SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methotrexate 25 mg/ml Injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains methotrexate (present in solution as methotrexate sodium) equivalent to 25 mg anhydrous methotrexate.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Sterile solution for injection or infusion.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Methotrexate is used for the treatment of neoplastic disease.

4.2 Posology and method of administration

Routes of administration: For intramuscular, intravenous (bolus injection or infusion), intrathecal, and intra-arterial use.

Methotrexate should only be administered by or under the direct supervision of a physician experienced in cytotoxic chemistry.

Adults and Children

Dosages are based on a patients bodyweight or surface area except when administering by the intrathecal routes when a maximum dose of 15 mg is recommended. If the patient has hepatic or renal impairment, or haematological deficiency, then the dosage should be reduced. When giving larger doses (more than 100 mg), the intravenous route is usually used with infusion over a period of up to 24 hours; part of the dosage may be given as an initial rapid intravenous infusion.

Methotrexate has been used with beneficial effects in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents, hormones, radiotherapy or surgery. Dosage schedules therefore vary considerably, depending on the clinical use, particularly when intermittent high-dose regimens are followed by the administration of calcium folinate to rescue normal cells from toxic effects.

Elderly

Due to diminished hepatic and renal function and decreased folate stores, methotrexate should be used with extreme caution in elderly patients. A reduction in dosage should be considered and these patients should be closely monitored for early signs of toxicity.

The following are examples of dosage regimes that have been used for particular indications.

Choriocarcinoma and other trophoblastic tumours:    Intramuscular

administration of 0.25 - 1 mg/kg to a maximum of 60 mg per dose every 48 hours (with calcium folinate rescue) for 4 doses. Repeated courses at 7 day intervals should be given until urinary chorionic gonadotrophin levels have returned to normal. This usually requires at least four courses of treatment. If patients have complications such as extensive metastases, they may be treated with combinations of other cytotoxic drugs and methotrexate. Similar doses are used for the treatment of hydatidiform mole and chorioadenoma destruens.

Leukaemia in children: To induce remissions in acute lymphocytic leukaemia, the use of a combination of other cytotoxic drugs and corticosteroids is reported to be best.

Methotrexate 15 mg/m , given parenterally or orally once weekly, in combination with other drugs appears to be the treatment of choice for maintenance of drug-induced remissions.

Meningeal Leukaemia in children: Doses of up to 15 mg, intrathecally, at weekly intervals, until the CSF appears to be normal (usually 2-3 weeks) have been found useful for the treatment of meningeal leukaemia.

central nervous system in children with poor prognosis lymphocytic leukaemia.

Lymphoma: Non-Hodgkin’s lymphoma, e.g. childhood lymphosarcoma, has recently been treated with 3-30mg/kg (approximately 90-900 mg/m²) of methotrexate given by intravenous injection and infusion followed by administration of calcium folinate with the higher doses. Some cases of Burkitt’s lymphoma, when treated in the early stages with courses of 15 mg/m² daily for five days, have shown prolonged remissions.

Combination chemotherapy is also commonly used in all stages of the disease.

Breast Cancer: In advanced breast cancer, methotrexate is often given in cyclical combinations with other cytotoxic drugs. The methotrexate is given in intravenous doses of 10 - 60 mg/m². Adjuvant therapy in early cases following mastectomy and/or radiotherapy has used similar dosage regimes.

Osteogenic Sarcoma: Adjuvant therapy to primary surgical treatment of osteosarcoma has recently included methotrexate either alone or in cyclical combination with other drugs. Doses have been from 20 - 300 mg/kg (approximately 600 - 9000 mg/m²) methotrexate given intravenously and followed by calcium folinate rescue. Treatment of metastatic cases of osteosarcoma has also employed the sole use of methotrexate.

Bladder Carcinoma: Doses of up to 100 mg of methotrexate intravenously every one or two weeks are reported to have given encouraging results for bladder carcinoma. The results vary from symptomatic relief to complete regressions, although these are unsustained. It is also reported that high dosage methotrexate with calcium folinate rescue is being evaluated.

Head and Neck Cancer: Pre-operative adjuvant therapy and the treatment of advanced tumours have used doses of 240 - 1080 mg/m methotrexate, given by intravenous infusions followed by calcium folinate rescue. Methotrexate is also reported to have been given by intra-arterial infusions in the treatment of head and neck cancers.

Bronchogenic Carcinoma: 20 - 100 mg/m methotrexate given by intravenous infusion has been used in cyclical combinations for the treatment of advanced tumours. High doses of methotrexate, followed by calcium folinate rescue have also been used as the sole treatment.

4.3 Contraindications

Profound impairment of renal or hepatic function or haematological impairment.

Alcoholism. Liver disease including alcoholic liver disease, fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s).

