Summary of Product Characteristics

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1 1 NAME OF THE MEDICINAL PRODUCT Methotrexate 2.5 mg tablets Summary of Product Characteristics 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 2.5 mg methotrexate. Excipient(s) with known effect: Each tablet contains 12.5 mg of lactose monohydrate. For the full list of excipients, see section PHARMACEUTICAL FORM Tablet. Yellow, circular, biconvex uncoated tablets plain on both sides. 4 CLINICAL PARTICULARS 4.1 Therapeutic Indications Methotrexate 2.5 mg tablet is a folic acid antagonist and is classified as an antimetabolite cytotoxic agent. used in the treatment of adults with severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy. used in the treatment of severe, uncontrolled psoriasis, which is not responsive to other therapy. used to produce regression in a wide range of neoplastic conditions including acute leukaemias, non-hodgkin s lymphoma, soft-tissue and osteogenic sarcomas, and solid tumours particularly breast, lung, head and neck, bladder, cervical, ovarian, and testicular carcinoma. 4.2 Posology and method of administration Method of administration: Oral Dosage and Administration with reference to Rheumatoid arthritis and Psoriasis 1.1.Dosage for Rheumatoid arthritis Adults: In adults with severe, active, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy, methotrexate should be taken as 7.5 mg orally once a week. The prescriber may specify the day of intake on the prescription. Elderly: Methotrexate should be used with extreme caution in elderly patients, a reduction in dosage should be considered. Children: Safety and effectiveness in children have not been established, other than in cancer chemotherapy. Date Printed 12/09/2016 CRN page number: 1

2 Dosage for psoriasis: For the treatment of severe psoriasis mg orally, once a week, is recommended. Dosage should be adjusted according to the patient s response and the haematological toxicity. The prescriber may specify the day of intake on the prescription. 1.2.Dosage for cancer treatment: A test dose of 5-10 mg parentally is recommended, one week prior to therapy to detect idiosyncratic adverse events. Single doses, not exceeding 30 mg/m 2, on not more than 5 consecutive days. A rest period of at least two weeks is recommended between treatments, in order to allow the bone marrow to return to normal. Doses in excess of 100 mg are usually given parentally, when the injectable preparation should be used. Doses in excess of 70 mg/m 2 should not be administered without leucovorin rescue (folinic acid rescue) or assay of serum methotrexate levels hours after dosing. If methotrexate is administered in combination chemotherapy regimens, the dosage should be reduced, taking into consideration any overlapping toxicity of the other drug components. Precaution to be taken before manipulating or administering the product: For special precautions related to the handling of the product by healthcare professionals (including pregnant healthcare professionals) or carers see section Contraindications Methotrexate is contra-indicated in the presence of severe/significant renal or significant hepatic impairment. Liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s). Serious cases of anaemia, leucopenia or thrombocytopenia. Methotrexate should not be used concomitantly with drugs with antifolate properties (eg co-trimoxazole). Methotrexate is teratogenic and should not be given during pregnancy or to mothers who are breast feeding. Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Methotrexate Tablets 2.5mg (see section 4.4, Special Warnings). Patients with a known allergic hypersensitivity to methotrexate or any of its excipients should not receive methotrexate. 4.4 Special warnings and precautions for use The prescriber may specify the day of intake on the prescription. Patients should be aware of importance of adhering to the once weekly intakes. Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, diarrhoea, and ulcerative disorders of the GI tract and psychiatric disorders. Hepatic toxicity has been observed, usually associated particular, to hepatic disease. The administration of low doses of methotrexate for prolonged periods may give rise, in particular, to hepatic toxicity. Liver function should be closely monitored. If hepatic function abnormalities develop, methotrexate dosing should be suspended for at least two weeks. It is only appropriate to restart methotrexate provided the abnormalities return to normal and the re-exposure is deemed appropriate Particular care and possible cessation of treatment are indicated if stomatitis or GI toxicity occurs as haemorrhagic enteritis and intestinal perforation may result. Reversible eosinophilic pulmonary reactions and treatment-resistant, interstitial fibrosis may occur, particularly after long-term treatment. Renal lesions may develop if the urinary flow is impended and urinary ph is low, especially if large doses have been administered. Renal function should be closely monitored before, during and after treatment. Date Printed 12/09/2016 CRN page number: 2

