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3/2015 : עלון מאושר.""פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר “This leaflet format has been determined by the Ministry of Health and the content thereof has been checked and approved.” Date of approval: 3/2015. 1. TRADE NAME OF THE MEDICINAL PRODUCT ABITREXATE 25 mg/ml Solution for Injection ABITREXATE 1g/10 ml (100 mg/ml) Solution for Injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Composition Abitrexate Injection 25 mg/ml Solution for Injection Each 1 ml contains: Active Ingredient Methotrexate 25 mg Other Ingredients Sodium chloride, sodium hydroxide (for pH adjustment) hydrochloric acid (for pH adjustment), water for injections. Sodium content: Each ml contains 1.93 mg sodium. Abitrexate Injection 1g/10 ml (100 mg/ml) Solution for Injection Each 1 ml contains: Active Ingredient Methotrexate 100 mg Other Ingredients Sodium hydroxide, hydrochloric acid (for pH adjustment), sodium hydroxide 1N (for pH adjustment), water for injections. Sodium content: Each ml contains 10.11 mg sodium. 3. PHARMACEUTICAL FORM Solution for injection 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Antineoplastic Chemotherapy Treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Palliation of acute lymphocytic leukemia. Abitrexate is also indicated in the treatment and prophylaxis of meningeal leukemia. Greatest effect has been observed in palliation of acute lymphoblastic (stem-cell) leukemias in children. In combination with other anticancer agents, Abitrexate may be used for the induction of remission, but is most commonly used in the maintenance of induced remissions. ABITREXATE Injection 8. 3. 2015, RH 2 Abitrexate may be used alone, or in combination with other antineoplastic drugs, in the management of breast cancer, epidermoid cancers of the head and neck, lung cancer (particularly squamous cell and small cell types), bladder cancer and osteogenic cancer. Abitrexate is effective in the treatment of the advanced stages (III and IV, Peter's Staging system) of lymphosarcoma, particularly in children, and in advanced cases of mycosis fungoides. Psoriasis Because of the high risk attending its use, Abitrexate is indicated only in the symptomatic control of severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established, as by biopsy and/or after dermatological consultation. Rheumatoid Arthritis Abitrexate can be used in the treatment of selected adults with severe rheumatoid arthritis, only when the diagnosis has been well established according to rheumatological standards, with inadequate response to other forms of antirheumatic therapy, including full dose NSAIDs and usually a trial of at least one or more disease-modifying antirheumatic drugs. 4.2 Posology and method of administration WARNINGS The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of tumour diseases. Fatal cases of intoxication have been reported after administration of incorrect calculated doses. Health care professionals and patients should be fully informed about toxic effects. Treatment should be initiated by or occur in consultation with a doctor with significant experience in cytostatic treatment. Abitrexate may be administered by intramuscular, intravenous (bolus injection or infusion), intrathecal, intraventricular or intra-arterial. For intrathecal administration, Abitrexate is administered as a 1 mg/ml solution, using an appropriate sterile preservative-free medium such as Sodium Chloride Injection. Dosages are based on the patient's bodyweight or surface area, except in the case of intrathecal or intraventricular administration, when a maximum dose of 15 mg is recommended. Dosage should be reduced in cases of hematological deficiency and hepatic or renal impairment. When administered by infusion, Abitrexate should only be diluted with normal saline. Larger doses (more than 100 mg) are usually administered by intravenous infusion over periods not exceeding 24 hours. Part of the dose may be administered as an initial rapid intravenous injection. ABITREXATE Injection 8. 3. 2015, RH 3 Abitrexate has been used with beneficial effects in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents, hormones, immunotherapy, radiotherapy or surgery. Therefore, dosage schedules vary considerably depending on the clinical use, particularly when intermittent high-dose regimens are followed by the administration of calcium leucovorin in order to rescue normal cells from toxic effects. Dosage regimens for calcium leucovorin rescue are discussed at the end of this section. The following are some examples of the dosages of Abitrexate that have been used for particular indications: Choriocarcinoma and Other Trophoblastic Tumors By the intramuscular route, in doses of 15-30 mg daily for a 5-day course. Such courses are usually repeated 3-5 times as required, with rest periods of 1 or more weeks between courses, until any toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24-hour quantitative analysis of urinary human chorionic gonadotrophin (HCG), which should return to normal or less than 50 IU/24 hours, usually after the 3rd or 4th course of treatment, and also usually followed by a complete resolution of measurable lesions in 4-6 weeks. After the normalization of HCG, 1 or 2 courses of Abitrexate are usually recommended. Before each course of the drug, careful clinical assessment is essential. Higher doses of up to 60 mg i.m. every 48 hours may be administered for 4 doses, followed by calcium leucovorin rescue. This course is repeated at 7-day intervals until levels of urinary HCG return to normal. Not less than 4 courses of treatment are usually necessary. Patients with complications, such as extensive metastases, may be treated with Abitrexate in cyclic combination with other cytotoxic drugs. Chorioadenoma Destruens and Hydatidiform Mole Since hydatidiform mole may be followed by choriocarcinoma, prophylactic chemotherapy with Abitrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Abitrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma. Lymphoblastic Leukemia Daily administration of Abitrexate 3.3 mg/m2, in combination with prednisone 60 mg/m2, is used as induction therapy in acute lymphatic (lymphoblastic) leukemia in children and young adolescents. Abitrexate alone, or in combination with other agents, appears to be a drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated with intramuscular methotrexate 30 mg/m2, twice weekly. It has also been administered intravenously in doses of 2.5 mg/kg body weight, every 14 days. If relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. ABITREXATE Injection 8. 3. 2015, RH 4 Meningeal Leukemia Administer 12 mg/m2 intrathecally, or an empirical dose of 15 mg. Dilute methotrexate to a concentration of 1 mg/ml using a sterile, preservative-free medium such as 0.9% Sodium Chloride Injection. Administer at intervals of 2-5 days, and repeat until the CSF cell count returns to normal. Then administer one additional dose. Administration at intervals of less than 1 week may result in increased subacute toxicity. For prophylaxis against meningeal leukemia, the dosage is the same as for treatment, except for the intervals of administration. The CSF volume is dependent on age, and not on body surface area (BSA). The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years. Intrathecal methotrexate 12 mg/m2 (maximum 15 mg) has resulted in low CSF methotrexate concentrations and reduced efficacy in children, and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of BSA, and appears to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Intrathecal Methotrexate Dosage According to Age. Age (years) Dose (mg) Under 1 6 1 8 2 10 Over 3* 12 *equal or higher than 3 years of age. Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients. Lymphomas In stage III, give methotrexate concomitantly with other antitumor agents. Treatment in all stages generally consists of several courses with 7-10 day rest periods between each course. Lymphosarcomas in stage III may respond to combined drug therapy with methotrexate 0.625-2.5 mg/kg body weight/day. Mycosis Fungoides Although the usual treatment is by orally-administered methotrexate, methotrexate has also been given intramuscularly in doses of 50 mg once a week, or 25 mg twice weekly. Breast Cancer Abitrexate in intravenous doses of 10-60 mg/m2 is commonly included in cyclical combination regimens with other cytotoxic drugs in the treatment of advanced breast cancer. Similar regimens have also been used as adjuvant therapy in early cases following mastectomy and/or radiotherapy. ABITREXATE Injection 8. 