Pre-existing blood dyscrasias, such as bone marrow hypoplasia, anaemia, leucopenia or thrombocytopenia. Methotrexate is contra-indicated in pregnant patients. Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast-feeding is contra-indicated in women taking methotrexate.

Patients with a known allergic hypersensitivity to methotrexate or any of the excipients in the formulation should not receive methotrexate.

Diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy.

4.4 Special warnings and precautions for use

WARNINGS

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.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported.

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

Pulmonary signs and symptoms, e.g. a dry non-reproductive cough, fever, cough, chest pain, dyspnoea, hypoxemia and an infiltrate on chest x-ray, or a non-specific pneumonitis may also be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Pulmonary lesions can occur at all dosages. Methotrexate induced lung disease may occur acutely at any time during therapy and has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. Infection (including pneumonia) needs to be excluded.

Patients should be monitored for pulmonary signs and symptoms at each follow up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop a persistent cough or dyspnoea.

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.

Deaths have been reported with the use of methotrexate in the treatment of malignancy, therefore it should only be used in life threatening neoplastic diseases.

Full blood counts should be closely monitored before, during and after treatment. Any profound drop in white-cell or platelet counts should result in immediate withdrawal of the drug and appropriate supportive therapy (see section 4.8). Patients should be advised to report all signs and symptoms suggestive of infection.

Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, methotrexate dosing should be suspended for at least 2 weeks. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

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.

Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in patients with renal impairment. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 - 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

Symptoms of gastro-intestinal toxicity, usually first manifested by diarrhoea and ulcerative stomatitis, necessitate 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.

The immunological response to concurrent vaccination could be decreased, as methotrexate has some immunosuppressive activity. A severe reaction could result from the concomitant use of a live vaccine, and it is therefore not generally recommended. There have been reports of disseminated vaccinia infections after smallpox immunisation in patients receiving methotrexate therapy.

Patients with pleural effusions or ascites should have these drained if appropriate before treatment and their plasma methotrexate levels monitored, or treatment should be withdrawn. The reason being that methotrexate exits slowly from third party compartments (e.g. pleural effusions, ascites). This results in a prolonged terminal halflife and unexpected toxicity.

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).

Concomitant administration of folate antagonists such as

rimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

A chest X-ray is recommended prior to initiation of methotrexate therapy.

If acute methotrexate toxicity occurs, patients may require folinic acid.

Folate deficiency states may increase methotrexate toxicity.

PRECAUTIONS

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.

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. Patients undergoing therapy should be subject to appropriate supervision every 2-3 months so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Renal function and full blood counts should be closely monitored before, during and after treatment.

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.

Carcinogenesis, mutagenesis and impairment of fertility: Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia. Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation.

In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction should be discussed with patients of child-bearing potential (see ‘warnings’).

Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leucopenia, neutropenia and/or thrombocytopenia. Haematopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Methotrexate should be used with caution, if at all in patients with malignancy and pre-existing haematopoietic impairment. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression.

It is essential that the following laboratory tests are included regularly (every 2-3 months) in the clinical evaluation and monitoring of patients receiving methotrexate: complete haematological analysis, urinalysis, renal function tests, liver function tests, chest X-ray and, when high doses are administered, determination of plasma levels of methotrexate.

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.

Liver biopsy may be considered after cumulative doses>1.5 g have been given, if hepatic impairment is suspected.

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.

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

Methotrexate should be used with extreme caution in patients with the presence of infection, haematological depression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhoea, debility, and also in young children and the elderly. 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.

Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution, and at reduced dosages because impairment of renal function will decrease methotrexate elimination.

Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

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. Toxic effects may be related in frequency and severity to dose or frequency of administration, but has been seen at all doses and can occur at any time during therapy. Most adverse reactions are reversible if detected early. When such reactions do occur, the dosage should be reduced or discontinued and appropriate corrective measures should be taken. If methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug, and with increased alertness as to possible recurrence of toxicity.

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

If vomiting resulting in dehydration happens, methotrexate should be discontinued until recovery occurs.

Like other cytotoxic drugs, methotrexate may induce “tumour lysis syndrome” in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this condition.

Severe, occasionally fatal, skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell’s syndrome) and erythema multiforme have been reported within days of administering single or multiple doses of methotrexate.

Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and do not appear predictive of subsequent hepatic disease. Persistent liver abnormalities and/or decrease of serum albumin may be indicators of serious liver toxicity. Liver biopsy after sustained use often shows histological changes, and fibrosis and cirrhosis have been reported.