3 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 by oral or intravenous administration of sodium bicarbonate (5x625mg tablets every three hours) is recommended as a preventative measure. Haematopoietic suppression caused by Methotrexate may occur abruptly and with apparently safe dosages. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white cell or platelet count develops, methotrexate therapy should be withdrawn immediately and appropriate supportive therapy given (see Undesirable Effects section). Patients should be advised to report all symptoms or signs suggestive of infection. Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy. Methotrexate has been shown to be teratogenic; it has been reported to cause foetal death and/or congenital abnormalities. Therefore, it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus. Following administration to a man or woman conception should be avoided by using an effective contraceptive method for at least 3 months after using Methotrexate Tablets 2.5mg (see section 4.3, Contraindications). Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause severe antigenic reaction. Methotrexate should only be used by clinicians that are familiar with the various characteristics of the drug and its mode of action. Before beginning Methotrexate therapy or reinstituting Methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor. Patients receiving low-dose methotrexate should: Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment. Patients should report all symptoms and signs suggestive of infection, especially sore throat. If acute methotrexate toxicity occurs, patients may require treatment with folinic acid. The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue. Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy or treatment should be withdrawn. When to perform a liver biopsy in rheumatoid arthritis patients has not been established either in terms of a cumulative Methotrexate dose or duration of therapy. Pleuropulmonary manifestation of rheumatoid arthritis has been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically altered to the potential for Methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea (see Undesirable Effects section). Date Printed 12/09/2016 CRN page number: 3

4 Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. Methotrexate should be withdrawn from patients with pulmonary symptoms, and a thorough investigation 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. Lung manifestations of RA and other connective tissue disorders are recognized to occur. In patients with RA, the physician should be specifically alerted to the potential for methotrexate induced adverse effects on the pulmonary system. The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Methotrexate is immunosuppressive and may therefore reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently. Methotrexate is extensively protein bound and may displace by, other acidic drugs. The concurrent administration of agents such as p-aminobenzoic acid, chloramphenicol, penicillines, ciprofloxacin, diphenylhydantoins, phenytoin, acidic anti-inflammatory agents, salicylates, sulphonamides, tetracyclines, thiazide diuretics, probenicid or sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity. Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indometacin (NSAID s) is commenced, as concomitant use of NSAID s has been associated with fatal methotrexate toxicity. Concomitant administration of folate antagonists such as trimethoprim, cotrimoxazole and nitrous oxide should be avoided. Hepatic and nephrotoxic drugs should be avoided. Acitretin (a treatment for psoriasis) is metabolised to eretinate. Methotrexate levels may be increased by eretinate and severe hepatitis has been reported following concomitant use. Vitamin preparations containing folic acid or its derivatives may alter response to Methotrexate. Proton-pump inhibitors A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case. 4.6 Fertility, pregnancy and lactation Methotrexate is contraindicated in pregnancy. Methotrexate affects spermatogenesis and oogenesis and may therefore decrease fertility. This effect appears to be reversible after discontinuation of therapy. Patients and their partners should be advised to avoid pregnancy until 3 months after cessation of methotrexate therapy. Patients should not breast feed whilst taking methotrexate. 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 Special Warnings sections). Date Printed 12/09/2016 CRN page number: 4

5 4.7 Effects on ability to drive and use machines Methotrexate has minor or moderate influence on the ability to drive and use machines. 4.8 Undesirable effects In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows: Skin: Stevens-Johnson Syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques has been reported. The recall phenomenon has been reported in both radiation and solar damaged skin. Haematopoietic: Bone marrow depression is most frequently manifested by leucopenia, thrombocytopenia (which are usually reversible) and anaemia, or any combination may occur. Infection or hypogammaglobulinaemia has been reported. Alimentary System: Mucositis (most frequently stomatitis although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of Methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur. Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration. Urogenital System: Renal failure and uraemia may follow Methotrexate administration, particularly after high doses or prolonged administration. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported. Methotrexate can decrease fertility. This effect appears to be reversible after discontinuation of therapy (see Pregnancy and Lactation section). Pulmonary System: Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses. In the treatment of rheumatoid arthritis, Methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation. 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). Central Nervous System: Headaches, drowsiness, ataxia and blurred vision have occurred following low doses of Methotrexate, transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses. There have been reports of leucoencephalopathy following intravenous Methotrexate in high doses, or low doses Date Printed 12/09/2016 CRN page number: 5

