renal function test and x-ray of the lungs. Toxic effects of methotrexate can occur even with low doses and therefore it is important to monitor treated patients carefully. Most undesirable effects are reversible if detected early.

After initiation of treatment or when there is a change in the dose, or during periods in which there is an increased risk of elevated levels of methotrexate (e.g. in dehydration), monitoring should be performed.

Bone marrow biopsy must be performed as necessary.

Serum methotrexate level monitoring can significantly reduce methotrexate toxicity and routine monitoring of serum methotrexate level is necessary depending on dosage or therapy protocol.

Leucopenia and thrombocytopenia occur usually 4 -14 days after administration of methotrexate. In rare cases recurrence of leucopenia may occur 12 – 21 days after administration of methotrexate. Methotrexate therapy should only be continued if the benefit outweighs the risk of severe myelosuppression (see section 4.2).

Haematopoietic suppression: Haematopoietic suppression induced by methotrexate may occur abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets, treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients must be instructed to report all signs and symptoms suggestive of infection. In patients concomitantly taking haematotoxic medications (e.g. leflunomide), the blood count and platelets should be closely monitored.

Liver function tests: Particular attention should be paid to the onset of liver toxicity. Treatment should not be initiated or should be discontinued if there are any abnormalities in liver function tests or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal within two weeks; after which, treatment may be resumed at the discretion of the doctor. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more.

Screening for liver-related enzymes in serum: A transient rise in transaminase levels to twice or three times the upper limit of normal has been reported with a frequency of 13 – 20%. In the event of a constant increase in liver related enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Patients suffering from insulin-dependent diabetes should be carefully monitored because liver cirrhosis and an increase in transaminase can occur.

Due to the potentially toxic effect on the liver, additional hepatotoxic medications should not be given during treatment with methotrexate unless clearly necessary and alcohol consumption should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medications (e.g. leflunomide). The same should also be taken into consideration if haematotoxic medications are co-administered.

Malignant lymphomas may occur in patients receiving low-dose methotrexate; in which case, methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of cytotoxic therapy is required.

Renal function: methotrexate treatment in patients with impaired renal function should be monitored via renal function tests and urinalysis, since impaired renal function reduces the elimination of methotrexate, which may result in severe adverse reactions.

In cases of possible renal impairment (e.g. in elderly patients), close monitoring of renal function is required. This is particularly applies to the co-administration of medicinal products which affect methotrexate excretion cause kidney damage (e.g. non-steroidal anti-inflammatory drugs) or which can potentially lead to haematopoietic disorder. Dehydration may also potentiate the toxicity of methotrexate. Alkalinisation of the urine and increase a high diuresis is recommended.

Respiratory System: 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.

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.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest x-ray) should be made to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pneumonitis can occur at all doses.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Children

Methotrexate should be used with caution in paediatric patients. Treatment should follow currently published therapy protocols for children. Serious neurotoxicity, frequently manifested as generalised or focal seizures has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous methotrexate (1 g/m2). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.

Elderly

Because of deterioration in liver and kidney function as well as reduced folic acid reserves, relatively low doses should be considered in elderly patients. These patients must be closely monitored for early signs of toxicity.

Sodium

Methotrexate injection contains 345.59 mg (15.033 mmol) of sodium per maximum daily dose (1800 mg). This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Ciprofloxacin

Excretion of methotrexate possibly reduced (increased risk of toxicity).

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAID preparations must not be given prior to or concomitantly with the high doses of methotrexate used in the treatment of conditions such as osteosarcoma. Concomitant administration of NSAIDs and methotrexate at high doses has reportedly elevated and prolonged serum methotrexate levels, resulting in deaths from severe haematological and gastrointestinal toxicity. NSAID preparations and salicylates have reportedly reduced the tubular secretion of methotrexate in animal models and may increase its toxicity by increasing methotrexate levels. Concomitant treatment with NSAIDs and low doses of methotrexate must therefore be administered with caution.

Nitrous oxide

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

Leflunomide

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

Probenecid

Renal tubular transport is diminished by probenecid, and its use together with methotrexate must be avoided.

