METHOTREXATE

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 incorrectly calculated doses.

Health care professionals and patients should be fully informed about toxic effects. Methotrexate 100mg/ml is hypertonic and must not be administered intrathecally. Treatment should be initiated by or occur in consultation with a doctor with significant experience in cytostatic treatment.

Methotrexate can be administered intramuscularly, intravenously or intra-arterial. Methotrexate 100mg/ml is hypertonic and must not be administered intrathecally. The dosage is generally calculated per m2 body surface area or body weight.

Doses of over 100 mg methotrexate always require subsequent administration of folinic acid (See calcium folinate rescue). The application and dosage recommendation for the administration of methotrexate for different indications varies considerably.

Some common dosages which have been used in different indications are given below. None of these dosages can currently be described as standard therapy. Since the application and dosage recommendations for therapy with methotrexate at high and low dosages vary, only the most commonly used guidelines are given, and should be considered as examples Current published protocols should be consulted for dosages and the method and sequence of administration.

6.

Posology:

Methotrexate can be given as convention low dose therapy, intermediate dose therapy and high dose therapy. Conventional low dose therapy: 15-50 mg/m2 body surface area per week intravenously or intramuscularly in one or more doses. 40-60 mg/m2 body surface area (for head and neck cancer) once weekly as intravenous bolus injection.

Intermediate dose therapy:

Between 100 mg/m2 to 1000 mg/m2 body surface area in single dose. In advanced squamous epithelial and bladder cancer, intermediate doses of methotrexate up to 100-200 mg/m2 can be used (See calcium folinate rescue).

High dose therapy:

In several malignant diseases, including malignant lymphoma, acute lymphatic leukaemia, osteogenic sarcoma and metastatic choriocarcinoma, doses of 1000 mg methotrexate or more per m2 body surface area may be used, administered over a 24-hour period.

High dose methotrexate therapy has to be followed by calcium folinate rescue therapy (further refer to therapy protocols, see calcium folinate rescue). High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules.

0 by oral or intravenous administration of sodium bicarbonate or acetazolamide is recommended as per individual therapy protocols as a preventive measure or current guidelines to be followed to achieve the desired urine pH. Before beginning combination therapy involving high-dose methotrexate the leukocyte and thrombocyte count should exceed the respective minimum values (leukocytes 1,000 to 1,500/microlitre, thrombocytes 50,000 to 100,000/microliter).

When applying high-dose methotrexate therapy, the serum methotrexate concentration must be checked at regular intervals. The sampling times and the maximum values for toxic serum methotrexate concentrations which require measures such as an increase in the calcium folinate dose or the intravenous fluid supply can be taken from the individual therapy protocols.

As a prophylactic measure against nephrotoxic effects, when conducting a course of therapy involving high-dose methotrexate an intravenous fluid supply and alkalisation of the urine is necessary. Urine flow and the pH value of the urine should be monitored during the methotrexate infusion.

Calcium folinate rescue Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue.

Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate. In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment.

During high dose treatment, folinic acid should be given concomitantly. The serum concentration of methotrexate is a valuable indicator for how long the folinic acid treatment should be continued. Forty-eight hours after the start of the methotrexate- infusion, the residual methotrexate-level should be measured.

5 μmol/l, no additional treatment with folinic acid is necessary. Renal function should be monitored through daily measurements of serum creatinine. For more detailed information, please refer to the Summary of Product Characteristics of Calcium Folinate.

If signs of leukopenia appear, temporary interruption of methotrexate is advisable. The following regimens are only examples. Adults Acute lymphocytic leukaemias (ALL) In low doses, methotrexate is applied within the scope of complex therapy protocols for maintaining remission in adults with acute lymphocytic leukaemias.

Normal single doses lie within the range of 20-40 mg/m2 methotrexate. The maintenance dose for ALL is 15-30 mg/m2 once or twice weekly. 3 mg/m2 in combination with other cytostatic agent once daily for 4-6 week. 5 mg/kg every week. v. 1-6 h) repeated every 1-3 weeks.

• 20 mg/m2 in combination with other cytostatic agents once week. Breast cancer Cyclic combination with cyclophosphamide, methotrexate and fluorouracil has been used as adjuvant treatment to radical mastectomy in primary breast […]

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. 9). 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.