6 following cranial-spinal radiation. Other reports include eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. Also opportunistic infections such as herpes zoster. Osteoporosis, abnormal (usually "megaloblastic") red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death in relation to or attributed to the use of Methotrexate. Although very rare, anaphylactic reactions to methotrexate have been reported. 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 at: HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: Fax: Website: medsafety@hpra.ie 4.9 Overdose Leucovorin is a specific antidote for methotrexate and, following accidental overdose, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary. In 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. Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate have been reported. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimetabolites, Folic acid analogues, ATC code: L01BA01 Mechanism of action Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division. The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium. 5.2 Pharmacokinetic properties When given in low doses, methotrexate is rapidly absorbed from the GI tract giving plasma concentrations equivalent to those achieved after i.v. administration. Higher doses are less well absorbed. About 50% has been shown to be protein bound. Biphasic and triphasic plasma clearance has been shown. Date Printed 12/09/2016 CRN page number: 6

7 The majority of the dose is excreted within 24 hours in the urine mainly as unchanged drug. 5.3 Preclinical safety data No further preclinical safety data are available. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Anhydrous calcium hydrogen phosphate Lactose monohydrate Sodium starch glycolate (Type A) Cellulose, microcrystalline Talc Magnesium stearate (E470b) 6.2 Incompatibilities Not applicable 6.3 Shelf life 24 months 6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Blister: Store in the original package in order to protect from light. Bottle: Store in the original container in order to protect from light. 6.5 Nature and contents of container Blister: Amber coloured PVC film and aluminium blister foil. Bottle: HDPE container with 28 mm non CRC HDPE cap with induction wad. Pack sizes: Blister pack: 10 tablets, 12 tablets, 15 tablets, 20 tablets, 24 tablets, 25 tablets, 28 tablets, 30 tablets, 50 tablets, 100 tablets. HDPE bottle: 15 tablets, 30 tablets, 100 tablets. PVC/Alu perforated unit dose blister in pack-sizes of 10x1, 12x1, 15x1, 20x1, 24x1, 25x1, 28x1, 30x1, 50x1 &100x1 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Cytotoxic drugs should only be handled by trained personnel in a designated area. Refer to local cytotoxic guidelines before use. The work surface should be covered with disposable plastic-backed absorbent paper. Protective gloves and goggles should be worn to avoid the drug accidentally coming into contact with the skin or eyes. Methotrexate is not a vesicant and should not cause harm if comes into contact with the skin. It should of course be washed off with water immediately. Medical advice should be sought if the eyes are affected. Date Printed 12/09/2016 CRN page number: 7

8 Any transient stinging may be treated with bland cream. If there is any danger of systemic absorption of significant quantities of Methotrexate by any route, Calcium Leucovorin cover should be given. Cytotoxic preparations should not be handled by pregnant staff. Any spillage or waste material should be dealt with by trained personnel, wearing appropriate personal protective equipment as outlined above, may be disposed of by incineration. We do not make any specific recommendations with regards to the temperature of the incinerator. 7 MARKETING AUTHORISATION HOLDER Accord Healthcare Limited Sage House, 319 Pinner Road North Harrow Middlesex HA1 4HF United Kingdom 8 MARKETING AUTHORISATION NUMBER PA1390/116/001 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 1 st July DATE OF REVISION OF THE TEXT September 2016 Date Printed 12/09/2016 CRN page number: 8

PACKAGE LEAFLET: INFORMATION FOR THE USER. Methotrexate 2.5mg Tablets

PACKAGE LEAFLET: INFORMATION FOR THE USER Methotrexate 2.5mg Tablets Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. Keep this