Penicillins

Penicillins can reduce renal clearance of methotrexate. Haematological and gastrointestinal toxicity have been observed in combination with high and low dose methotrexate.

Oral antibiotics

Oral antibiotics such as tetracycline, chloramphenicol and non-absorbable broad-spectrum antibiotics may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and hence the metabolism of methotrexate by bacteria. In isolated cases, trimethoprim/sulfamethoxazole has reportedly increased myelosuppression in patients treated with methotrexate, probably due to reduced tubular secretion and/or an additive antifolate effect.

Chemotherapeutic products

An increase in renal toxicity can be observed when high doses of methotrexate are given in combination with potentially nephrotoxic chemotherapeutic agents (e.g. cisplatin).

Radiotherapy

Concurrent methotrexate and radiotherapy can increase the risk of soft tissue necrosis and osteonecrosis.

Cytarabine

Concomitant therapy with cytarabine and methotrexate can increase the risk of severe neurological side effects ranging from headache to paralysis, coma and stroke-like episodes.

Hepatotoxic products

The risk of increased hepatotoxicity when methotrexate is administered concurrently with other heptatotoxic products has not been studied. Hepatotoxicity has however been reported in such cases. Patients receiving concomitant treatment with drugs with a known hepatotoxic effect (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) must be carefully monitored for signs of any increase in hepatotoxicity.

Theophylline

Methotrexate can reduce clearance of theophylline. Theophylline levels must therefore be monitored during concomitant treatment with methotrexate.

Mercaptopurine

Methotrexate increases plasma content of mercaptopurine. The combination of methotrexate and mercaptopurine can therefore require dose adjustment.

Drugs with high plasma protein binding

Methotrexate is partially bound to serum albumin. Other highly bound drugs such as salicylates, phenylbutazone, phenytoin and sulfonamides can increase the toxicity of methotrexate by means of displacement.

Furosemide

Concomitant administration of furosemide and methotrexate can result in increased levels of methotrexate due to competitive inhibition of tubular secretion.

Vitamins

Vitamin preparations containing folic acid or its derivatives can cause a reduced response to systemically administered methotrexate, however conditions in which there is a deficiency of folic acid can increase the risk of methotrexate toxicity.

Proton pump inhibitors

Literature data indicate that co-administration of proton pump inhibitors and methotrexate, especially at high dose, may result in elevated and prolonged plasma levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicity.

4.6 Fertility, pregnancy and lactation

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 contraindicated 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.

Breastfeeding

Methotrexate passes into breast milk in quantities such that there is a risk to the child even at therapeutic doses. Breast feeding must therefore be discontinued during treatment with methotrexate.

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).

4.7 Effects on ability to drive and use machines

Since fatigue and dizziness can occur as an undesirable effect, ability to react and judgement can be impaired, which should be taken into account for example when driving or carrying out work involving a high degree of precision.

4.8 Undesirable effects

Conventional and high dose therapy

The frequency and degree of severity of undesirable effects depends on the dose administered, the duration of exposure and method of administration, but side effects have been seen at all doses and can occur at any time during treatment. Most undesirable effects are reversible when detected at an early stage. When severe reactions occur, the dose should be reduced or treatment discontinued and appropriate measures initiated. If treatment with methotrexate is resumed, this should be done with caution after adequate consideration of the further need for the drug. Increased vigilance with regard to any recurrence of toxicity is required.

The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness, chills and fever, dizziness, reduced resistance to infections. Treatment with folinic acid during high dose therapy can counteract or alleviate a number of undesirable effects. Temporary discontinuation of therapy is recommended if there are signs of leukopenia.

The following undesirable effects have also been reported, but their frequency has not been established: Pneumocystis carinii pneumonia, (including reversible cases), foetal death, damage to the foetus, abortion.

Systemic organ toxicity

Lymphoma

Malignant lymphoma which can go into remission after discontinuation of the treatment with methotrexate can occur in patients on low dose therapy, and may not therefore require any cytotoxic treatment. Methotrexate should be discontinued first and appropriate treatment initiated if the lymphoma does not regress.