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) Common (≥1/100 to <1/10 ) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Not known (Cannot be estimated from the available data) Infections and infestations Herpes zoster Sepsis, Opportunistic infections (may be fatal in some cases), infections caused by the cytomegaly virus Cardiac disorders Pericardial effusion, pericarditis, pericardial tamponade Blood and lymphatic system disorders leukocypenia, thrombocytope nia and anaemia Pancytopenia, agranulocytos is, haematopoieti c disorders Megaloblastic anaemia Severe courses of bone marrow depression,aplasti c anaemia.

Lymphadenopath y, eosinophilia and neutropenia, Lymphoproliferati ve disorders Haemorrhage, haematoma Immune system disorders Anaphylactoi d reactions, allergicvasculi tis Immunosuppressi on, hypogammaglobu linaemia Metabolism and nutrition disorders Diabetes mellitus Psychiatric disorders Insomnia, cognitive dysfunction psycosis Nervous system disorders Headache, fatigue, drowsiness Vertigo, confusion, depression, seizures, convulsion, Severely impaired vision, mood alterations, paresis, Pain, muscular asthenia or paresthesia of the extremities, myasthenia, encephalopath y, speech impairment incl.

dysarthria and aphasia, myelopathy changes in sense of taste (metallic taste), meningism (paralysis, vomiting), acute aseptic meningitis Eye disorders visual disturbances, blurred vision Conjunctivitis, Retinopathy, transient blindness/loss of vision, periorbital oedema, blepharitis, epiphora, photophobia 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.

Tumour lysis syndrome Vascular disorders Vasculitis hypotension, thromboembol ic events reactions (incl. arterial thrombosis, cerebral thrombosis, thrombophlebi tis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism) Cerebral oedema, petechie Respiratory, thoracic and mediastinal disorders Pulmonary complications due to interstitial alveolitis/pneu monitis 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, Pulmonary fibrosis Pharyngitis, apnoea, bronchial asthma Pneumocystis jirovecii pneumonia, shortness of breath, chronic obstructive pulmonary disease.

Infections including pneumonia have also been observed. Pleural effusion Acute pulmonary oedema methotrexate treatment must be discontinued immediately and infections (including pneumonia) must be excluded. Gastrointesti nal disorders Loss of appetite, nausea, vomiting, abdominal pain, inflammatio n and ulcerations of the mucous membrane of mouth and throat (especially during the first 24-48 hours after administratio n of methotrexate ).

Stomatitis, dyspepsia Diarrhoea (especially during the first 24-48 hours after administration of methotrexate) gastrointestina l bleeding and ulcers, pancreatitis Gingivitis, Enteritis, melaena (bloody stools), malabsorption Haematemesis (vomiting blood), toxic megacolon Hepato- biliary disorders Increase in liver-related enzymes (ALAT, ASAT, alkaline phosphatase and bilirubin).

Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes); diabetic metabolism; drop of serum albumin. Acute hepatitis, and hepatotoxicity Reactivation of chronic hepatitis, acute liver degeneration.

4). Metabolic disorder Skin and subcutaneou s tissue disorders Exanthema, erythema, itching urticaria, 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, Increased pigmentary changes of nails, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions.

Furunculosis, teleangiectasis, acute paronychia, Furthermore, nocardiosis, histoplasma and cryptococcus mycosis and disseminated herpes simplex have been reported. Allergic vasculitis, hidradenitis Skin exfoliation / dermatitis exfoliative, skin necrosis Stevens- Johnson syndrome, toxic epidermal necrolysis (Lyells syndrome), photosensitivi ty reactions Musculoskel etal system, connective tissue and bone disorders Osteoporosis, Arthralgia, myalgia Stress fracture Osteonecrosis of jaw (secondary to lympho- proliferative disorders) Renal and urinary disorders Inflammation and ulceration of the urinary bladder (possibly with haematuria), dysuria.

Renal failure, […]

Fatal toxicity in association with intravenous administration due to dose miscalculation has been reported. 2 posology and administration). Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay.

Therefore methotrexate should only be administered by, or under the supervision of physicians whose knowledge and experience includes the use of antimetabolite therapy. 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. 5). Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.

In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co- administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment. 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.

Fertility Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of treatment, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy.

Teratogenicity – Reproductive risk Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. 6). In non-oncologic indications, the absence of pregnancy must be confirmed before Methotrexate is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.

For contraception advice for men see section

1. 2). • Alcohol abuse. 2). • Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia. • Serious, acute or chronic infections such as tuberculosis and HIV. • Ulcers of the oral cavity and known active gastrointestinal ulcer disease.

6) • Concurrent vaccination with live vaccines.