Nordimet 25 mg solution for injection in pre-filled pen

Summary of Product Characteristics Updated 04-Dec-2017 | Nordic Pharma Limited

1. Name of the medicinal product

Nordimet 7.5 mg solution for injection in pre-filled pen

Nordimet 10 mg solution for injection in pre-filled pen

Nordimet 12.5 mg solution for injection in pre-filled pen

Nordimet 15 mg solution for injection in pre-filled pen

Nordimet 17.5 mg solution for injection in pre-filled pen

Nordimet 20 mg solution for injection in pre-filled pen

Nordimet 22.5 mg solution for injection in pre-filled pen

Nordimet 25 mg solution for injection in pre-filled pen

Nordimet 7.5 mg solution for injection in pre-filled syringe

Nordimet 10 mg solution for injection in pre-filled syringe

Nordimet 12.5 mg solution for injection in pre-filled syringe

Nordimet 15 mg solution for injection in pre-filled syringe

Nordimet 17.5 mg solution for injection in pre-filled syringe

Nordimet 20 mg solution for injection in pre-filled syringe

Nordimet 22.5 mg solution for injection in pre-filled syringe

Nordimet 25 mg solution for injection in pre-filled syringe

2. Qualitative and quantitative composition

One ml of solution contains 25 mg of methotrexate.

Nordimet 7.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 7.5 mg methotrexate in 0.3 mL

Nordimet 10 mg solution for injection in pre-filled pen

Each pre-filled pen contains 10 mg methotrexate in 0.4 mL

Nordimet 12.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 12.5 mg methotrexate in 0.5 mL

Nordimet 15 mg solution for injection in pre-filled pen

Each pre-filled pen contains 15 mg methotrexate in 0.6 mL

Nordimet 17.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 17.5 mg methotrexate in 0.7 mL

Nordimet 20 mg solution for injection in pre-filled pen

Each pre-filled pen contains 20 mg methotrexate in 0.8 mL

Nordimet 22.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 22.5 mg methotrexate in 0.9 mL

Nordimet 25 mg solution for injection in pre-filled pen

Each pre-filled pen contains 25 mg methotrexate in 1.0 mL

Nordimet 7.5 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 7.5 mg methotrexate in 0.3 mL

Nordimet 10 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 10 mg methotrexate in 0.4 mL

Nordimet 12.5 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 12.5 mg methotrexate in 0.5 mL

Nordimet 15 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 15 mg methotrexate in 0.6 mL

Nordimet 17.5 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 17.5 mg methotrexate in 0.7 mL

Nordimet 20 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 20 mg methotrexate in 0.8 mL

Nordimet 22.5 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 22.5 mg methotrexate in 0.9 mL

Nordimet 25 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 25 mg methotrexate in 1.0 mL

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

Clear, yellow solution with a pH of 8.0-9.0 and an osmolality of approximately 300 mOsm/kg.

4. Clinical particulars
4.1 Therapeutic indications

Nordimet is indicated for the treatment of

- active rheumatoid arthritis in adult patients,

- polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA), when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

- severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, psoralens and ultraviolet A (PUVA), and retinoids, and severe psoriatic arthritis in adult patients.

4.2 Posology and method of administration

Nordimet should only be prescribed by physicians with experience in the various properties of the medicinal product and its mode of action.

Important warning with reference to the dosing of methotrexate: methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used once weekly. Faulty dosing of methotrexate may lead to serious adverse effects including fatal course. Please read this paragraph of the SmPC very carefully.

When switching from oral use to subcutaneous use, a reduction in the dose may be required, due to the variable bioavailability of methotrexate after oral administration.

Folic acid or folinic acid supplementation may be considered in accordance with current therapeutic guidelines.

The overall duration of treatment is decided by the doctor.

Posology

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. Depending on the individual activity of the disease and patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4-8 weeks. Once the desired therapeutic result has been achieved, the dose should be reduced gradually to the lowest possible effective maintenance dose. Symptoms may return after treatment discontinuation.

Methotrexate treatment of rheumatoid arthritis represents long-term treatment.

Dosage in patients with psoriasis vulgaris and psoriatic arthritis

It is recommended that a test dose of 5-10 mg be administered subcutaneously one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. The recommended initial dose is 7.5 mg methotrexate once weekly. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can generally be expected after approximately 2-6 weeks. Depending on the clinical picture and the changes of laboratory parameters, the therapy is then continued or discontinued.

Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance dose. In a few exceptional cases a higher dose than 25 mg might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Methotrexate treatment of severe psoriasis vulgaris and psoriatic arthritis represents long-term treatment.

Special populations

Elderly

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age (see sections 4.4, 4.5, 4.8 or 5.2)

Renal impairment

Methotrexate should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The dose should be adjusted as follows:

Creatinine clearance (ml/min)

Dose

≥ -60

100 %

30-59

50 %

< 30

Nordimet must not be used

Patients with hepatic impairment

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) (see section 4.3).

Use in patient with a third distribution space (pleural effusions, ascitis)

As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space, dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see sections 5.2 and 4.4).

Paediatric population

Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis

The recommended dose is 10-15 mg/m2 body surface area (BSA) per week.

In therapy-refractory cases the weekly dose may be increased up to 20 mg/m2 BSA per week. However, an increased monitoring frequency is indicated if the dose is increased. Parenteral administration is limited to subcutaneous injection. Patients with JIA should always be referred to a rheumatology unit specializing in the treatment of children/adolescents.

The safety and efficacy of Nordimet in children < 3 years of age have not been established (see section 4.4). No data available.

Method of administration

It must be explicitly pointed out to the patient that Nordimet is applied only once a week. It is recommended to specify a certain day of the week as “day for injection”.

Nordimet is for subcutaneous use (see section 6.6.).

The medicinal product is for single use only. The solution is to be visually inspected prior to use. Only clear solutions practically free from particles should be used.

Any contact of methotrexate with skin and mucosa is to be avoided. In case of contamination, the affected parts are to be rinsed immediately with plenty of water (see section 6.6).

Please refer to the patient information leaflet for instructions on how to use the pre-filled pen or pre-filled syringe.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Severe hepatic impairment, if serum if bilirubin is > 5 mg/dl (85.5 µmol/l) (see section 4.2).

- Alcohol abuse.

- Severe renal impairment (creatinine clearance less than 30 ml/min) (see sections 4.2 and 4.4).

- Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia.

- Immunodeficiency.

- Serious, acute or chronic infections such as tuberculosis and HIV.

- Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease.

- Pregnancy and breast-feeding (see section 4.6).

- Concurrent vaccination with live vaccines.

4.4 Special warnings and precautions for use

Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Incorrect administration of methotrexate can lead to severe, including potentially lethal adverse reactions. Healthcare professionals and patients should be clearly instructed.

Patients receiving therapy should be appropriately monitored, so that signs of possible toxic effects or adverse reactions can be recognised and assessed without delay. Hence, methotrexate should be only administered by, or under the supervision of, doctors whose knowledge and experience include the use of antimetabolite therapy.

Due to the risk of severe or even fatal toxic reactions, patients should be thoroughly informed by the doctor about the risks (including early signs and symptoms of toxicity) and recommended safety measures. They are to be informed about the necessity to immediately consult the physician if symptoms of intoxication occur, as well as about the subsequent necessary monitoring of symptoms of intoxication (including regular laboratory tests).

Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression.

Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with male and female patients of childbearing potential (see section 4.6). Effective contraception in men and women should be performed during treatment and for at least six months after. Since treatment with methotrexate can lead to severe and possibly irreversible disorders in spermatogenesis, men should seek advice about the possibility of sperm preservation before starting therapy.

Skin and mucosal contact with methotrexate is to be avoided. In the case of contamination, the parts concerned should be rinsed with plenty of water.

Recommended examinations and safety measures

Before initiating therapy or upon resuming therapy after a rest period

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest X-ray and renal function tests must be conducted. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy

The tests below must be conducted every week during the first two weeks, then every two weeks for the next month; afterwards, depending on leukocyte count and stability of the patient, at least once monthly during the next six months and at least every three months thereafter.

Increased monitoring frequency should also be considered when increasing the dose. Particularly elderly patients should be examined for early signs of toxicity in short intervals.

- Examination of the oral cavity and throat for mucosal changes.

- Complete blood count with differential blood count and platelets.

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 medicinal products (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.

Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent anomalies of liver-related enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity.

Enzyme diagnostics does not allow any reliable prediction of the development of a morphologically detectable hepatotoxicity, i.e. even in case of normal transaminases, hepatic fibrosis only histologically identifiable or, more rarely, also hepatocirrhosis may be present.

In rheumatological indications, there is no evidence to support use of liver biopsies in monitoring hepatotoxicity. For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. 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 medicinal products or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more.

In the event of a constant increase in liver-related enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Due to the potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary and alcohol consumption should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products (e.g. leflunomide).