Haematological

Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. Methotrexate must be administered with caution to patients with malignancies and underlying factors affecting haematopoiesis. When treating neoplastic conditions, treatment with methotrexate should only be given provided the potential benefits outweigh the risk of myelosuppression.

Lungs

Lung disease caused by methotrexate, including acute or chronic interstitial pneumonitis, is a potentially dangerous complication, which can occur at any time during the course of treatment. This undesirable effect has been reported at low doses and is not always totally reversible. Deaths have been reported. Signs of pulmonary involvement or symptoms such as dry non-productive cough, fever, chest pains, dyspnoea, hypoxemia and infiltrate on x-ray of the lungs, or non-specific pneumonitis which occurs in connection with methotrexate therapy, may indicate potentially serious damage and requires discontinuation of treatment and careful investigation. Lung changes can occur at all doses. The possibility of infection (including pneumonia) must be excluded.

Gastrointestinal

If vomiting, diarrhoea or stomatitis occur, with resulting dehydration, methotrexate therapy must be discontinued until the patient has recovered. Haemorrhagic enteritis and deaths caused by intestinal perforation can occur. Methotrexate must be used with great caution in patients with peptic ulcers or ulcerative colitis. Stomatitis can be prevented or alleviated by folinic acid mouthwashes.

Liver

Methotrexate involves a potential risk of acute hepatitis and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal and occurs commonly after long-term use (in general after 2 years or more) and after a total cumulative dose greater than 1.5 g. In studies of psoriasis patients hepatotoxicity was seen to be proportional to the cumulative dose and was potentiated by alcoholism, overweight, diabetes and age.

Transient deterioration in liver enzyme values is frequently seen after methotrexate treatment and does not usually necessitate adjustment of treatment. Existing abnormal liver values and/or reduction in serum albumin can indicate severe hepatotoxicity.

Methotrexate has caused reactivation of hepatitis B infections and exacerbation of hepatitis C infections, in some cases with fatal outcome. Some cases of hepatitis B reactivation have occurred following discontinuation of methotrexate. Clinical and laboratory tests should be performed to investigate any occurrence of liver disease in patients with prior hepatitis B or C infections. Based on these investigations, treatment with methotrexate may prove unsuitable for certain patients.

In the event of impaired liver function, the undesirable effects of methotrexate (in particular stomatitis) can be exacerbated.

Kidneys

Methotrexate can cause kidney damage which can result in acute renal failure. Renal function can be exacerbated following high dose therapy to such an extent that the excretion of methotrexate is inhibited, as a result of which systemic methotrexate toxicity can occur. In order to prevent renal failure, alkalinisation of the urine and adequate fluid intake (at least 3 l/day) are recommended. Measurement of serum methotrexate and renal function is recommended.

Skin

Serious, in some cases fatal skin reactions, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome and erythema multiforme have been reported within a few days of oral, intramuscular, intravenous or intrathecal treatment with methotrexate in single or repeat doses. Radiation dermatitis and sunburn can be accentuated after use of methotrexate.

CNS

There are reports of leukoencephalopathy after intravenous treatment with methotrexate in patients who have undergone craniospinal radiotherapy. Severe neurotoxicity, often manifested as generalised or focal seizures have been reported with an unexpected increase in frequency in children with acute lymphoblastic leukaemia treated with a moderately high dose of intravenous methotrexate (1 g/m2). Symptomatic patients frequently had leukoencephalopathy and/or microangiopathic calcifications in x-ray investigations.

Chronic leukoencephalopathy has also been reported in patients treated with repeated high doses of methotrexate together with folinic acid, even without concomitant cranial radiotherapy. Discontinuation of the methotrexate therapy did not always result in full recovery. Leukoencephalopathy has also been reported in patients treated with methotrexate tablets.

One transient acute neurological syndrome has been observed in patients undergoing high dose therapy. Manifestations of this neurological syndrome can include abnormal behaviour, focal sensorimotor symptoms including transient blindness, and abnormal reflexes. The exact cause is unclear.