3. 2015, RH 5 Osteosarcoma Effective therapy requires several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the Table below. The starting dose for high-dose methotrexate treatment is 12g/m2. If this is insufficient to produce a peak serum concentration of 1,000 micromole per L (0.001 mol/l) at the end of the methotrexate infusion, the dose may be increased to 15g/m2 in subsequent treatments. If the patient is vomiting or unable to tolerate leucovorin orally, administer leucovorin I.V. or I.M. at the same dose and schedule. Chemotherapy Regimens for Osteosarcoma DRUG* DOSE* TREATMENT WEEK AFTER SURGERY 2 12 g/m IV as 4-hour 4,5,6,7,11,12,15, 16,29,30,44,45 infusion (starting dose) Methotrexate Leucovorin Doxorubicin as drug** Doxorubicin** Cisplatin** a Bleomycin** Cyclophosphamide** Dactinomycin** 15 mg orally every 6 hours for 10 doses, starting 24 hours after start of methotrexate infusion single 30mg/m2/day IV x 3 days 8,17 50 mg/m2IV 100 mg/m2 IV 20,23,33,36 20,23,33,36 15 units/m2 IV x 2 days 600 mg/m2 IV x 2 days 0.6 mg/m2 IV x 2 days 2,13,26,39,42 2,13,26,39,42 2,13,26,39,42 * Link MP, Goorin AM, Miseer AW et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity, N. Engl. J. Med. 1986;3 14(25):1600-6. ** See each respective monograph for more complete information. Dosage modifications may be necessary because of drug-induced toxicity. Bronchogenic Carcinoma Intravenous infusions of 20-100 mg/m2 of Abitrexate have been included in cyclical combination regimens for the treatment of advanced tumors. Higher doses of Abitrexate with calcium leucovorin rescue may also be employed as sole treatment. ABITREXATE Injection 8. 3. 2015, RH 6 Head and Neck Cancer Intravenous infusions of 240-1,080 mg/m2 of Abitrexate with calcium leucovorin rescue may be used both as preoperative adjuvant therapy and in the treatment of advanced tumors. Intra-arterial infusions of Abitrexate are indicated for certain head and neck cancers, although this route of administration is not used extensively. Bladder Carcinoma Intravenous injections or infusions of Abitrexate in doses up to 100 mg every 1-2 weeks may be used in the treatment of bladder carcinoma. Diuretics and hydration are employed in an attempt to reduce the excessive drug toxicity that may occur in patients with renal impairment. Psoriasis Patients should be fully informed of the potential risks involved, and should be under the constant supervision of the treating physician. The usual dose in cases of severe, uncontrolled psoriasis unresponsive to conventional therapy is 10-25 mg, administered intramuscularly or intravenously once a week and adjusted according to the patient's response. Rheumatoid Arthritis Note: The following recommendation is based on clinical studies whose tabulated dosages, as well as the references appear at the end of the paragraph. Initially, 10 mg/week may be administered either intramuscularly or intravenously. The dosage may be increased to 25 mg/week. Duration of treatment varied in clinical studies from 6 weeks to 13 weeks. An intramuscular dosage of 15 mg/week has been administered over a period of 6 months. An initial dosage of 10 mg/week IV, increased to a maximum of 50 mg/week IV has been administered over a period of 2 months. Tabulated Summary of Dosages for the Use of Methotrexate (Parenteral) in Rheumatoid Arthritis STUDY Herman (1) Ahern (2) Steinson (4) DOSE 10 mg/m2, IV 15 mg , oral 15 mg, IV 30 mg/m2, oral 30 mg/m2, IV 30 mg/m2,, IM 7.5 mg-25 mg per week; IM/oral ABITREXATE Injection 8. 3. 2015, RH Campbell (3) 7 STUDY Michaels (5) Andersen (6) Thompson (7) Hoffmeister (8) Weinstein (9) Szanto (10) Tishler (11) Suarez-Almazor (12) Rau (13) DOSE 10 mg-50 mg per week, IV 10 mg per week, IM, increased up to 25 mg if required. 10 mg or 25 mg per week, IM 10 mg-15 mg per week, oral and IM 7.5 mg-25 mg per week, oral and IM 5 mg-15 mg per week oral/IM 12.5 mg (7.5 mg-15 mg) per week, oral/IM 10 mg per week IM 15 mg per week IM References 1. Herman, R.A., Veng-Pedersen, P., Hoffman, J., Koehnke, R., and Furst, D.E.: Pharmacokinetics of Low-Dose Methotrexate in Rheumatoid Arthritis Patients. J. Pharm. Sci. 78: 165-171, 1989. 2. Ahern, M., Booth, J., Loxton, A., McCarthy, P.M., Meffin, P., Kevant, S.: Methotrexate Kinetics in Rheumatoid Arthritis: Is there an Interaction with Nonsteroidal Anti-Inflammatory Drugs. J. Rheumatol. 15: 1356-1360, 1988. 3. Campbell, M.A., Perrier, D.G., Dorr, R. T., et. al.: Methotrexate Bioavailability .Cancer Treat. Rev. 69: 833-838, 1985. 4. Steinson, K., Weinstein, A., Korn, J., Abeles, M.: Low-Dose Methotrexate in Rheumatoid Arthritis. J. Rheumatol. 9: 860-866, 1982. 5. Michaels, R. M., Nashel, D.J., Leonard, A., Sliwinski, A.J., Derbes, A. J.: Weekly Intravenous Methotrexate in the Treatment of Rheumatoid Arthritis. Arthritis Rheum. 25: 339-341, 1982. 6. Andersen, P.A., West S.G., O'Dell, J. R., Via C.S.,Claypool, R. G., Kotzin B. L. Weekly Pulse Methotrexate in Rheumatoid Arthritis. Clinical and Immunologic Effects in a Randomized, Double-Blind Study. Ann. Intern. Med., 103: 489-496, 1985. 7. Thompson, R. N., Watts, C., Edelman, J., Russell, A. S.,: A Controlled Two-Center Trial of Parenteral Methotrexate Therapy for Refractory Rheumatoid Arthritis. J. Rheumatol. 11: 760-763, 1984. 8. Hoffmeister, R. T., :Methotrexate in Rheumatoid Arthritis: 15 Years Experience. Am. J. Med. 75: 69-73, 1983. 9. Weinstein, A., Marlowe, S., Korn, J., Farouhan, F. Low-Dose Methotrexate Treatment of Rheumatoid Arthritis. Long-Term Observations. Am. J. Med. 79: 331-337, 1985. 10. Szanto, E., Low-Dose Methotrexate in Rheumatoid Arthritis: Effect and Tolerance. An Open Trial and a DoubleBlind Randomized Study. Scand. J. Rheumatol. 15: 97-102, 1986. 11. Tishler, M., Caspi, D., Rosenbach, T. O., Fishel, B., Wigler, I., Segal, R., Gazit, E., Yaron, M.: Methotrexate in Rheumatoid Arthritis; A Prospective Study in Israeli Patients with immunogenetic Correlations. Ann. Rheum. Dis. 47: 654-659, 1988. 12. Suarz-Almazor M. E., Fitzgerald, A., Grace, M., Russell, A. S.: a Randomized Controlled Trial of Parenteral Methotrexate Compared with Sodium Aurothiomalate (Myochrysine) in the Treatment of Rheumatoid Arthritis. J. Rheumatol. 15: 753-756, 1988. 13. Rau, R., Herborn, G., Kargen, T., Menninger, H., Elhardt, D.A Blinded Randomized Trial of Methotrexate and Gold Sodium Aurothiomalate in Early Erosive Rheumatoid Arthritis. Arthritis Rheum. 32: S43, 1981 (Abstract). Particular attention should be given to the appearance of liver toxicity by performing liver function tests before initiating Abitrexate treatment, and repeating the tests at 2-4 month intervals during therapy. Therapy should not be instituted, or should be discontinued, if any abnormality of liver function tests or of a liver biopsy is present or develops during therapy. Such abnormalities should return to normal within 2 weeks, after which, treatment may be recommended at the discretion of the physician. The use of Abitrexate may permit the return to conventional topical therapy which should be encouraged. Calcium Leucovorin Rescue When administering high doses of methotrexate, the following guidelines for methotrexate therapy with leucovorin rescue should be closely observed: ABITREXATE Injection 8. 3. 2015, RH 8 Methotrexate administration should be delayed until recovery if: -the WBC count is less than 1500mm3 -the neutrophil count is less than 500mm3 -the platelet count is less than 75,000mm3 -the serum bilirubin level is more than 1.2 mg/dl -the ALT level is more than 450 U -mucositis is present, until there is evidence of healing -persistent pleural effusion and ascite are present; drain dry prior to infusion Adequate renal function must be documented Serum creatinine must be normal and creatinine clearance must be more than 60 ml/min. before the initiating of therapy. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more in comparison to a prior value, the creatinine clearance must be measured and documented to be more than 60 ml/min. (even if the serum creatinine is still within the normal range). Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. Administer 1,000 ml/m2 of intravenous fluid over 6 hours prior to initiating of the methotrexate infusion. Continue hydration at 125 ml/m2/hour (3L/m2/day) during methotrexate infusion, and for 2 days after the infusion has been completed. Alkalinize urine to maintain a pH above 7.0 during methotrexate infusion and leucovorin calcium therapy by giving sodium bicarbonate orally or by incorporation into a separate i.v. solution. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate, and at least once daily until the methotrexate level is below 5x10-8 mol/l (0.05 micromolar). Leucovorin Rescue Schedules Following Treatment with Higher Doses of Methotrexate CLINICAL SITUATION LABORATORY FINDINGS Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours and less than 0.2 micromolar at 72 hours Serum methotrexate level remaining above 0.2 micromolar at 72 hours and more than 0.05 micromolar at 96 hours after administration. Delayed Late Methotrexate Elimination Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury. ABITREXATE Injection Serum methotrexate level of equal or higher than 50 micromolar at 24 hours or equal or higher than 5 micromolar at 48 hours after administration, or a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g. an increase from 0.5 mg/dl to a level equal or higher than 1.0 mg/dl or more) 8. 3. 2015, RH LEUCOVORIN CALCIUM DOSAGE AND DURATION 15 mg PO or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Continue 15 mg PO or IV every 6 hours until methotrexate level is less than 0.05 micromolar. 150 mg IV every 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV every 3 hours, until methotrexate level is less than 0.05 micromolar. 9 Patients who experience delayed/early methotrexate elimination are likely to develop irreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to less than 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or abnormalities in renal function following methotrexate administration which are significant, but less severe, than those described in the Table. These abnormalities may, or may not be, associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. When laboratory abnormalities or clinical toxicities are observed, the possibility that the patient is taking other medications which interact with methotrexate should be considered. Older People Dose reduction should be considered in elderly patient due to reduced liver and kidney functin as well as reserves which occur with increased age. Hepatic Function Impairment If the bilirubin is between 3-5, or AST more than 180, dosage should be reduced by 25%. If bilirubin is more than 5, omit the dose. Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated if bilirubin values are >5 mg/dl (85.5 μmol/L). 4.3 Contraindications Methotrexate should not be used in pregnancy, and in patients in a poor state of nutrition. Methotrexate is furthermore contraindicated in patients with serious renal (Creatinine clearance less than 20 ml/min) severe liver disorders, bone marrow hypoplasia, leucopenia, thrombocytopenia, anaemia, alcohol abuse, methotrexate hypersensitivity and lung toxicity due to methotrexate. During methotrexate therapy no breastfeeding should be given. Serious, acute or chronic infections such as tuberculosis and HIV. Ulcers of the oral cavity and known active gastrointestinal ulcer disease. Concurrent vaccination with live vaccines 4.4 Special warnings and special precautions for use The cytostatic drug methotrexate may only be used under strict supervision of a physician who is experienced in oncology. Treatment should take place in a hospital experienced in cancer chemotherapy. Fatal toxicity in association with intravenous and intrathecal administration due to dose miscalculation has been reported. Particular caution should be exercised when calculating the dose. ABITREXATE Injection 8. 3. 2015, RH 10 Because of the risk of severe toxic reactions (which can be fatal), methotrexate must only be used in life-threatening neoplastic diseases. Deaths have been reported during treatment of malignancies with methotrexate. The doctor should inform the patient of the risks of treatment and the patient should be monitored constantly by the doctor. Methotrexate has reportedly caused fetal death and/or congenital malformations. Treatment of neoplastic diseases is not recommended in women of childbearing potential unless there are clear medical indications that the benefits of treatment can be expected to outweigh the conceivable risks. Methotrexate affects spermatogenesis and oogenesis during the period in which it is administered, which can result in reduced fertility. These effects may be reversible on discontinuing treatment. Tumor lysis syndrome Like other cytotoxic agents, methotrexate can induce tumour lysis syndrome in patients with rapidly growing tumours. Appropriate supportive treatment and pharmacological measures can prevent or alleviate such complications. Methotrexate and NSAIDs Unexpected severe (including fatal) myelosuppression, aplastic anaemia and gastrointestinal toxicity have been reported in connection with concomitant treatment with methotrexate (usually at a high dose) and non-steroidal anti-inflammatory agents (NSAIDs). Concomitant methotrexate treatment and radiotherapy can increase the risk of soft tissue necrosis and osteonecrosis. Intrathecal and intravenous administration of methotrexate can result in acute encephalitis and acute encephalopathy, possibly with a fatal outcome. Patients with periventricular CNS lymphoma who are given methotrexate intrathecally have reportedly developed cerebral herniation. Methotrexate and pleural effusion/ascites Methotrexate is eliminated slowly from collections of fluid (e.g. pleural effusion, ascites). This results in a prolonged terminal half-life and unexpected toxicity. In patients with significant collections of fluid, drainage of the fluid before treatment is started and monitoring of plasma methotrexate levels are recommended. If stomatitis, diarrhoea, haematemesis or black stool occurs, therapy with methotrexate should be discontinued due to the danger of haemorrhagic enteritis or death from intestinal perforation or dehydration. Conditions in which there is folic acid deficiency can increase the risk of methotrexate toxicity. In association with intrathecal administration or in high dose treatment, methotrexate must not be mixed with solutions which contain preservatives. ABITREXATE Injection 8. 3. 2015, RH 11 Solutions of methotrexate which contain the preservative benzyl alcohol are not recommended for use in infants. Gasping syndrome with fatal outcome has been reported in infants following intravenous treatment with solutions containing the preservative benzyl alcohol. Symptoms include rapid onset of respiratory problems, hypotension, bradycardia and cardiovascular collapse. Infection or immunological conditions Methotrexate must be used with great care in connection with active infection and is usually contraindicated in patients with manifest suppression of the immune response or where immunodeficiency is demonstrated by laboratory tests. Pneumonia (which in certain cases can lead to respiratory failure) can occur. Potentially fatal opportunistic infections including Pneumocystis carinii pneumonia can occur in association with methotrexate treatment. When a patient exhibits pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered. Immunisation Methotrexate may interfere with results of immunological tests Immunisation after a vaccination may be less effective in association with methotrexate treatment. Particularly caution should be exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) due to possible activation. Immunisation with live viruses is not normally recommended. Skin toxicity: Due to the risk of phototoxicity, the patient must avoid sunlight and solarium. Monitoring treatment Patients on methotrexate treatment must be closely monitored so that toxic effects can be detected immediately. Analyses before treatment must include a full blood count with differential and platelet counts, liver enzymes, testing for hepatitis B and C infections, renal function test and x-ray of the lungs. Toxic effects of methotrexate can occur even with low doses and therefore it is important to monitor treated patients carefully. Most undesirable effects are reversible if detected early. After initiation of treatment or when there is a change in the dose, or during periods in which there is an increased risk of elevated levels of methotrexate (e.g. in dehydration), monitoring should be performed. Bone marrow biopsy must be performed as necessary. Serum methotrexate level monitoring can significantly reduce methotrexate toxicity and routine monitoring of serum methotrexate level is necessary depending on dosage or therapy protocol. ABITREXATE Injection 8. 