4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

Important warning about the dosage of Methotrexate

In the treatment of psoriasis, Methotrexate must only be used once a week. Dosage errors in the use of Methotrexate can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

Antineoplastic Chemotherapy

Methotrexate is active orally and parenterally. Methotrexate Injection may be given by the intramuscular, intravenous, intraarterial or intrathecal routes. Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents. Please refer to locally approved dosing recommendations for methotrexate and folinic acid rescue therapy guidance.

Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for a 5 day course. Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

The effectiveness of therapy can be evaluated by 24 hours quantitative analysis of urinary human chorionic gonadotrophin (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

Hydatidiform mole may precede or be followed by choriocarcinoma, and methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

Breast Carcinoma

Prolonged cyclic combination with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40 mg/m2 intravenously on the first and eighth days.

Leukaemia

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral methotrexate dosage 3.3 mg/m2 daily, and prednisolone 40-60 mg/m2 daily for 4-6 weeks has been used. After a remission is attained, methotrexate in a maintenance dosage of 20-30 mg/m2 orally or by intramuscular injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5 mg/kg has been administered intravenously every 14 days.

Meningeal Leukaemia

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. The dose of intrathecal methotrexate is constant regardless of age or body surface area in patients over the age of 3 years of age, the maximum intrathecal dose should be 12 mg in such patients. Patients under the age of 3 years should be treated in accordance with combination chemotherapy protocols. The administration is at weekly intervals and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

Lymphomas

In Burkitt's Tumour, stages 1-2, methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days. In stage 3, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin's disease responds poorly to methotrexate and to most types of chemotherapy.

Mycosis Fungoides (cutaneous T-cell lymphoma)

Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated. Methotrexate has been given intramuscularly in doses of 50 mg once weekly or 25 mg twice weekly. Dose reduction or cessation is guided by patient response and haematologic monitoring.

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 pharmacokinetic variability.

Table 2 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 2 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.

Psoriasis

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, intramuscular or intravenous doses of 10-25 mg per week, and adjusted according to the patient's response. A total weekly dose of 25 mg should not ordinarily be exceeded. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10 mg.

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

Use in the elderly

Due to diminished hepatic and renal function as well as decreased folate stores in elderly patients, methotrexate should be used with extreme caution in this population. A reduction in dosage should be considered and these patients should be closely monitored for early signs of toxicity (see section 4.4).

Folate supplementation

Calcium folinate rescue therapy may be required at higher doses of methotrexate. Calcium folinate dose depends on methotrexate dose and duration of therapy. Please refer to local treatment recommendations for methotrexate and folinic acid rescue therapy.

Folate supplementation is an antidote to methotrexate mechanism of action. It helps replenish the folate, the body loses because of the methotrexate. By replenishing folate, folic acid supplementation can help prevent common methotrexate side effects like nausea, vomiting, and mouth sores.

In patients with psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes. Before taking a folate supplement, it is advisable to check B12 levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B12 deficiency.

Pre-hydration instructions includes pre-hydrate for 12 hours to establish an alkaline diuresis using 1.5 L/m2 fluid containing 10 mEq bicarbonate and 20 mEq KCl/L (urine should be ≥pH 7.0).

Method of administration

Methotrexate can be administered intravenously, intramuscularly, intraarterially or intrathecally. Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy.

Note: Only the 50 mg/2 ml presentation should be used for the intrathecal route of administration, due to the risk of accidental overdose with the larger volume presentations.

Intrathecal administration

Adults

Dilute preservative-free methotrexate to a concentration of 1 mg/ml in an appropriate sterile, preservative-free medium such as 0.9% Sodium Chloride Injection.

The following recommendations are provided for intrathecal administration and may be modified based on specific treatment protocols taking into consideration individual patient requirements.

Remove a volume of cerebrospinal fluid equivalent to the volume of methotrexate being administered.

The maximum recommended single dose is 15 mg.

Administer 10 to 15 mg intrathecally two times weekly until cerebrospinal fluid is clear, then a weekly dose for 2 to 6 weeks, followed by a monthly dose.

Alternatively, administer a dose of 10 mg/m2 (but do not exceed the maximum absolute dose of 15 mg) at 2 to 5 day intervals until cerebrospinal fluid cell counts return to normal. One or more additional doses can be administered weekly for 2 weeks and monthly thereafter.