Cases of neurological side effects ranging from headache to paralysis, coma and stroke-like episodes have been reported, primarily in children and adolescents receiving concomitant medication with cytarabine.

Intrathecal therapy

The subacute neurotoxicity is usually reversible after discontinuing methotrexate.

Organ system class Common (>1/100)
Central and peripheral nervous system disordersHeadache, chemical arachnoiditis, subacute neurotoxicity, necrotising demyelinating leukoencephalopathy
Gastrointestinal disordersNausea and vomiting
General disorders and administration site conditionsFever

Chemical arachnoiditis, which can occur a few hours after intrathecal administration of methotrexate is characterised by headache, back pain, stiff neck, vomiting, fever, meningism and pleocytosis in the cerebrospinal fluid similar to that in bacterial meningitis. Arachnoiditis generally disappears within a few days.

Subacute neurotoxicity, common after frequently repeated intrathecal administration, mainly affects the motor functions in the brain or spinal cord. Paraparesis/paraplegia, with involvement of one or more spinal nerve roots, tetraplegia, cerebellar dysfunction, cranial nerve paralysis and epileptic seizures can occur.

Necrotising demyelinating leukoencephalopathy can occur several months or years after starting intrathecal therapy. The condition is characterised by progressive neurological deterioration with insidious onset, confusion, irritability and somnolence. Ultimately severe dementia, dysarthria, ataxia, spasticity, seizures and coma can occur. The condition can be fatal. Leukoencephalopathy occurs primarily in patients who have received large quantities of intrathecal methotrexate in combination with cranial radiotherapy and/or systemically administered methotrexate.

Signs of neurotoxicity (meningeal inflammation, transient or permanent paresis, encephalopathy) must be followed up after intrathecal administration of methotrexate.

Reporting of side effects

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

4.9 Overdose

Experience of overdose with the product has in general been associated with oral and intrathecal treatment, although overdose in association with intravenous and intramuscular administration has also been reported.

Reports of oral overdose have often been due to accidental daily instead of weekly ingestion. Commonly reported symptoms following oral overdose include the symptoms and signs seen at pharmacological doses, in particular haematological and gastrointestinal reactions such as leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In certain cases no symptoms were reported. There are reports of deaths associated with overdose. In these cases there were also reports of conditions involving sepsis or septic shock, renal failure and aplastic anaemia.

The most common symptoms of intrathecal overdose are CNS symptoms including headache, nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In certain cases, no symptoms were reported. There have been reports of deaths following intrathecal overdose. In these cases there were also reports of cerebellar herniation accompanying elevated intracranial pressure and toxic encephalopathy.

Recommended treatment

Antidote therapy: Folinic acid should be given parenterally at a dose at least the size of the methotrexate dose and should wherever possible be administered within an hour. Folinic acid is indicated to minimise toxicity and counter the effect of methotrexate overdose. Folinic acid treatment should be initiated as soon as possible. The longer the interval between the administration of methotrexate and the initiation of folinic acid, the less the effect of folinic acid in suppressing the toxic effect. Monitoring of serum methotrexate concentrations is necessary to be able to determine the optimum dose of folinic acid and the length of the treatment.

In the event of a major overdose, hydration and alkalinisation of the urine may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to increase the elimination of methotrexate. Acute intermittent haemodialysis with the use of highly permeable dialyser may be attempted for methotrexate intoxication.

Intrathecal overdose may require intensive systemic supportive measures such as systemic administration of high doses of folinic acid, alkaline diuresis, acute CSF drainage and ventricular lumbar perfusion.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic agent: folic acid analogue

Methotrexate is a folic acid antagonist with a cytostatic effect. Methotrexate inhibits the conversion of folic acid to tetrahydrofolic acid since the compound has a greater affinity for the enzyme dihydrofolate reductase than the natural substrate folic acid. As a result, DNA synthesis and new cell formation are inhibited. Methotrexate is s-phase specific. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, epithelium and buccal and intestinal mucosa are generally most susceptible to methotrexate.