3. 2015, RH 12 Leucopenia and thrombocytopenia occur usually 4 -14 days after administration of methotrexate. In rare cases recurrence of leucopenia may occur 12 - 21 days after administration of methotrexate. Methotrexate therapy should only be continued if the benefit outweighs the risk of severe myelosuppression. Haematopoietic suppression: Haematopoietic suppression induced by methotrexate may occur abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets, treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients must be instructed to report all signs and symptoms suggestive of infection. In patients concomitantly taking haematotoxic medications (e.g. leflunomide), the blood count and platelets should be closely monitored. Liver function tests: Particular attention should be paid to the onset of liver toxicity. Treatment should not be initiated or should be discontinued if there are any abnormalities in liver function tests or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal within two weeks; after which, treatment may be resumed at the discretion of the doctor. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more. Screening for liver-related enzymes in serum: A transient rise in transaminase levels to twice or three times the upper limit of normal has been reported with a frequency of 13 - 20%. In the event of a constant increase in liver related enzymes, consideration should be given to reducing the dose or discontinuing therapy. Patients suffering from insulin-dependent diabetes should be carefully monitored because liver cirrhosis and an increase in transaminase can occur. Due to the potentially toxic effect on the liver, additional hepatotoxic medications should not be given during treatment with methotrexate unless clearly necessary and alcohol consumption should be avoided or greatly reduced. Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medications (e.g. leflunomide). The same should also be taken into consideration if haematotoxic medications are co-administered. Malignant lymphomas may occur in patients receiving low-dose methotrexate; in which case, methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of cytotoxic therapy is required. Renal function: methotrexate treatment in patients with impaired renal function should be monitored via renal function tests and urinalysis, since impaired renal function reduces the elimination of methotrexate, which may result in severe adverse reactions. ABITREXATE Injection 8. 3. 2015, RH 13 In cases of possible renal impairment (e.g. in elderly patients), close monitoring of renal function is required. This is particularly applies to the co-administration of medicinal products which affect methotrexate excretion cause kidney damage (e.g. non-steroidal anti-inflammatory drugs) or which can potentially lead to haematopoietic disorder. Dehydration may also potentiate the toxicity of methotrexate. Alkalinisation of the urine and increase a high diuresis is recommended. Respiratory System: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest x-ray) should be made to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted. Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pneumonitis can occur at all doses. Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate. Children Methotrexate should be used with caution in paediatric patients. Treatment should follow currently published therapy protocols for children. Serious neurotoxicity, frequently manifested as generalised or focal seizures has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous 2 methotrexate (1 g/m ). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Elderly Because of deterioration in liver and kidney function as well as reduced folic acid reserves, relatively low doses should be considered in elderly patients. These patients must be closely monitored for early signs of toxicity. Sodium Abitrexate solution or injection contains sodium as follows: Abitrexate Injection 25 mg/ml Solution for Injection Each ml contains 1.93 mg sodium. Abitrexate Injection 1g/10 ml (100 mg/ml) Solution for Injection Sodium content: Each ml contains 10 mg sodium. ABITREXATE Injection 8. 3. 2015, RH 14 This should be taken into consideration by patients on a controlled sodium diet. Treatment of psoriasis and rheumatoid arthritis should only take place under strict supervision of a physician experienced with dermatology and rheumatology. During the use of methotrexate the following laboratory tests are generally advised: hemograms, counting of the platelets and haematocrit; renal function tests and urine analysis; liver enzyme determination; chest X-ray is recommended. During the treatment of psoriasis it is recommended to repeat those tests regularly: monthly haematology, every 1-3 months liver and kidney function. Usually during antineoplastic treatment a more frequent control procedure is applied. On treatment initiation or a dose modification or during periods which an enhanced risk on increased methotrexate blood levels (e.g. in case of dehydratation), a more frequent control is to be done. A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established. Transient deviation in liver function tests have often been observed after methotrexate administration and usually do not lead to therapy modification. Permanent abnormalities in liver function tests just prior to administration and/or serum albumin level decrease may indicate serious liver toxicity and require further examination. Lung function tests may be useful in case a methotrexate induced lung disease is suspected, in particular when initial base line values are available. Methotrexate should be used with extreme care in patients with infection, peptic ulcer, ulcerative colitis, debility and in the very young or aged. In case of severe leucopenia occurring during treatment bacterial infections could set in. When infection occurs, discontinuation of methotrexate and adequate antibacterial therapy is indicated. At the onset of nephrotoxicity also immediate discontinuation of therapy is indicated. In case of severe bone marrow depression blood- or thrombocytes transfusion may be necessary. Methotrexate induced lung disease is a potentially dangerous condition which may occur at any moment during therapy with dosages higher than 7.5 mg weekly. The condition is not always completely reversible. Pulmonary symptoms (in particular a dry, non-productive cough) may require treatment interruption and thorough examination. In the treatment of methotrexate induced (interstitial) pneumonitis after immediate discontinuation of therapy, corticosteroid treatment is indicated. In case of the occurrence of lung toxicity re-initiation of therapy is contra-indicated. Diarrhoea and ulcerative stomatitis require discontinuation of treatment because of the risk of haemorrhagic enteritis and death by intestinal perforation. ABITREXATE Injection 8. 3. 