A standard dose of methotrexate is 12.5 mg.

Paediatrics

The following dosage regimen is based on patient age instead of body surface area since the cerebral spinal fluid (CSF) volume approaches adult size years before body surface area does.

A constant dose should be administered to children as follows:

• under the age of 1 year: 6 mg

• 1 year of age: 8 mg

• 2 years of age: 10 mg

• 3 years of age or older: 12 mg

See section 4.4 for warnings on concomitant central nervous system (CNS) radiotherapy.

4.3. Contraindications

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 (see section 4.2).

• 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, or patients with overt or laboratory evidence of immunodeficiency syndrome(s).

• Patients with a known hypersensitivity to methotrexate or any of the other excipients listed in 6.1.

• Pregnancy (see section 4.6).

• Breast-feeding, because of the potential for serious adverse reactions from methotrexate in breast fed infants (see section 4.6).

4.4. Special warnings and precautions for use

WARNINGS

General

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

Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in neoplastic diseases (as indicated), or in patients with severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy. The patient should be informed by the physician of the risks involved and should be under a physician's constant supervision.

In all instances where the use of methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity

The prescriber should specify the day of intake on the prescription for patients being treated for psoriasis. The prescriber should make sure that patients being treated for psoriasis understand that methotrexate should only be taken once a week. 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.

Pulmonary

Acute or chronic interstitial pneumonitis and pleural effusion, often associated with blood eosinophilia, may occur at any time during therapy and has been reported at low doses. It is not always fully reversible, 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.

Pulmonary signs and symptoms, e.g. a dry non-productive cough, fever, cough, chest pain, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, or a nonspecific pneumonitis occurring during methotrexate therapy, may be indicative of a potentially dangerous lesion. Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection (including pneumonia). If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted. Methotrexate-induced pneumonitis can occur at all doses.

Potentially fatal opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jirovecii pneumonia should be considered.

Pulmonary function tests may be useful if lung disease (e.g. interstitial pneumonitis) is suspected, especially if baseline measurements are available.

Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

Methotrexate toxicity

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 the potential benefits and risks in the use of methotrexate (including the early signs and symptoms of toxicity), the need to see their physician promptly if they occur, and of the need for close follow up, including periodic laboratory tests to monitor toxicity (see also 'Laboratory Monitoring'). Folate deficiency states may increase methotrexate toxicity. If acute methotrexate toxicity occurs, patients may require folinic acid.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life. Blood counts should be monitored closely.

High-dose and low-dose regimens

The use of methotrexate high-dose regimens (≥500 mg/m2) requires meticulous care (see section 4.2 for pre-hydration instructions and folinic acid rescue).

Malignant lymphomas may occur in patients receiving low-dose methotrexate. These lymphomas may regress following withdrawal of methotrexate without requiring treatment.

Neurological

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.

There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. See 'Paediatric use' for specific warnings. Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.

Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with folinic acid rescue even without cranial irradiation. There are also reports of leukoencephalopathy in patients who received oral methotrexate. Discontinuation of methotrexate does not always result in complete recovery.

A transient acute neurologic syndrome has been observed in patients treated with high-dosing regimens. Manifestations of this neurologic syndrome may include behavioural abnormalities, focal sensorimotor signs, including transient blindness, and abnormal reflexes. The exact cause is unknown.

After the intrathecal use of methotrexate, the central nervous system toxicity that may occur can be classified as follows:

- acute chemical arachnoiditis manifested by e.g. headache, back pain, nuchal rigidity, and fever

- sub-acute myelopathy characterised by e.g. paraparesis/paraplegia associated with involvement with one or more spinal nerve roots

- chronic leukoencephalopathy manifested by e.g. confusion, irritability, somnolence, ataxia, dementia, seizures, and coma.

This central nervous system toxicity can be progressive and even fatal. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy. Signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.

Intrathecal and intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.

There have been reports of patients with periventricular CNS lymphoma who developed cerebral herniation with the administration of intrathecal methotrexate.

Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intrathecal methotrexate in combination with intravenous cytarabine.

Proton-pump inhibitors

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.

Psoriasis

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.

Hepatic

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 (see sections 4.5). 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.