5.2 Pharmacokinetic properties

Following intravenous administration, peak serum concentrations of methotrexate are reached after approx. 0.5 – 1 hour. There is wide inter-individual and intra-individual variation, especially with repeated doses. Saturation of oral absorption occurs at doses above 30 mg/m2. About half of the absorbed methotrexate is bound to plasma proteins, but binding is reversible, and methotrexate is easily diffused into the cells, with the highest concentrations reached in the liver, spleen and kidneys in the form of polyglutamate can be found which can be retained for few weeks or months. Methotrexate also passes to a lesser degree into cerebrospinal fluid. The half-life is approx. 3 to 10 hours with low dose therapy and approx. 8 to 15 hours with high dose therapy. Elimination from plasma is triphasic and the majority of the methotrexate is excreted unchanged in urine within 24 hours.

5.3 Preclinical safety data

Animal studies show that methotrexate impairs fertility and that it is embryotoxic, foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro, but the clinical significance is unknown since rodent carcinogenicity studies have produced differing results. Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.

  1. Pharmaceutical particulars

6.1 List of excipients

Sodium chloride

Sodium hydroxide (For pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

Owing to the absence of compatibility studies, this medicine should not be mixed with other medicines except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials – 2 years

Vial after first opening – Use immediately after opening.

After dilution – 24 hours

Chemical and physical stability of the diluted solution have been demonstrated for 24 hours. For microbial point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and condition prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store below 25°C.

For storage conditions after dilution, see section 6.3.

6.5 Nature and contents of container

For 2 ml: Clear glass vial (USP type 1), sealed with a grey butyl rubber stopper and orange flip-off cap.

For 20 ml and 40 ml: Clear glass vial (USP type 1), sealed with a grey butyl rubber stopper and lavender flip-off cap.

Package size:1 vial in carton for 2 ml, 20 ml and 40 ml pack size

10 vials per packs for 20 ml and 40 ml

Not all the pack size may be marketed.

6.6 Special precautions for disposal and other handling

The solution should be visually inspected prior to use. Only clear solution practically free from particles should be used.

Methotrexate injection may be further diluted with an appropriate preservative-free medium such as glucose solution (5%) or sodium chloride solution (0.9%).

With respect to the handling the following general recommendations should be considered: The product should be used and administered only by trained personnel; the mixing of the solution should take place in designated areas, designed to protect personnel and the environment (e.g safety cabins); protective clothing should be worn (including gloves, eye protection, and masks if necessary).

Pregnant healthcare personnel should not handle and/or administer Metotrexate.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be irrigated immediately with copious quantities of water at least ten minutes.

For single use only. Any unused solution should be discarded. Waste should be disposed of carefully in suitable separate containers, clearly labelled as to their contents (as the patient’s body fluids and excreta may also contain appreciable amounts of antineoplastic agents and it has been suggested that they, and material such as bed linen contaminated with them, should also be treated as hazardous waste). Any unused product or waste should be disposed of in accordance with local requirements by incineration.

Adequate procedures should be in place for accidental contamination due to spillage; staff exposure to antineoplastic agents should be recorded and monitored.

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 Injection IP 50mg/2ml (Imutaj) Taj Pharma

Package Leaflet: Information For The User

  1. Methotrexate Injection IP 15mg/1ml
  2. Methotrexate Injection IP 50mg/2ml
  3. Methotrexate Injection IP 1000mg/10ml
(Methotrexate)

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

  • Keep this You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist or
  • This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness symptoms are the same as yours.
  • If you get any side effects, talk to your doctor, or pharamcist or This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet:
  1. What Methotrexate Injection IP is and what it is used for
  2. What you need to know before you use Methotrexate Injection IP
  3. How to use Methotrexate Injection IP
  4. Possible side effects
  5. How to store Methotrexate Injection IP
  6. Contents of the pack and other information
1.   What Methotrexate Injection IP is and what it is used for

 Methotrexate Injection IP contains the active substance methotrexate. Methotrexate is a cytostatic that inhibits cell growth. Methotrexate has its greatest effect on cells which increase frequently like cancer cells, bone marrow cells and skin cells.