2015, RH 15 Special care should be taken in the treatment of patients with decreased renal function, and with reduced doses, as the methotrexate elimination time is increased in renal dysfunction. Thus far there are no indications for an increased risk of carcinogenicity in humans undergoing prolonged therapy, such as psoriasis patients. The data on the carcinogenicity risk in case of use of methotrexate by rheumatoid arthritis patients are limited. While preparing methotrexate injections protective gloves, a mask and safety goggles should be worn. The preparation of methotrexate, like the preparation of any cytostatic drug, has to take place in a vertical laminar air flow hood. Spillage of methotrexate should be washed with ample water. During methotrexate therapy and until at least three months after treatment with methotrexate contraceptive precautions should be taken by female as well as male patients. While in general a low dose of methotrexate is applied in the treatment of psoriasis and rheumatoid arthritis, as compared to the doses used in antineoplastic therapy, intoxication and death may occur. Patients should be fully informed on the risks of methotrexate therapy and should be instructed to report any manifestation of toxicity immediately. It is recommended to carry out a liver biopsy in psoriasis and rheumatoid arthritis patients after a total cumulative dose of 1.5 g. Fibrosis of intermediate revering or any cirrhosis usually requires discontinuation of therapy. Although mild changes usually are no reason to avoid or discontinue methotrexate therapy, methotrexate should be used with care in patients. The combined administration of methotrexate and other potentially hepatotoxic drugs and alcohol should be avoided. Malignant lymphomas may develop in patients, treated with low dose methotrexate. Spontaneous remission may occur when methotrexate therapy is stopped; therefore, treatment with oncolytics is not necessarily indicated. First, it is necessary to stop methotrexate treatment, when this adverse event occurs. If remission fails to appear, an adequate treatment has to be started. When concurrent administration of methotrexate and radiotherapy takes place there can be an increased risk of necrosis of soft tissue (see section 4.8 ‘Undesirable effects’). Periodic evaluation by specific cognitive tests to detect early signs of cognitive impairment is advised in children. ABITREXATE Injection 8. 3. 2015, RH 16 4.5 Interaction with other medicaments and other forms of interaction Non steroidal anti-inflammatory drugs (NSAIDS) should not be administered prior to or simultaneously with high dose methotrexate treatment (>10 mg methotrexate per week). Increased serum levels of methotrexate have been reported at simultaneous administration of some NSAIDS with high dose methotrexate resulting in death by serious haematologic or gastrointestinal toxicity. NSAIDS, salicylates and other weak organic acids, like probenecid, can lower tubularly secretion of methotrexate resulting in increased toxicity. Use of methotrexate with these drugs should be made carefully under strict supervision. The potential toxicity of methotrexate is increased in particular at simultaneous use of NSAIDS when also diuretics are used. In rheumatology, a combination therapy of low-dose methotrexate and a NSAID is commonly used. Methotrexate bound to serum proteins may be displaced by salicylates, NSAID's, sulphonamides, phenytoin, tetracyclines, chloramphenicol, p-amino-benzoic acid, doxorubicin, bleomycin, cyclophosphamide, aminoglycosides, allopurinol, vincristine, hydrocortisone, prednisone, asparaginase and cytosine arabinoside, hereby increasing the fraction of free methotrexate in plasma. Care should be taken in combining high dose methotrexate with potentially nephrotoxic therapy (e.g. cisplatin). Oral antibiotics (including tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics) may influence the intestinal flora and inhibit methotrexate (re)absorption. In isolated cases, trimethoprim/sulfamethoxazole has reportedly increased myelosuppression in patients treated with methotrexate, probably due to reduced tubular secretion and/or an additive antifolate effect Interaction with therapeutic radiation may occur (see section 4.4 ‘Special warnings and special precautions for use’ and section 4.8 ‘Undesirable effects). In combination with other cytostatic drugs pharmacodynamic interactions may occur; resulting in increased therapeutic activity and increased toxicity. No vaccination with live virus vaccines should be performed in patients receiving methotrexate. Partial or total protection can be obtained through inactivated vaccines. Vitamin preparations containing folic acid or folic acid derivatives may decrease the effect of systemically administered methotrexate. Preliminary human and animal studies have shown that after intravenous administration of calcium folinate a small amount penetrates into the cerebrospinal fluid, predominantly as 5-methyltetrahydrofolate, and this amount is a factor 1 to 3 lower than the normal methotrexate concentration after intrathecal administration. ABITREXATE Injection 8. 3. 2015, RH 17 Nevertheless high doses of calcium folinate may lower the effectivity of intrathecally administered methotrexate. Folate deficiencies may increase methotrexate toxicity. In some cases a potentiation of the bone marrow suppression in patients treated with methotrexate by trimethoprim/sulphamethoxazole was reported, probably by additional folic acid antagonism. The combined use of methotrexate and sulphonamides is therefore strongly advised against. Ciprofloxacin: Excretion of methotrexate possibly reduced (increased risk of toxicity). Leflunomide: Methotrexate in combination with leflunomide can increase the risk of pancytopenia. Probenecid: Renal tubular transport is diminished by probenecid, and its use together with methotrexate must be avoided. Penicillins:Penicillins can reduce renal clearance of methotrexate. Haematological and gastrointestinal toxicity have been observed in combination with high and low dose methotrexate. Chemotherapeutic products: An increase in renal toxicity can be observed when high doses of methotrexate are given in combination with potentially nephrotoxic chemotherapeutic agents (e.g. cisplatin). Cytarabine: Concomitant therapy with cytarabine and methotrexate can increase the risk of severe neurological side effects ranging from headache to paralysis, coma and stroke-like episodes. Hepatotoxic products: The risk of increased hepatotoxicity when methotrexate is administered concurrently with other heptatotoxic products has not been studied. Hepatotoxicity has however been reported in such cases. Patients receiving concomitant treatment with drugs with a known hepatotoxic effect (e.g. leflunomide, azathioprine, sulfasalazine, retinoids) must be carefully monitored for signs of any increase in hepatotoxicity. Theophylline: Methotrexate can reduce clearance of theophylline. Theophylline levels must therefore be monitored during concomitant treatment with methotrexate. Mercaptopurine: Methotrexate increases plasma content of mercaptopurine. The combination of methotrexate and mercaptopurine can therefore require dose adjustment. Drugs with high plasma protein binding: Methotrexate is partially bound to serum albumin. Other highly bound drugs such as salicylates, phenylbutazone, phenytoin and sulfonamides can increase the toxicity of methotrexate by means of displacement. Furosemide: Concomitant administration of furosemide and methotrexate can result in increased levels of methotrexate due to competitive inhibition of tubular secretion. ABITREXATE Injection 8. 3. 2015, RH 18 Proton pump inhibitors: Literature data indicate that co-administration of proton pump inhibitors and methotrexate, especially at high dose, may result in elevated and prolonged plasma levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicity. 4.6 Fertility, pregnancy and lactation (see Contraindications) Pregnancy Methotrexate can cause foetal death, embryotoxicity, abortion or teratogenic effects when administered to pregnant women. During pregnancy, especially in the first trimester, cytotoxic drugs must only be given when strictly indicated, weighing the needs of the mother against the risks to the foetus. Treatment with methotrexate during the first trimester has resulted in a high risk of malformations (in particular cranial malformation and malformation of the extremities). Breastfeeding Methotrexate passes into breast milk in quantities such that there is a risk to the child even at therapeutic doses. Breast feeding must therefore be discontinued during treatment with methotrexate. Fertility Methotrexate may be genotoxic. Women of childbearing potential must not be treated with methotrexate until pregnancy has been excluded. Since in men spermatogenesis can be affected by methotrexate, pregnancy should be avoided if either partner is receiving methotrexate. The optimum time interval between discontinuation of methotrexate therapy in either partner and pregnancy has not been established. The recommended interval in published literature varies between three months and one year. 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 fetus should they become pregnant during methotrexate therapy. 