Increased caution should generally be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy hepatocirrhosis developed in isolated cases without intermittent increase in transaminases.

- Renal function should be monitored via renal function tests and urinanalysis (see sections 4.2 and 4.3). If serum creatinine is increased, the dose should be reduced. As methotrexate is predominantly excreted via the renal route, increased concentrations can be expected in cases of renal impairment, which may result in severe adverse reactions. In cases of possible renal impairment (e.g. in elderly patients), closer monitoring is required. This particularly applies to the co-administration of medicinal products which affect methotrexate excretion, cause kidney damage (e.g. NSAIDs) or can potentially lead to haematopoietic disorders. In patients with impaired renal function, concomitant administration of NSAIDs is not recommended. Dehydration may also potentiate the toxicity of methotrexate.

- Assessment of respiratory system.

Questioning the patient with regard to possible pulmonary dysfunctions, if necessary lung function test. 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), thoracic pain and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

Methotrexate should be discontinued in patients with pulmonary symptoms and a thorough investigation (including chest x-ray) should be made to exclude infection and tumours. If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Pulmonary diseases induced by methotrexate were not always completely reversible.

Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate therapy. Pulmonary diseases induced by methotrexate, like pneumonitis, can occur acutely at any time of therapy, they were not always completely reversible and have been reported already at all doses (inclusive low doses of 7.5 mg/week).

During methotrexate therapy, opportunistic infection can occur including pneumocystis jiroveci pneumonia, which may take a lethal course. If a patient presents with pulmonary symptoms, the possibility of pneumocystis jiroveci pneumonia should be taken into account.

Special caution is required in patients with impaired pulmonary function.

- Methotrexate may, due to its effect on the immune system, impair the response to vaccinations and interfere with the result of immunological tests. Concurrent vaccination using live vaccines must not be carried out.

Particular caution should be exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) due to possible activation.

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.

In patients with pathological accumulation of liquid in body cavities (“third space”), such as ascites or pleural effusions, the plasma elimination half-life of methotrexate is prolonged. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment.

Conditions leading to dehydration such as emesis, diarrhoea or stomatitis, can increase the toxicity of methotrexate due to elevated levels of the active substance. In these cases use of methotrexate should be interrupted until the symptoms cease.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

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

Encephalopathy / Leukoencephalopathy have been reported in oncologic patients receiving methotrexate therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. These effects appear to be reversible on discontinuing therapy. Effective contraception in men and women should be performed during treatment and for at least six months thereafter. The possible risks of effects on reproduction should be discussed with patients of childbearing potential and their partners should be advised appropriately (see section 4.6). The absence of pregnancy should be confirmed before Nordimet is used.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-free“.

4.5 Interaction with other medicinal products and other forms of interaction

In animal experiments non-steroidal anti-inflammatory drugs (NSAIDs) including salicylic acid caused reduction of tubular methotrexate secretion and consequently increased its toxic effects. However, in clinical studies, where NSAIDs and salicylic acid were given as concomitant medicinal products to patients with rheumatoid arthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with such drugs can be continued during low-dose methotrexate therapy but only under close medical supervision.

Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the probability of hepatotoxic effects of methotrexate.

Patients taking potentially hepatotoxic and haematoxic medicinal products during methotrexate therapy (e.g. leflunomide, azathioprine, sulphasalazine, and retinoids) should be closely monitored for possibly increased hepatotoxicity. Alcohol consumption must be avoided during treatment with methotrexate.

Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematoxic effects of methotrexate.

One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsant medicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t½ of 5--fluorouracil).

Salicylates, phenylbutazone, phenytoin, barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability (indirect dose increase).

Probenecid and mild organic acids may also reduce tubular methotrexate secretion, and thus cause indirect dose elevations, too.

Antibiotics, like penicillin, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal methotrexate absorption or interfere with the enterohepatic circulation, due to inhibition of the intestinal flora or suppression of bacterial metabolism.

Under (pre-)treatment with substances that may have adverse effects on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine), the possibility of marked haematopoietic disorders should be considered.

Co-administration of medicinal products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular caution should therefore also be exercised in the presence of existing folic acid deficiency.

On the other hand, concomitant administration of folinic acid containing drugs or of vitamin preparations, which contain folic acid or derivatives, may impair methotrexate efficacy.

A rise in the toxicity of methotrexate is generally not anticipated when methotrexate is used concomitantly with other antirheumatic agents (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporin).