Methotrexate Injection IP is used in the treatment of the following types of cancer:

  • acute lymphocytic leukaemia,
  • prophylaxis of meningeal leukaemia,
  • non-Hodgkin’s lymphomas,
  • osteogenic sarcoma,
  • adjuvant and in advance disease of breast cancer,
  • metastatic or recurrent head and neck cancer,
  • choriocarcinoma and similar trophoblastic diseases,
  • advanced cancer of urinary

What you need to know before you take Methotrexate Injection IP Do not use Methotrexate Injection IP

  • If you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6).
  • If you have significant liver disease (Your doctor decides the severity of your disease).
  • If you have significant kidney disease (Your doctor decides the severity of your disease)
  • If you have disorders of the blood-forming
  • If you have severe or existing infection such as tuberculosis and
  • If you have ulcers in the mouth and throat or ulcers in the stomach and
  • If you are pregnant or breastfeeding (see section Pregnancy, breast-feeding and fertility).
  • If you have increased alcohol 1

You should not be given live vaccines during treatment with Methotrexate Injection IP.

Warnings and precautions
  • Methotrexate can cause serious and sometimes life-threatening undesirable Your doctor will talk to you about the advantages and risks of the treatment and what the early signs and symptoms of undesirable effects are.
  • Your skin or eyes can be extremely sensitive to sunlight or other forms of light during the treatment with Methotrexate Injection IP. Therefore sunlight and solarium should be
  • Methotrexate may cause decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting, thereby increasing chances of you getting the infections (e.g. pneumonia) or increased
  • Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with
  • Methotrexate temporarily affects sperm and egg 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”.

Talk to your doctor, pharmacist or nurse before taking Methotrexate Injection IP

  • If you are to undergo radiotherapy at the same time as the Methotrexate The risk of tissue and bone damage can increase with simultaneous treatment.
  • If you are having treatment in your spine (intrathecally) or in a vein (intravenously) this can cause a potentially life-threatening inflammation in the
  • If you have symptoms connected to a medical condition that means that fluid is retained in your body, for example in the lungs or in the
  • If you have impaired kidney
  • If you have impaired liver
  • If you have an
  • If you need to be Methotrexate can reduce the effect of the vaccines.
  • If you have insulin dependent diabetes, methotrexate treatment should be carefully
Recommended follow-up examinations and precautions:

Even when methotrexate is used at low doses, serious side effects can occur. In order to recognise these in good time, your doctor must carry out check-ups and laboratory tests.

Before the start of treatment:

Before treatment is started your doctor may carry out blood tests, and also to check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests.

Other medicines and Methotrexate Injection IP

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, Methotrexate affects or is affected by certain other medicinal products against:

  • Pain and inflammation (so called NSAIDs and salicylates)
  • Cancer (cisplatin, cytarabine, mercaptopurine)
  • Infections (antibiotics such as penicillins, tetracycline, ciprofloxacin and chloramphenicol)
  • Asthma (theophylline)
  • Vitamin preparations containing folic acid or substances like folic acid
  • Rheumatism (leflunomide)
  • High blood pressure (furosemide)
  • Gout (probenicide)
  • Radiotherapy
  • Stomach ulcers, heartburn, reflux (such as omeprazole, pantoprazole, lanzoprazol
  • Epilepsy (phenytoin)
  • Psoriasis or severe acne (retinoids, such as acitretin or isotretinoin)
  • Reumatiod arthitis or bowel disease (sulphsalazine)
  • Rejection after an organ transplant (azathioprine)
  • If you need to be vaccinated with a live vaccination
Methotrexate Injection IP with food, drink and alcohol

During treatment with Methotrexate Injection IP, you should not drink any alcohol and you should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea. Also make sure you drink plenty of liquids during treatment with Methotrexate Injection IP because dehydartion (reduction in body water) can increase the toxicity of Methotrexate Injection IP.

Pregnancy, breast-feeding and fertility

Pregnancy

Do not use Methotrexate Injection IP 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 Injection IP 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.

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 is excreted in breast milk in such quantities that there are risks of affecting the baby. Breast-feeding should therefore be suspended during treatment with Methotrexate.