4.7 Effect on ability to drive and use machines Because methotrexate may cause blurred vision, paresis and hemiparesis, fatigue and dizziness, the ability to drive and use machines may be adversely affected. 4.8 Undesirable effects Conventional and high dose therapy The frequency and degree of severity of undesirable effects depends on the dose administered, the duration of exposure and method of administration, but side effects have been seen at all doses and can occur at any time during treatment. Most undesirable effects are reversible when detected at an early stage. When severe reactions occur, the dose should be reduced or treatment discontinued and appropriate measures initiated. If treatment with methotrexate is resumed, this should be done with caution after adequate consideration of the further need for the drug. Increased vigilance with regard to any recurrence of toxicity is required. ABITREXATE Injection 8. 3. 2015, RH 19 The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness, chills and fever, dizziness, reduced resistance to infections. Treatment with folinic acid during high dose therapy can counteract or alleviate a number of undesirable effects. Temporary discontinuation of therapy is recommended if there are signs of leukopenia. Organ system class Very common (≥1/10) Infections and infestations Common Uncommon (≥1/100 to <1/10) (≥1/1,000 to <1/100) Herpes zoster Not known (cannot be estimated from the available data) Pericarditis, pericardial effusion, pericardial tamponade leukocytopenia, Pancytopenia, thrombo-cytopenia agranulo-cytosis, and anaemia haematopoietic disorders Immune system disorders Anaphylactoid reactions, allergic vasculitis Psychiatric disorders ABITREXATE Injection Very rare (<1/10,000) Sepsis, opportunistic infections (may be fatal in some cases), infections caused by the cytomegaly virus Cardiac disorders Blood and lymphatic system disorders Rare (≥1/10,000 to <1/1,000) Megaloblastic anaemia Severe courses of Haemorrhage, bone marrow haematoma depression aplastic anaemia Lymphadenopathy, lymphoproliferative disorders (partly reversible) eosinophilia and neutropenia Immunosuppression hypogammaglobulinaemia Insomnia, cognitive dysfunction 8. 3. 2015, RH psychosis 20 Organ system class Very common (≥1/10) Nervous system disorders Common Uncommon (≥1/100 to <1/10) (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Headache fatigue drowsiness Severely impaired vision mood alterations paresis, effect on speech including dysarthria and aphasia, myelopathy Pain, muscular asthenia or paresthesia of the extremities, myasthenia, changes in sense of taste (metallic taste), meningism (paralysis, vomiting), acute aseptic meningitis visual disturbances, blurred vision Conjunctivitis Retinopathy, transient blindness/loss of vision, periorbital oedema, blepharitis, epiphora, photophobia Vertigo confusion depression seizures convulsion encephalo-pathy Eye disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) individual cases of lymphoma which abated in a number of cases once methotrexate treatment had been discontinued. In a recent study, it was not possible to establish that methotrexate therapy increases the incidence of lymphomas Vascular disorders Vasculitis ABITREXATE Injection 8. 3. 2015, RH Not known (cannot be estimated from the available data) Tumour lysis syndrome hypotension thrombo-embolic events reactions (incl. arterial thrombosis, cerebral thrombosis, thrombo-phlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism) Cerebral oedema, petechie 21 Organ system class Very common (≥1/10) Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Loss of appetite, nausea, vomiting, abdominal pain, inflammation and ulcerations of the mucous membrane of mouth and throat (especially during the first 2448 hours after administration of methotrexate). Stomatitis, dyspepsia ABITREXATE Injection Common Uncommon (≥1/100 to <1/10) (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Pulmonary Pulmonary complications due fibrosis to interstitial alveolitis / pneumonitis and related deaths (independent of dose and duration of methotrexate treatment). Typical symptoms may be: general illness; dry, irritating cough; shortness of breath progressing to rest dyspnoea, chest pain, fever. If such complications are suspected, methotrexate treatment must be discontinued immediately and infections (including pneumonia) must be excluded. Pharyngitis, Pneumocystis Acute pulmonary apnoea, bronchial carinii pneumonia, oedema asthma shortness of breath, chronic obstructive pulmonary disease. Infections including pneumonia have also been observed. Pleural effusion Diarrhoea gastrointestinal (especially during bleeding and the first 24-48 ulcers, pancreatitis hours after administration of methotrexate). Gingivitis, Haematemesis Toxic megacolon Enteritis, melaena (vomiting blood), (bloody stools), toxic megacolon malabsorption 8. 3. 2015, RH Very rare (<1/10,000) Not known (cannot be estimated from the available data) 22 Organ system class Very common (≥1/10) Common Uncommon (≥1/100 to <1/10) (≥1/1,000 to <1/100) Hepato-biliary disorders Increase in liverrelated enzymes (ALAT, ASAT, alkaline phosphatase nd bilirubin). Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (cannot be estimated from the available data) Development of Acute hepatitis liver fattening, and hepatotoxicity fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes); diabetic metabolism; drop of serum albumin. Reactivation of Metabolic disorder chronic hepatitis, acute liver degeneration. Furthermore, herpes simplex hepatitis and liver insufficiency have been observed (also see the notes regarding liver biopsy in section 4.4). Urticaria, photosensibility, enhanced pigmentation of the skin, hair loss, increase of rheumatic nodules, herpes zoster, painful lesions of psoriatic plaque; severe toxic reactions: vasculitis, herpetiform eruption of the skin, StevensJohnson syndrome, toxic epidermal necrolysis (Lyell's syndrome). Increased pigmentary changes of nails, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions. Furunculosis, Exfoliative teleangiectasis, dermatitis, skin acute paronychia, necrosis, Furthermore, nocardiosis, histoplasma and cryptococcus mycosis and disseminated herpes simplex have been reported. Allergic vasculitis, hidradenitis Musculoskeletal system, connective tissue and bone disorders Osteoporosis, Arthralgia, myalgia Stress fracture Renal and urinary disorders Inflammation and ulceration of the urinary bladder (possibly with haematuria), dysuria. Renal failure, Proteinuria oliguria, anuria, azotaemia, hyperuricaemia, elevated serum creatinine and urea level Skin and subcutaneous tissue disorders ABITREXATE Injection Exanthema, erythema, itching 8. 3. 2015, RH 23 Organ system class Very common (≥1/10) Common Uncommon (≥1/100 to <1/10) (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Reproductive system and breast disorders Inflammation and ulceration of the vagina Loss of libido, impotence, oligospermia, impaired menstruation, Vaginal discharge, infertility, gynaecomastia General disorders and administration site conditions Severe allergic reactions progressing to anaphylactic shock; Fever, impaired wound healing Metabolism and nutrition disorders Not known (cannot be estimated from the available data) Diabetes Mellitus The following undesirable effects have also been reported, but their frequency has not been established: Pneumocystis carinii pneumonia, (including reversible cases), foetal death, damage to the foetus, abortion. Systemic organ toxicity Lymphoma Malignant lymphoma which can go into remission after discontinuation of the treatment with methotrexate can occur in patients on low dose therapy, and may not therefore require any cytotoxic treatment. Methotrexate should be discontinued first and appropriate treatment initiated if the lymphoma does not regress. Haematological Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia. Methotrexate must be administered with caution to patients with malignancies and underlying factors affecting haematopoiesis. When treating neoplastic conditions, treatment with methotrexate should only be given provided the potential benefits outweigh the risk of myelosuppression. Lungs Lung disease caused by methotrexate, including acute or chronic interstitial pneumonitis, is a potentially dangerous complication, which can occur at any time during the course of treatment. This undesirable effect has been reported at low doses and is not always totally reversible. Deaths have been reported. ABITREXATE Injection 8. 