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

The use of methotrexate high-dose regimens recommended for osteosarcoma requires meticulous care. High dosage regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Drugs such as salicylates, sulphonamides, tetracyclines, chloramphenicol, diuretics, p-aminobenzoic acid, acidic anti-inflammatory drugs, diphenylhydantoins, hypoglycaemics may displace methotrexate, which is extensively protein bound, increasing the potential for toxicity when given concurrently. Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should generally be avoided, unless considered clinically justified, in which case the patient should be closely monitored.

The response to methotrexate may be altered if vitamin preparations which contain folic acid or its derivatives are also being taken. High doses of calcium folinate may reduce the efficacy of intrathecally administered methotrexate.

If methotrexate is given prior to or concomitantly with NSAID’s, including salicylates, extreme caution should be exercised as there have been reports of severe methotrexate toxicity and even death due to reduced methotrexate excretion. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and thereby may enhance its toxicity. It is recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.

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

Renal tubular transport is also diminished by probenecid, penicillins, and omeprazole, which may result in potentially toxic methotrexate levels. The use of methotrexate with these drugs should be carefully monitored. Haematologic and gastrointestinal toxicity have been observed in combination with high and low dose methotrexate.

It has been reported rarely that the use of folate antagonists e.g. trimethoprim, co-trimoxazole, when given concomitantly with methotrexate may cause bone marrow depression, acute megaloblastic pancytopenia. Methotrexate-induced stomatitis and other toxic effects may be increased by the use of nitrous oxide. Methotrexate should be used with caution in patients taking drugs with an anti-folate potential.

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxic agents (e.g. alcohol, leflunomide, azathioprine, sulfasalazine, retinoids) should generally be avoided, unless clinically justified, in which case the patient should be closely monitored for possible increased risk of hepatotoxicity.

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

Existing data suggests that etretinate is formed from acitretin after ingestion of alcoholic beverages. However, the formation of etretinate without concurrent alcohol intake cannot be excluded. Methotrexate serum levels may be increased by etretinate (acitretin metabolite) and severe hepatitis has been reported following concomitant use. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

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.

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

4.6 Pregnancy and lactation

Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Therefore it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded. If the drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.

Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction have been reported in patients receiving methotrexate. To date, this effect appears to be reversible on discontinuing therapy. Conception should be avoided for at least 3 months after treatment with methotrexate has ceased. Patients receiving methotrexate and their partners should be advised appropriately.

Methotrexate has been detected in human breast milk and is contra-indicated during breast-feeding.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

The most common adverse reactions include ulcerative stomatitis, leucopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are eye-irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. In general, the incidence and severity of side-effects are considered to be dose-related.

Opportunistic infections (sometimes fatal) have been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis and disseminated Herpes simplex.

Conjunctivitis and serious visual changes of unknown etiology have been reported.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, stress fractures, nodulosis, reversible lymphomas, tumour lysis syndrome, abnormal (usually megaloblastic) red cell morphology, precipitation of diabetes, other metabolic changes, anaphylactoid reactions and sudden death have been reported.

Adverse reactions for the various systems are as follows:

Skin: Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell’s Syndrome), erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin.

Blood: Bone marrow depression is a common effect of methotrexate therapy and can occur abruptly, resulting in thrombocytopenia, anaemia or leucopenia. Infection (e.g. pneumonia) or septicaemia and haemorrhage from various sites may result. Aplastic anaemia, pancytopenia and neutropenia, lymphadenopathy, lymphoproliferative disorders (including reversible) have been reported, as has hypogammaglobulinaemia.

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, decrease in serum albumin, acute liver atrophy, necrosis, acute hepatitis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital system: High dose methotrexate therapy may result in renal failure and uraemia. Other reactions reported to occur include cystitis, azotemia, dysuria, severe nephropathy, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects. Vaginitis, vaginal discharge, nephropathy and vaginal ulcers.

Pulmonary system: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported (see Section 4.4 Warnings and Precautions for Use). After oral and intrathecal use, acute pulmonary oedema has been reported. Pulmonary fibrosis, respiratory failure and chronic interstitial pulmonary disease have been reported. After high doses, pleuritic pain and pleural thickening have been reported.

Central nervous system: Observed effects include headaches, blurred vision and drowsiness. Occasionally after low doses it is reported that short lived subtle cognitive dysfunction, alterations in moods and unusual cranial sensations may be observed. Higher doses occasionally result in hemiparesis, paresis, speech impairment including dysarthria and aphasia, and convulsions. Following high intravenous doses or low doses of methotrexate following cranial-spinal radiation, leucoencephalopathy has been reported. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

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 (1gm/m²).

Symptomatic patients were commonly noted to have leucoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leucoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with calcium folinate rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery.

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

Cardiac: Pericarditis, pericardial effusion, hypotension, and thromboembolic events including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis and pulmonary embolus.