Driving and using machines

Undesirable effects such as tiredness and dizziness may occur. If you feel tired or dizzy do not drive and do not use machines.

Methotrexate Injection IP contains 345.59 mg (15.033 mmol) of sodium per maximum daily dose (1800 mg).

To be taken into consideration by patients on a controlled sodium diet.

2.  How to take Methotrexate Injection IP

Methotrexate Injection IP is given to you by healthcare professionals.

The dose you receive and how often you receive the dose, depend on the disease you are being treated for your state of health and your age, weight and body surface. Methotrexate Injection IP can be given in a muscle (intramuscularly), in a vein (intravenously), in an artery (intra-arterially) or in the spine (intrathecally).

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

3.   Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Methotrexate Injection IP can have undesirable effects which may be dangerous or life-threatening. During the treatment you should be alert to signs of undesirable effects and report them to your doctor.

Contact a doctor immediately if you notice any of the following undesirable effects. You may need immediate medical care.

  • Unexplained breathlessness, dry cough or wheezing (symptoms of lung problems).
  • Sudden itching, skin rash (urticaria), swollen hands, feet, ankles, face, lips, mouth or throat (which can make it hard to breathe and swallow). It can also feel as if you are going to faint (symptoms of a severe allergic reaction).
  • Vomiting, diarrhoea or stomatitis and peptic ulcers (Symptoms of effect on gastrointestinal track).
  • Yellowing of the skin or eyes, dark-coloured urine (symptoms of effect on the liver).
  • Fever, shivering, aching body and sore throat (symptoms of infection).
  • Unexpected bleeding (for example bleeding gums, dark urine, blood in the urine or vomit) or unexpected bruising, black, tar-like faeces – this can be due to a reduced coagulation capacity or bleeding from the stomach or gut).
  • Skin rashes with flaking or blistering and effects on mucous membranes g. in the nose (symptoms

of Stevens-Johnsons syndrome, toxic epidermal necrolysis and erythema multiforme).

  • Abnormal behaviour, transient blindness and generalised seizures (Symptoms of effect on central nervous system).
  • Paralysis (paresis).

A list of undesirable effects that have been reported in treatment with Methotrexate is set out below according to how common they are.

Very common (may affect more than 1 in 10 people):

  • Loss of appetite, nausea, vomiting, abdominal pain, impaired digestion, dyspepsia
  • Inflammation and ulceration in mouth and throat
  • Increase in level of liver enzyme

Common (may affect up to 1 in 10 people):

  • Herpes zoster
  • Effects on the blood e.g. anaemia, leukocytopenia, thrombocytopenia
  • Headache, Tiredness, drowsiness
  • Dry cough, shortness of breath, chest pain, fever
  • Diarrhoea
  • Rashes, redness and itching

Uncommon (may affect up to 1 in 100 people)

  • Pancytopenia, agranulocytosis
  • Inflammation of blood vessels
  • Anaphylactoid reactions and allergic vasculitis
  • Vertigo, confusion, depression
  • Convulsions, encephalopathy
  • Lymphoma (tumour in lymph tissue)
  • Pulmonary fibrosis
  • Bleeds and ulcers in the stomach and intestinal tract
  • Inflammation of pancreas
  • Liver fibrosis and cirrhosis, fatty liver
  • Diabetic complications
  • Reduced levels of albumin
  • Skin becoming hypersensitive to sunlight, urticaria
  • Hair loss, herpes zoster, painful lesions of scaly patches caused by psoriasis
  • Increase of rheumatic nodules (lumps of tissues)
  • Effects on skin and mucous membrane, sometimes serious (Stevens-Johnsons syndrome, toxic epidermal necrolysis)
  • Inflammation and ulceration of urinary bladder, haematuria, dysuria
  • Inflammation and ulceration of vagina
  • Brittle bones (osteoporosis), arthralgia, myalgia

Rare (may affect up to 1 in 1,000 people)