3. 2015, RH 24 Signs of pulmonary involvement or symptoms such as dry non-productive cough, fever, chest pains, dyspnoea, hypoxemia and infiltrate on x-ray of the lungs, or non-specific pneumonitis which occurs in connection with methotrexate therapy, may indicate potentially serious damage and requires discontinuation of treatment and careful investigation. Lung changes can occur at all doses. The possibility of infection (including pneumonia) must be excluded. Gastrointestinal If vomiting, diarrhoea or stomatitis occur, with resulting dehydration, methotrexate therapy must be discontinued until the patient has recovered. Haemorrhagic enteritis and deaths caused by intestinal perforation can occur. Methotrexate must be used with great caution in patients with peptic ulcers or ulcerative colitis. Stomatitis can be prevented or alleviated by folinic acid mouthwashes. Liver Methotrexate involves a potential risk of acute hepatitis and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal and occurs commonly after long-term use (in general after 2 years or more) and after a total cumulative dose greater than 1.5 g. In studies of psoriasis patients hepatotoxicity was seen to be proportional to the cumulative dose and was potentiated by alcoholism, overweight, diabetes and age. Transient deterioration in liver enzyme values is frequently seen after methotrexate treatment and does not usually necessitate adjustment of treatment. Existing abnormal liver values and/or reduction in serum albumin can indicate severe hepatotoxicity. Methotrexate has caused reactivation of hepatitis B infections and exacerbation of hepatitis C infections, in some cases with fatal outcome. Some cases of hepatitis B reactivation have occurred following discontinuation of methotrexate. Clinical and laboratory tests should be performed to investigate any occurrence of liver disease in patients with prior hepatitis B or C infections. Based on these investigations, treatment with methotrexate may prove unsuitable for certain patients. In the event of impaired liver function, the undesirable effects of methotrexate (in particular stomatitis) can be exacerbated. Kidneys Methotrexate can cause kidney damage which can result in acute renal failure. Renal function can be exacerbated following high dose therapy to such an extent that the excretion of methotrexate is inhibited, as a result of which systemic methotrexate toxicity can occur. In order to prevent renal failure, alkalinisation of the urine and adequate fluid intake (at least 3 l/day) are recommended. Measurement of serum methotrexate and renal function is recommended. Skin Serious, in some cases fatal skin reactions, including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome and erythema multiforme have been reported within a few days of oral, intramuscular, intravenous or intrathecal treatment with methotrexate in single or repeat doses. Radiation dermatitis and sunburn can be accentuated after use of methotrexate. ABITREXATE Injection 8. 3. 2015, RH 25 CNS There are reports of leukoencephalopathy after intravenous treatment with methotrexate in patients who have undergone craniospinal radiotherapy. Severe neurotoxicity, often manifested as generalised or focal seizures have been reported with an unexpected increase in frequency in children with acute lymphoblastic leukaemia treated with a moderately high dose of intravenous methotrexate (1 g/m2). Symptomatic patients frequently had leukoencephalopathy and/or microangiopathic calcifications in x-ray investigations. Chronic leukoencephalopathy has also been reported in patients treated with repeated high doses of methotrexate together with folinic acid, even without concomitant cranial radiotherapy. Discontinuation of the methotrexate therapy did not always result in full recovery. Leukoencephalopathy has also been reported in patients treated with methotrexate tablets. One transient acute neurological syndrome has been observed in patients undergoing high dose therapy. Manifestations of this neurological syndrome can include abnormal behaviour, focal sensorimotor symptoms including transient blindness, and abnormal reflexes. The exact cause is unclear. Cases of neurological side effects ranging from headache to paralysis, coma and stroke-like episodes have been reported, primarily in children and adolescents receiving concomitant medication with cytarabine. Intrathecal therapy The subacute neurotoxicity is usually reversible after discontinuing methotrexate. Organ system class Common (>1/100) Central and peripheral nervous system disorders Headache, chemical arachnoiditis, subacute neurotoxicity, necrotising demyelinating leukoencephalopathy Gastrointestinal disorders Nausea and vomiting General disorders and administration site conditions Fever Chemical arachnoiditis, which can occur a few hours after intrathecal administration of methotrexate is characterised by headache, back pain, stiff neck, vomiting, fever, meningism and pleocytosis in the cerebrospinal fluid similar to that in bacterial meningitis. Arachnoiditis generally disappears within a few days. Subacute neurotoxicity, common after frequently repeated intrathecal administration, mainly affects the motor functions in the brain or spinal cord. Paraparesis/paraplegia, with involvement of one or more spinal nerve roots, tetraplegia, cerebellar dysfunction, cranial nerve paralysis and epileptic seizures can occur. ABITREXATE Injection 8. 3. 2015, RH 26 Necrotising demyelinating leukoencephalopathy can occur several months or years after starting intrathecal therapy. The condition is characterised by progressive neurological deterioration with insidious onset, confusion, irritability and somnolence. Ultimately severe dementia, dysarthria, ataxia, spasticity, seizures and coma can occur. The condition can be fatal. Leukoencephalopathy occurs primarily in patients who have received large quantities of intrathecal methotrexate in combination with cranial radiotherapy and/or systemically administered methotrexate. Signs of neurotoxicity (meningeal inflammation, transient or permanent paresis, encephalopathy) must be followed up after intrathecal administration of methotrexate. Reporting of 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 to the Ministry of Health according to the National Regulation by using an online form (http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@m oh.health.gov.il ) or by email ([email protected] ). 4.9 Overdose Experience of overdose with the product has in general been associated with oral and intrathecal treatment, although overdose in association with intravenous and intramuscular administration has also been reported. Reports of oral overdose have often been due to accidental daily instead of weekly ingestion. Commonly reported symptoms following oral overdose include the symptoms and signs seen at pharmacological doses, in particular haematological and gastrointestinal reactions such as leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In certain cases no symptoms were reported. There are reports of deaths associated with overdose. In these cases there were also reports of conditions involving sepsis or septic shock, renal failure and aplastic anaemia. The most common symptoms of intrathecal overdose are CNS symptoms including headache, nausea and vomiting, seizures or convulsions and acute toxic encephalopathy. In certain cases, no symptoms were reported. There have been reports of deaths following intrathecal overdose. In these cases there were also reports of cerebellar herniation accompanying elevated intracranial pressure and toxic encephalopathy. ABITREXATE Injection 8. 3. 