Though the combination of methotrexate and sulfasalazine may enhance methotrexate efficacy by sulfasalazine related inhibition of folic acid synthesis, and thus may lead to an increased risk of adverse reactions, these were only observed in single patients within several trials.

Co-administration of proton-pump inhibitors such as omeprazole or pantoprazole can lead to interactions: concomitant administration of methotrexate and omeprazole has led to a delay in the renal elimination of methotrexate. In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case.

Methotrexate may reduce theophylline clearance. Therefore, theophylline blood levels should be monitored under concomitant methotrexate administration.

Excessive consumption of beverages containing caffeine or theophylline (coffee, soft drinks containing caffeine, black tea) should be avoided during methotrexate therapy since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors.

The combined use of methotrexate and leflunomide may increase the risk for pancytopenia. Methotrexate leads to increased plasma levels of mercaptopurines. Therefore, the combination of these may require dose adjustment.

Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution.

Anaesthetics on nitric oxide base potentiate the effect of methotrexate on the folic acid metabolism and lead to severe unpredictable myelosuppression and stomatitis. This can be reduced by administering calcium folinate.

Colestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation. Delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products. Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.

On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out (see sections 4.3 and 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / contraception in males and females

Women must not get pregnant during methotrexate therapy, and patients of a sexually mature age (women and men) must use effective contraception during treatment with methotrexate and at least 6 months thereafter (see section 4.4).

Pregnancy

Methotrexate is contraindicated during pregnancy (see section 4.3). In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to have a teratogenic effect in humans; it has been reported to cause foetal death and/or congenital abnormalities. Exposure of a limited number of pregnant women (42) resulted in an increased incidence (1:14) of malformations (cranial, cardiovascular and extremity-related). When methotrexate was discontinued prior to conception, normal pregnancies have been reported. In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test, prior to initiating therapy (see section 4.4). If, nevertheless, pregnancy occurs during this period, medical advice should be given regarding the risk of harmful effects on the child associated with treatment.

Breast-feeding

As methotrexate is transferred into human milk and may cause toxicity in breast-feeding children, treatment is contraindicated during breast-feeding (see section 4.3). If use of methotrexate during the breast-feeding period should become necessary, breast-feeding is to be stopped prior to treatment.

Fertility

As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible, already prior to therapy, and men should seek advice about the possibility of sperm preservation before starting therapy (see sections 4.4 and 5.3).

4.7 Effects on ability to drive and use machines

Nordimet has minor influence on the ability to drive and use machines. Central nervous system (CNS) symptoms, such as fatigue and confusion, can occur during treatment.

4.8 Undesirable effects

Summary of the safety profile

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.

The most relevant adverse reaction is suppression of the haematopoietic system and gastrointestinal disorders.

List of adverse reactions

Frequencies are defined using the following convention:

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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Uncommon: Pharyngitis.

Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis.

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very rare: lymphoma (see “description” below)

Blood and lymphatic system disorders

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression.

Not known: Eosinophilia

Immune system disorders

Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Metabolism and nutrition disorders

Uncommon: Precipitation of diabetes mellitus.

Psychiatric disorders

Uncommon: Depression, confusion.

Rare: Mood alterations.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness.

Very rare: Pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis.

Not known: Encephalopathy/ Leukoencephalopathy.

Eye disorders

Rare: Visual disturbances.

Very rare: Impaired vision, Retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, shortness of breath and fever.

Rare: Pulmonary fibrosis, Pneumocystis jiroveci pneumonia, shortness of breath and bronchial asthma, pleural effusion.

Not known: Epistaxis.

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain.

Common: Oral ulcers, diarrhoea.

Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis.

Rare: Gingivitis.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders (see section 4.4)

Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin).

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Skin and subcutaneous tissue disorders

Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia, myalgia, osteoporosis.

Rare: Stress fracture.

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Not known: Proteinuria.

Reproductive system and breast disorders

Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.

General disorders and administration site conditions

Rare: Fever, wound-healing impairment.

Not known: Asthenia.

Description of selected adverse reactions

Lymphoma: there have been reports of individual cases of lymphoma which subsided in a number of cases once treatment with methotrexate had been discontinued. In a recent study, it could not be established that methotrexate therapy increases the incidence of lymphomas

The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.

Only mild local skin reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed with subcutaneous use, decreasing during therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms of overdose

The adverse toxic effects of methotrexate mainly affect the haematopoietic and gastrointestinal system. Symptoms include leukocytopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow depression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and gastrointestinal bleeding. Some patients showed no signs of overdose. There are reports of death due to sepsis, septic shock, renal failure and aplastic anaemia.

