MethoCedal^®

1. Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia, and the symptomatic treatment of severe recalcitrant disabling psoriasis which is not adequately responsive to other forms of therapy.

• Methotrexate is contraindicated in:

  • Patients with 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.
  • Patients with significantly impaired hepatic function.
  • Patients with pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.
  • Patients with active infections.
  • Patients with overt or laboratory evidence of immunodeficiency syndrome(s).
  • Methotrexate is contraindicated in pregnancy.
  • Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contraindicated in women taking methotrexate.
  • Patients with a known hypersensitivity to methotrexate or any of the excipients.

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

Because of the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that methotrexate should only be taken once a week. Patients should be instructed on the importance of adhering to the once-weekly intakes.

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), thoracic pain 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 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.

When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.

Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects may be related in frequency and severity to the dose or frequency of administration but have been seen at all doses. Because the toxic reactions can occur at any time during therapy, the patients have to be observed closely and must be informed of early signs and symptoms of toxicity.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.

Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

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

In 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 the diagnosis has been established by biopsy and/or after dermatological consultation.

1. 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 should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported.

Liver function tests: Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies.

Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient’s comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include 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.

Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided. Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive methotrexate.
4. Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination.

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.

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.

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, 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.

5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
6. Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.
7. Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Immunisation with live virus vaccines is generally not recommended.
8. Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.
9. Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).
10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.
11. A chest X-ray is recommended prior to initiation of methotrexate therapy.
12. If acute methotrexate toxicity occurs, patients may require folinic acid.
13. Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g., toxic epidermic necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, vasculitis and extensive herpetiform skin eruptions) may occur after the administration of methotrexate and recovery ensured mostly after discontinuation of the therapy.

• Radiotherapy Interaction
  Concomitant radiation therapy increases the risk of soft tissue necrosis and osteonecrosis associated with methotrexate.

This medicine may be given by injection (using a syringe) into a vein (intravenously), into muscle (intramuscularly), into an artery (intraarterially) or infusion (drip) into a vein.
This product should be diluted for I.V. infusion.
It may be diluted with dextrose 5% injection or sodium chloride 0.9% injection before it is given.

Adverse Reactions Significant 

Note: Adverse reactions vary by route and dosage. Hematologic and/or gastrointestinal toxicities may be common at dosages used in chemotherapy; these reactions are much less frequent when used at typical dosages for rheumatic diseases.

• >10%:

Central nervous system (with intrathecal administration or very high-dose therapy):

Arachnoiditis: Acute reaction manifested as severe headache, nuchal rigidity, vomiting, and fever; may be alleviated by reducing the dose

Subacute toxicity: 10% of patients treated with 12-15 mg of intrathecal methotrexate may develop this in the second or third week of therapy; consists of motor paralysis of extremities, cranial nerve palsy, seizure, or coma. This has also been seen in pediatric cases receiving very high-dose I.V. methotrexate.

Demyelinating encephalopathy: Seen months or years after receiving methotrexate; usually in association with cranial irradiation or other systemic chemotherapy

Dermatologic: Reddening of skin

Endocrine & metabolic: Hyperuricemia, oligospermia

Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, intestinal perforation, mucositis (dose dependent; appears in 3-7 days after therapy, resolving within 2 weeks)

Hematologic: Leukopenia, myelosuppression (nadir: 7-10 days), thrombocytopenia

Renal: Renal failure, azotemia, nephropathy

Respiratory: Pharyngitis

Miscellaneous: Immunosuppression

• 1% to 10%:

Cardiovascular: Vasculitis

Central nervous system: Dizziness, malaise, fever, chills

Dermatologic: Alopecia, rash, photosensitivity, depigmentation or hyperpigmentation of skin, pruritus, dermatitis

Endocrine & metabolic: Diabetes

Genitourinary: Cystitis

Hematologic: Hemorrhage

Hepatic: Cirrhosis (chronic therapy), liver function tests increased (chronic therapy), portal fibrosis (chronic therapy)

Neuromuscular & skeletal: Arthralgia

Ocular: Blurred vision

Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine and BUN and a fall in urine output; more common with high-dose methotrexate, and may be due to precipitation of the drug.