Methotrexate has caused reactivation of hepatitis B infection or worsening of hepatitis C infections, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate. Clinical and laboratory evaluation should be performed to evaluate pre-existing liver disease in patients with prior hepatitis B or C infections. Based on these evaluations, treatment with methotrexate may not be appropriate for some patients.

Renal

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 (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.

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinisation, and measurement of serum methotrexate and renal function are recommended.

As methotrexate is eliminated mainly via the kidney's, 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. non-steroidal anti-inflammatory drugs (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.

Skin Reactions

Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g., toxic epidermal 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 usually ensures after discontinuation of the therapy.

Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking methotrexate (see section 4.8). Exposure to intense sunlight or UV rays should be avoided unless medically indicated. Patients should use adequate sun-protection to protect themselves from intense sunlight.

Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.

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

Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.

Other

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

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. See 'Fertility and reproduction'.

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.

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 NSAIDs (see section 4.5).

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

Like other cytotoxic drugs, methotrexate may induce “tumour lysis syndrome” in patients with rapidly growing tumours. In rare cases, following intrathecal administration, tumour lysis syndrome has been observed. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Special populations

Paediatric use

Overdose by intravenous and intrathecal miscalculation of dosage (particularly in juveniles) has occurred. Special attention must be given to dose calculation (see section 4.2).

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 intravenous methotrexate (1 g/m2).

Use in the elderly

Methotrexate should be used with extreme caution in elderly patients. Elderly patients should be monitored closely for early signs of methotrexate toxicity. Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age (see section 4.2).

PRECAUTIONS

Methotrexate toxicity and folate rescue

Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures (see section 4.2).

Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria and impaired renal function.

Some patients may have delayed methotrexate clearance in the absence of these features. It is important that patients be identified within 48 hours since methotrexate toxicity may not be reversible if adequate folinic acid rescue is delayed for more than 42 to 48 hours.

The method of monitoring methotrexate concentrations varies from institution to institution. Monitoring of methotrexate concentrations should include determination of a methotrexate level at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue folinic acid rescue).

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Fertility and reproduction

Fertility

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before methotrexate is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least 6 months after. Pregnant psoriatic patients should not receive methotrexate.

For contraception advice for men see section 4.6.

Haematologicical

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay.

Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Clinical sequelae such as fever, infections and haemorrhage from various sites may be expected. Pre-treatment and periodic haematological studies are essential to the use of methotrexate in chemotherapy as haematopoietic suppression may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all (refer to section 4.3). In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression.

Laboratory monitoring

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: complete haemogram, haematocrit, urinalysis, renal function tests, liver function tests and chest X-ray. The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

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.

These laboratory parameters should be performed with reference to local or national clinical guidelines, at regular intervals, with increased frequency in specific circumstances as per clinician's discretion.

Other

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established. See section 4.5

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. 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.

Excipient information

Methotrexate 50 mg/2 ml and 250 mg/10 ml contain less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium free'.

Methotrexate 500 mg/20 ml contains 41.1 mg sodium per vial, equivalent to 2.06% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Methotrexate 1 g/40 ml contains 82.2 mg sodium per vial, equivalent to 4.11% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Drugs highly bound to plasma proteins

Methotrexate is extensively protein bound and toxicity may be increased because of displacement by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, phenytoin, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents.

Nephrotoxic agents

Concomitant use with chemotherapeutic and other drugs with nephrotoxic potential (including alcohol) should be avoided due to the risk of enhanced nephrotoxicity, especially when high dose methotrexate is administered.

Chemotherapeutic agents

Mercaptopurine: Methotrexate may increase the bioavailability of mercaptopurine by interference with first-pass metabolism. Combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Cytarabine: Intrathecal methotrexate given concomitantly with intravenous cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke like episodes.

L-asparaginase: The administration of L-asparaginase has been reported to antagonise the effect of methotrexate.

Hepatotoxic agents

Concomitant therapy with methotrexate and other potential hepatotoxic agents (e.g., leflunomide, azathioprine, sulfasalazine, retinoids, alcohol) should be closely monitored for heightened risk of hepatoxicity.

Vitamins

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate, however folate deficiency states may increase methotrexate toxicity.

Disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs should not be administered prior to or concomitantly with the high doses of methotrexate such as used in the treatment of osteosarcoma. Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic (including bone marrow suppression and aplastic anaemia) and gastrointestinal toxicity.

Caution should also be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity by increasing methotrexate levels. 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.

Probenecid

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

Proton-pump inhibitors (PPIs)

Co-administration of PPIs (e.g. omeprazole, pantoprazole) with methotrexate may decrease the clearance of methotrexate causing elevated methotrexate plasma levels with clinical signs and symptoms of methotrexate toxicity. Concomitant use of PPIs and high dose methotrexate should therefore be avoided, especially in patients with renal impairment.

Antibiotics

Ciprofloxacin: Renal tubular transport is diminished by ciprofloxacin; use of methotrexate with this drug should be carefully monitored.

Penicillins and sulfonamides: Penicillins and sulfonamides may reduce the renal clearance of methotrexate; haematologic and gastrointestinal toxicity has 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 suppressing metabolism of methotrexate by bacteria.

Bone marrow suppression, sometimes severe, has been reported rarely in patients receiving methotrexate and co-trimoxazole or trimethoprim/sulfamethoxazole. This is probably due to decreased tubular secretion and/or additive antifolate effect. Concurrent use should probably be avoided.

Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive antifolate effect.

Nitrous oxide anaesthesia

The use of nitrous oxide anaesthesia 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.

Haematotoxic agents

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

Acitretin

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.

Theophylline

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

Amiodarone

Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions.

Leflunomide

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

Packed red blood cells

Care should be exercised whenever packed red blood cells and methotrexate are given concurrently: patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum-methotrexate concentrations.

Psoralen plus ultraviolet light (PUVA) therapy

Skin cancer has been reported in few patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy (methoxalen and ultraviolet light).

Diuretics

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

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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 6 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

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.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans. 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 3 months after cessation of methotrexate. Men should not donate semen during therapy or for 3 months following discontinuation of methotrexate.

4.7. Effects on ability to drive and use machines

Central nervous symptoms such as fatigue and drowsiness can occur during treatment. Methotrexate has moderate influence on the ability to drive and use machines.

4.8. Undesirable effects

The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Frequencies in this table are defined using the following convention:

very common (≥ 1/10), common (≥ 1/100 < 1/10), uncommon (≥ 1/1,000 < 1/100), rare (≥ 1/10,000 < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

System Organ Class

Common

(≥ 1/100 < 1/10)

Uncommon

≥ 1/1,000

< 1/100

Rare

≥ 1/10,000

< 1/1,000

Very rare

< 1/10,000

Not known (cannot be estimated from the available data)

Infections and Infestations

Sepsis, Pharyngitis, Gingivitis

Furuncle

Opportunistic infections (sometimes fatal e.g. fatal sepsis)K, Pneumonia, Pneumocystis jirovecii pneumonia, Nocardiosis, Histoplasmosis, Cryptococcosis, Herpes Zoster, Hepatitis, Herpes simplex, Cytomegalovirus infection, including cytomegaloviral pneumonia, Reactivation of hepatitis B infection, Worsening of hepatitis C Infection, Cystitis, Vaginitis

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps)

LymphomaP

Tumor lysis syndromeL

Blood and lymphatic system disorders

Myelosuppression, Anaemia, Thrombocytopenia

Aplastic anaemia, Lymphoproliferative disorders

Agranulocytosis, Pancytopenia, Leukopenia, Neutropenia, Lymphadenopathy, Eosinophilia, Anaemia megaloblastic

Immune system disorders

Anaphylactic reactions

Hypogammaglobulinemia

Metabolism and nutrition disorders

Decreased appetite

Diabetes mellitus

Metabolic changes

Psychiatric disorders

Mood altered, Transient cognitive dysfunction

Nervous system disorders

HemiparesisA, Leukoencephalopathy/ encephalopathyC, SeizureA, HeadachesA, ParesisB

Dysarthria, AphasiaA, SomnolenceA

Paraesthesia, Cranial nerve disorderR, Hypoesthesia,

Guillain-Barre syndromeB, Neurotoxicity, ArachnoiditisB, ParaplegiaB, Stupor, AtaxiaB, Dizziness, Cognitive disorderA

Eye disorders

Vision blurredA, Visual impairment

Conjunctivitis

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Pericardial effusion, Pericarditis