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, paraparesis/paraplegia associated with involvement with one or more spinal nerve roots, nerve palsies, and cerebellar dysfunction. The chronic form is a leucoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma and rarely, death. This central nervous system toxicity can be progressive. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increased the incidence of leucoencephalopathy. Signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

4.9 Overdose

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

Symptoms of intrathecal overdose are generally 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 have been reported.

Calcium folinate is the antidote 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.

Other supporting therapy such as blood transfusion and renal dialysis may be required. Calcium folinate administration should begin as promptly as possible. As the time interval between methotrexate administration and calcium folinate initiation increases, the effectiveness of calcium folinate in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with calcium folinate.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Following intrathecal overdose, CSF drainage may remove up to 95% of the dose if commenced within 15 minutes of administration, although this falls to 20% after 2 hours. For intrathecal doses over 100 mg, ventriculolumbar perfusion should accompany CSF drainage. In addition, high dose systemic calcium folinate or alkaline diuresis may be required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: LO1B A01 Folic acid analogues

Methotrexate, a derivative of folic acid, belongs to the class of cytotoxic agents known as antimetabolites. It acts principally during the “S” phase of cell division, by the competitive inhibition of the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, a necessary step in the process of DNA synthesis and cellular replication.

5.2 Pharmacokinetic properties

Methotrexate distributes rapidly following a bolus intravenous injection; its disappearance from the plasma compartment is a triphasic: t/ (alpha) = 0.250.7 hour; t/ (beta) = 2.0-3.5 hours; t/ (gamma) = 10-15 hours. The initial plasma half-life value is often obscured because methotrexate is infused over 2 to 12 hours periods.

Methotrexate metabolites account for less than 10% of the total dose if the drug is given intravenously at 30 mg/m . The two major metabolites are 2,4-diamino-N¹⁰-methylpteroic acid (DAMPA) and 7-hydroxy-methotrexate (7-OH MTX). Both metabolites are biologically inactive. The 7-OH MT in the kidney tubules may contribute to nephrotoxicity especially with high-dose therapy.

Under conditions of normal renal function, drug clearance from plasma is 103 ml/min/m . Young children are able to tolerate considerably more systemic methotrexate, presumably because of improved renal clearance.

Methotrexate is concentrated in the liver and the bile, and can reach bile:plasma ratios as high as 200:1. However, the actual amount of methotrexate excreted by this route has been reported to be only 6.3% because most biliary methotrexate is reabsorbed from the GI tract.

With intrathecal administration, the slow rate of release of methotrexate from the CSF is rate controlling, therefore the elimination from the body is delayed, t/ (beta) for methotrexate following intrathecal administration is 5.2-7.8 hours. The terminal elimination phase is greatly prolonged (t/ (gamma) - 5278 hours).

Methotrexate is distributed mainly in the extracellular spaces but a proportion penetrates cell membranes and is strongly bound to dihydrofolate reductase. About 50% is bound to plasma proteins. Bound methotrexate may be retained in the body for many months.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of methotrexate has been established after many years of clinical use. Please refer to section 4.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Sodium hydroxide Hydrochloric acid (1:20)

Water for injection.

6.2 Incompatibilities

Mixed injections should be avoided.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 25°C in the original package.

6.5 Nature and contents of container

Clear Type 1 glass ampoules in 1 ml or 2 ml sizes (in a pack of 5), or Clear Type 1 glass vials with elastomeric closures in 2 ml, 4 ml, 8 ml, 20 ml & 40 ml sizes.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Methotrexate may be diluted with the following infusion fluids: 0.9% sodium chloride, glucose, sodium chloride and glucose. Solutions are stable for up to 24 hours when stored at 2 - 8°C.

Discard any unused solution.

Other drugs should not be mixed with methotrexate in the same infusion container.

As with all cytotoxic preparations, special precautions should be taken for safe handling and disposal and only trained personnel should prepare the drug. Preparation should be performed in a designated area ideally in a vertical laminar flow hood, with the work surface covered with disposable plastic-backed absorbent paper.

In the event of contact with either the eyes or skin, wash thoroughly with water and seek medical advice. Seek immediate medical attention if the drug is ingested, or if there is a danger of systemic absorption of significant quantities of methotrexate, by any route, as leucovorin cover will be required.

Adequate protective clothing should be worn, such as PVC gloves, safety glasses, disposable gowns and masks. It is recommended that luer lock fittings are used in the assembly of syringes and giving sets to avoid leakage.

All used material, needles, syringes, vials and other items which have come into contact with cytotoxic drugs should be incinerated. Excreta should be similarly treated.

Pregnant staff should not be involved in the handling of cytotoxic preparations.

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Eastbourne BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0466

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

27/05/03

10 DATE OF REVISION OF THE TEXT

25/04/2012