Respiratory: Pneumonitis: Associated with fever, cough, and interstitial pulmonary infiltrates; treatment is to withhold methotrexate during the acute reaction; interstitial pneumonitis has been reported to occur with an incidence of 1% in patients with RA (dose 7.5-15 mg/week)

Miscellaneous: Infection

• <1% (Limited to important or life-threatening):

Acute neurologic syndrome (at high dosages; symptoms include confusion, hemiparesis, transient blindness, and coma); acute respiratory distress syndrome, agranulocytosis, alveolitis, anaphylaxis, arrhythmia, arterial occlusion (acute), arterial thrombosis, cerebral thrombosis, cerebrovascular accident, chronic leukoencephalopathy, cognitive dysfunction (has been reported at low dosage), cryptococcosis, cytomegalovirus infection (including cytomegaloviral pneumonia, sepsis, nocardiosis), deep vein thrombosis, disseminated vaccinia (following smallpox immunization), dysarthria, enteritis, eosinophilia, erythema multiforme, exfoliative dermatitis, GI bleeding, gynecomastia, hepatic failure, hepatitis, herpes simplex, herpes zoster, histoplasmosis, hypogammaglobulinemia, hypotension, impotence, infertility, intestinal perforation, leukoencephalopathy (especially following craniospinal irradiation or repeated high-dose therapy), lymphoma (may regress with discontinuation), lymphoproliferative disorders, mesenteric ischemia (acute), MI, myocardial ischemia, nasal septum perforation, neutropenia, nodulosis, osteoporosis, pancreatitis, pericardial effusion, osteonecrosis and soft tissue necrosis (with radiotherapy), pericarditis, plaque erosions (psoriasis), Pneumocystis carinii pneumonia, pneumonia, proteinuria, pulmonary embolism, pulmonary fibrosis, radiation recall dermatitis, respiratory failure, retinal vein thrombosis, reversible posterior leukoencephalopathy syndrome (RPLS), seizure (more frequent in pediatric patients with ALL), skin ulceration, Stevens-Johnson syndrome, stroke, supraventricular arrythmia, syncope, telangiectasia, thromboembolism, thrombophlebitis, toxic epidermal necrolysis, tumor lysis syndrome, upper respiratory tract infection, ventricular arrythmia

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. Please report any adverse drug reactions via contacting Cedal Nano.⁽¹⁾

Effects of Other Drugs on Methotrexate

Drugs that Increase Methotrexate Exposure

Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of severe adverse reactions to methotrexate:

• Penicillin or sulfonamide antibiotics
  • Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines)
  • Proton pump inhibitors
  • Probenecid
  • Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides)
  • Aspirin and other nonsteroidal anti-inflammatory drugs

Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs).

• Mercaptopurine
  • Weak acids (e.g., salicylates)

Increased organ-specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.

If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions.

Nitrous Oxide

Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.

Folic Acid

Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider.

Effects of Methotrexate on Other Drugs

Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently.

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided.

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed.

Treatment with more than one DMARD in various regimens is being tried but there is little evidence available to assess benefit. A meta-analysis of 5 different combinations of DMARDs demonstrated that although efficacy might be greater than single DMARDs, toxicity was also increased.

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

A potential interaction may exist between methotrexate and proton-pump inhibitors (e.g. omeprazole, pantoprazole). Omeprazole may inhibit methotrexate clearance resulting in potentially toxic methotrexate levels.

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

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

Concurrent administration of metamizole and methotrexate can increase the haematotoxic effect of methotrexate, especially in elderly patients. Therefore, coadministration should be avoided.

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

Methotrexate may increase the bioavailability of mercaptopurine by interference with first-pass metabolism.

Concomitant application of methotrexate and theophylline can reduce theophylline clearance

• • Pregnancy

  Methotrexate is contraindicated during pregnancy in non-oncological indications.

  Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during methotrexate therapy. In cancer chemotherapy, methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

  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 ultrasonographic examinations should be performed to confirm normal foetal development.

  In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester. 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 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 is distributed into breast milk. Because of the potential for serious adverse reactions to methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

• Methocedal^® is supplied as vial containing Methotrexate 1000 mg (100 mg/ml) as solution for injection.

  Handling and disposal:
  Single use only. Discard any unused contents.

  Storage:

  • Store Methocedal^® between 15° – 30°C. Protect from light and freezing.
  • From a microbiological point of view, solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
  • Methocedal^®, when diluted to a concentration of 1 mg/ml with sodium chloride 0.9% injection, glucose 5% injection is stable for 24 hours when stored at 25°C or 2° – 8°C.
  • In order to protect from light, keep the vial in the original package.

  Keep the medicine out of the reach and sight of children.