Vascular disorders

Hypotension, Thromboembolic events (e.g. thrombophlebitis, pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis)

Vasculitis

Haemorrhage

Respiratory, thoracic and mediastinal disorders

Acute or chronic interstitial lung diseaseD, Pleural effusion

Pulmonary fibrosis

Alveolitis, Dyspnoea, Cough, Acute pulmonary oedemaE, Pulmonary alveolar haemorrhageF

Syndrome consisting of pleuritic pain and pleural thickeningO

Gastrointestinal disordersQ

Pancreatitis, Vomiting, Diarrhoea, Stomatitis

Gastrointestinal ulceration and bleeding, Melena, Enteritis, Toxic megacolonM, MalabsorptionM

Haematemesis,

Nausea

Hepatobiliary disorders

Hepatic fibrosis, Hepatic cirrhosis, Portal fibrosisG, Hepatitis acuteG, HepatotoxicityG,

Blood albumin decreased

Hepatic failure, Hepatic atrophyG, Hepatic steatosisG, Hepatic necrosis, DeathG

Skin and subcutaneous tissue disorders

Toxic epidermal necrolysis (Lyell's syndrome)H, Stevens-Johnson syndromeH, Alopecia, Photosensitivity reactionsJ,

Erythema multiformeH, Erythematous rashes, Painful erosion of psoriatic plaques, Skin ulcer, Urticaria, Acne, Ecchymosis, Pigmentation disorder, Pruritus

Telangiectasia

Aggravation of psoriatic lesionsI, Dermatitis, Petechiae, Skin necrosisH, Skin exfoliation, Dermatitis exfoliative

Musculoskeletal and connective tissue disorders

Arthralgia, Myalgia, Osteoporosis

Osteonecrosis, Osteonecrosis of jawN

Renal and urinary disorders

Renal failure, Nephropathy

Dysuria

Haematuria, Azotaemia

Proteinuria

Pregnancy, puerperium and perinatal conditions

Foetal defects

Abortion

Foetal death

Reproductive system and breast disorders

Menstrual dysfunction

Defective oogenesis or spermatogenesis, Infertility, Transient oligospermia, Vaginal discharge

Sexual dysfunction, Vaginal ulceration

General disorders and administration site conditions

Nodulosis

Sudden death, Pyrexia, Chills, Malaise, Fatigue, Chest pain, Oedema, Mucositis, Injection site reaction, Injection site necrosis

Investigations

Hepatic enzyme increasedG

CSF pressure increasedB

Injury, poisoning and procedural complications

Stress fractures

Footnotes:

A: Have occurred possibly related to haemorrhage or to complications from intraarterial catheterization

B: Have followed intrathecal administration

C: There have been reports of leukoencephalopathy following intravenous administration of methotrexate in high doses, or low doses following cranial-spinal radiationD: Often associated with blood eosinophilia, may occur and deaths have been reported (see section 4.4)E: Has also been reported after oral and intrathecal useF: Has been reported for methotrexate used in rheumatologic and related indications G: May occur, usually following chronic administrationH: Severe, occasionally fatal, dermatologic reactionsI: Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiationJ: The recall phenomenon has been reported in both radiation and solar damaged skinK: Have also been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis jirovecii pneumonia being the most common L: TLS has been observed in rare cases following intrathecal administrationM: In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolonN: Secondary to lymphoproliferative disorders

O: Has been reported following high doses

P: Including reversible lymphoma

Q: Including intestinal perforation

R: Optic nerve disorder

Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

Reports of oral overdose indicate accidental daily administration instead of weekly (single or divided doses). Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions.

Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have been reports of death following intrathecal overdose. In these cases, cerebellar herniation associated with increased intracranial pressure, and acute toxic encephalopathy has also been reported.

Recommended treatment

Calcium folinate (calcium leucovorin) is a potent agent for neutralising the immediate toxic effects of methotrexate on the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than, the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective. As the time interval between methotrexate administration and folinic acid initiation increases, the effectiveness of folinic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with folinic acid.

Other supporting therapy such as blood transfusion and renal dialysis may be required. In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Accidental intrathecal overdosage may require intensive systemic support, high-dose systemic (intravenous) folinic acid, alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion.

There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.