  • Pericarditis, pericarditis effusion and tamponade
  • Megaloblastic anaemia
  • Mood swings
  • Paresis
  • Effects on speech including dysarthria and aphasia
  • Myelopathy
  • Visual disturbance, blurred vision
  • Thrombosis (cerebral, deep vein and retinal vein)
  • Low blood pressure
  • Pharyngitis apnoea, bronchial asthma
  • Gingivitis
  • Inflammation in the small intestine
  • Blood in the faeces
  • Malabsorption
  • Liver damage
  • Acne, sores on the skin, pigment changes of the nails, bruises
  • Fractures
  • Renal failure, oliguria, azotaemia and anuria
  • Hyperuricemia
  • Elevated serum creatinine and urea level
  • Abnormal development of mammary glands
  • Raised blood sugar levels (diabetes mellitus)

Very rare (may affect up to 1 in 10,000 people)

  • Infections, sepsis opportunistic infections
  • Severe failure of the bone marrow, anaemia due to the fact that the bone marrow cannot produce blood cells (aplastic anaemia), Lymphadenopathy, lymphoproliferative disorder (excessive growth of white blood cells), eosinophilia and neutropenia .
  • Immunosuppression
  • Hypogammaglobulinaemia
  • Insomnia
  • mpaired intellectual functions such as thinking, remembering and reasoning
  • Joint and/or muscle pain, lack of strength
  • Myasthenia (muscle weakness)
  • Abnormal sensations, changes in sense of taste (metallic taste)
  • Meningism (Paralysis, vomiting), acute aseptic meningitis
  • Conjunctivitis, retinopathy, loss of vision, puffy eye
  • Inflammation eye follicles epiphora and photophobia
  • Tumour lysis syndrome
  • Problem with lung function, shortness of breath, pneumonia
  • Infections of lungs
  • Pleural effusion
  • Dilation of colon (Toxic megacolon)
  • Reactivation of chronic hepatitis, acute liver degeneration, herpes simplex hepatitis, liver insufficiency
  • Painful swelling of skin around nail
  • Expansion of small blood vessels in the skin (paronychia)
  • Allergic vasculitis, hidradentis
  • Proteinuria
  • Loss of libido impotence
  • Menstrual disorder
  • Discharge from the vagina
  • Infertility
  • Fever, impaired wound healing

Not known (frequency cannot be estimated from the available data):

  • Bleeding, blood outside of vessels
  • Psychosis
  • Accumulation of fluid in brain and lungs
  • Metabolic disorder
  • Skin necrosis, exfoliative dermatitis
  • Bone damage in the jaw (secondary to excessive growth of white blood cells)

If you receive Methotrexate Injection IP in the spine the following undesirable effects are common (may affect up to 1 in 100 people):

  • Headache
  • Fever
  • Inflammation in the so-called arachnoid membrane in the brain and spinal cord which can cause backache, stiffness in the neck, vomiting, fever and impaired general state of health this can occur within a couple of hours after you have received the Methotrexate injection but usually disappears within a few days
  • Hemiplegia or total paralysis, weakness in one or all extremities and cramp attacks (usually

occurring after repeated Methotrexate injected into the spinal cord)

  • Effect on the nervous system which may start with confusion, irritation and This gets worse over time and leads to dementia (increasing loss of memory, disorientation and confusion), speech difficulties, coordination and balance difficulties, increased muscle stiffness, cramps and coma. This state can occur several months or years after the start of treatment with Methotrexate injected into the spinal cord. The condition can be life-threatening; it chiefly occurs if you have

large quantities of Methotrexate injected into the spinal cord in combination with radiotherapy to the head and/or Methotrexate in some other form.

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.

4.  How to store Methotrexate Injection IP

 Keep this medicines out of the sight and reach of children.

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

Store below 25°C.

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

  1. Contents of the pack and other information What Methotrexate Injection IP contains

The active substance is methotrexate. 1 ml solution contains 25 mg methotrexate.

The other ingredients are sodium chloride, sodium hydroxide/hydrochloric acid (to adjust the pH) and water for injection.

  1. What Methotrexate Injection IP looks like and contents of the pack

 The medicinal product is a clear yellow solution.

Package size: 1 vial in carton for 2 ml, 20 ml and 40 ml pack size 10 vials per packs for 20 ml and 40 ml

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)