2015, RH 27 Recommended treatment Antidote therapy: Folinic acid should be given parenterally at a dose at least the size of the methotrexate dose and should wherever possible be administered within an hour. Folinic acid is indicated to minimise toxicity and counter the effect of methotrexate overdose. Folinic acid treatment should be initiated as soon as possible. The longer the interval between the administration of methotrexate and the initiation of folinic acid, the less the effect of folinic acid in suppressing the toxic effect. Monitoring of serum methotrexate concentrations is necessary to be able to determine the optimum dose of folinic acid and the length of the treatment. In the event of a major overdose, hydration and alkalinisation of the urine may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to increase the elimination of methotrexate. Acute intermittent haemodialysis with the use of highly permeable dialyser may be attempted for methotrexate intoxication. Intrathecal overdose may require intensive systemic supportive measures such as systemic administration of high doses of folinic acid, alkaline diuresis, acute CSF drainage and ventricular lumbar perfusion. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Methotrexate belongs to the group of antimetabolites. It is a folic acid antagonist, which binds to dihydrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This binding results in inhibition of the biosynthesis of thymine and purine. In high concentrations methotrexate also prevents the influx of folate into the cell. Resistance to methotrexate may occur due to a decreased transport of methotrexate through cell membranes and as result of an altered affinity of the enzyme dihydrofolate reductase for methotrexate. At very high concentrations (> 20 mol/l) methotrexate may penetrate cells not only through an active transport mechanism but also by diffusion. This concept is the rationale for high-dose methotrexate therapy. 5.2 Pharmacokinetic properties Absorption Methotrexate is usually completely absorbed after parental administration. After intramuscular injection the peak blood level is reached after 30-60 min. Distribution After intravenous administration the initial volume of distribution is about 0.18 l/kg (18 % of the body weight) and at equilibrium about 0.4-0.8 l/kg (40 - 80 % of the body weight). Methotrexate slowly penetrates into third compartments as pleural effusions and ascites, where after 6 hours a steady-state with the plasma concentration has been established. Methotrexate competes with reduced folates for the carrier of the active cell membrane transport. ABITREXATE Injection 8. 3. 2015, RH 28 At serum concentration higher than 100 M passive diffusion becomes the most important route to achieve effective intracellular concentrations of methotrexate. In serum methotrexate is bound for about 50% to proteins. Methotrexate does not penetrate the blood-brain barrier in therapeutic concentrations after oral or parental administration. In the cerebrospinal fluid high concentrations can be reached after intrathecal administration. Biotransformation After absorption methotrexate is metabolized in the liver and intracellularly into polyglutamates which can be re-converted into methotrexate by hydrolases. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may be present in tissue during prolonged periods of time. The retention and the protracted action of these active metabolites varies between the different cells, tissues and tumors. At normal dose, a small amount of methotrexate may be metabolized in the liver into 7-hydroxymethotrexate. Cumulation of this inactive metabolite may be of importance in the high dose treatment. The aqueous solubility of 7-hydroxymethotrexate is 3-5 times lower than that of the original molecule. The half-life of methotrexate is about 3-10 hours in patients under treatment for psoriasis and in case of antineoplastic therapy with low dosages (less than 30 mg/m2). In patients on high dose methotrexate therapy the half-life is 8-15 hours. Elimination Elimination is predominantly by renal excretion and is dependent on dose and route of administration. After intravenous administration 44-100% of the dose administered is excreted unchanged within 24 hours into the urine. Less than 10% of the dose administered is excreted via the bile. Enterohepatic recirculation of methotrexate has been suggested. Renal excretion is by glomerular filtration and active tubular excretion. Non-linear elimination is due to saturation of renal tubular re-absorption and has been observed in psoriasis patients treated with doses of 7.5-30 mg. A decreased renal function and also concomitant administration of drugs which also undergo tubular secretion (such as weak organic acids) may increase considerably the serum methotrexate concentration. There is a good correlation between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance varies highly and is normally lowered at high dosages. It has been shown that a diminished clearance is one of the most important factors responsible for methotrexate toxicity. Toxicity of methotrexate in normal tissue is dependent rather on duration of exposition than on the peak concentration achieved. In case a patient displays decreased elimination because of compromised kidney function, effusion of the third compartment or by another reason, serum methotrexate concentration may remain increased during prolonged periods of time. The possibility of toxicity after administration of high dosages or in case of decreased elimination is lowered by the administration of calcium folinate during the last phase of the methotrexate plasma elimination. On the solubility methotrexate in the kidneys: at high dose therapy the probability of precipitation is higher at pH <7. During the administration of high dose methotrexate hyperhydratation and alkalinization of the urine is recommended to avoid renal toxicity. ABITREXATE Injection 8. 3. 2015, RH 29 Pharmacokinetic monitoring of the serum methotrexate concentration may be useful to detect patients with an increased risk on methotrexate toxicity and may facilitate calcium folinate dosing. Guidelines to monitor serum methotrexate levels and to adapt the calcium folinate dose to lower the risk of methotrexate toxicity are monitored under "Dosage and method of administration". 5.3 Preclinical safety data Animal studies show that methotrexate impairs fertility and that it is embryotoxic, foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro, but the clinical significance is unknown since rodent carcinogenicity studies have produced differing results. Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients See section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 6.2 Incompatibilities Methotrexate should not be mixed in the infusion bottle with other drugs. 6.3 Special precautions for storage Store in a dry place at room temperature (15-25°C) in a well closed packaging. Protect from light. Do not use this medicine if the solution is not clear. Abitrexate solution can be further diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Abitrexate diluted solution stored between 15-250C and protected from light has a chemical and physical in-use stability of 24 hours. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. 6.4 Instructions for use/handling Abitrexate solution is further diluted in normal saline and administered by IV injection or IV infusion over periods not exceeding 24 hours. Abitrexate solution may be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Part of the dose may be given as an initial bolus IV injection. Any unused solution must be discarded. Other drugs should not be mixed with Abitrexate in the same infusion container. ABITREXATE Injection 8. 3. 2015, RH 30 6.6 Special precautions for disposal and other handling Every form of contact with the fluid must be avoided. During preparation a strictly aseptic working technique should be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of vertical laminar airflow (LAF) hood is recommended. If the solution is spilled, rinse with plenty of water. Gloves should be worn during administration. Waste-disposal procedures should take into account the cytotoxic nature of this substance. 6.5 Presentation Abitrexate 1g/10ml, packs of 1 vial Abitrexate 5g/50ml, packs of 1 vial Abitrexate 50 mg/2ml, packs of 1 vial Abitrexate 100mg/4ml, packs of 1 vial Abitrexate 200 mg/8ml, packs of 1 vial Abitrexate 500 mg/20ml, packs of 1 vial Abitrexate 1000 mg/40ml, packs of 1 vial Not all packs may be marketed. 7. PRODUCT REGISTRATION NO.: Abitrexate 1g/10ml Vials: 100 38 24914 05 Abitrexate 25 mg/ml Vials: 048 96 23819 05 8. MANUFACTURER Pharmachemie BV, Haarlem, Holland 9 LICENSE HOLDER Salomon Levin & Elstein Ltd P.O.Box 3696, Petach Tikva, 49133 ABITREXATE Injection 8. 3. 2015, RH