Treatment of overdose

Calcium folinate is the specific antidote for neutralising the adverse toxic effects of methotrexate. In the event of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within 1 hour, and dosing continued until serum level of methotrexate are below 10-7 mol/L.

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

In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis or psoriasis vulgaris, administration of folic or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, inflammation of oral mucosa, hair loss and increase of liver enzymes) (see section 4.5). Prior to using folic acid products, monitoring of vitamin B12 levels is recommended, since folic acid may mask an existing vitamin B12 deficiency, particularly in adults over 50 years of age.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other immunosuppressants. ATC code: L04AX03

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriatic arthritis and chronic polyarthritis, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.

5.2 Pharmacokinetic properties

Absorption

After oral application, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 mg/m2 to 80 mg/m2 BSA), methotrexate has a mean bioavailability of approximately 70%, although considerable inter- and intra-subject variations are possible (25-100%). Plasma peak concentrations are attained within 1-2 hours. Subcutaneous, intravenous and intramuscular administration demonstrated similar bioavailability.

Distribution

Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations particularly in liver, kidneys and spleen in form of polyglutamates can be found, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the body fluids in minimal amounts; under high doses (300 mg/kg body weight), concentrations between 4 and 7 µg/ml have been measured in the body fluids. Average terminal half-life is 6-7 hours and demonstrates considerable variation (3-17 hours). Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites).

Biotransformation

Approximately 10% of the administered methotrexate is metabolised intrahepatically. The major metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx. 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are eliminated via the bile. Pronounced enterohepatic blood flow exists.

In case of renal insufficiency, elimination is delayed significantly. Impaired elimination in presence of hepatic insufficiency is not known.

Methotrexate passes the placental barrier in rats and monkeys.

5.3 Preclinical safety data

Chronic toxicity

Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.

Mutagenic and carcinogenic potential

Long-term studies in rats, mice and hamsters did not show any evidence of a tumorigenic potential of methotrexate. Methotrexate induces gene and chromosome mutations both in vitro and in vivo. A mutagenic effect is suspected in humans.

Reproductive toxicology

Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys, no malformations comparable to humans occurred.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 25°C.

Keep the pre-filled pen and pre-filled syringe in the outer carton in order to protect from light.

6.5 Nature and contents of container

Pre-filled pen

Pre-filled pen with a 1 mL type I glass syringe with attached stainless steel needle and a chlorobutyl rubber plunger stopper. The pre-filled pens contain 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1 ml of solution for injection. Each pack contains 1 pre-filled pen and one alcohol swab and multipacks containing 4 (4 packs of 1) and 6 (6 packs of 1) pre-filled pens and alcohol swabs.

Pre-filled syringe

1 mL type I glass syringe with attached stainless steel needle, a chlorobutyl rubber plunger stopper and a needle guard to prevent needlestick injury and re-use. The pre-filled syringes contain 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml or 1 ml solution for injection. Each pack contains 1 pre-filled syringe and two alcohol swabs and multipacks containing 4 (4 packs of 1) and 6 (6 packs of 1) pre-filled syringes and alcohol swabs.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer methotrexate.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water.

Nordimet is for single use only and any unused solution must be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

7. Marketing authorisation holder

Nordic Group BV

Siriusdreef 22

2132 WT Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

Nordimet 7.5 mg solution for injection in pre-filled pen

EU/1/16/1124/001 - 1 pack

EU/1/16/1124/009 - 4 pack

EU/1/16/1124/010 - 6 pack

Nordimet 10 mg solution for injection in pre-filled pen

EU/1/16/1124/002 - 1 pack

EU/1/16/1124/011 - 4 pack

EU/1/16/1124/012 - 6 pack

Nordimet 12.5 mg solution for injection in pre-filled pen

EU/1/16/1124/003 - 1 pack

EU/1/16/1124/013 - 4 pack

EU/1/16/1124/014 - 6 pack

Nordimet 15 mg solution for injection in pre-filled pen

EU/1/16/1124/004 - 1 pack

EU/1/16/1124/015 - 4 pack

EU/1/16/1124/016 - 6 pack

Nordimet 17.5 mg solution for injection in pre-filled pen

EU/1/16/1124/005 - 1 pack

EU/1/16/1124/017 - 4 pack

EU/1/16/1124/018 - 6 pack

Nordimet 20 mg solution for injection in pre-filled pen

EU/1/16/1124/006 - 1 pack

EU/1/16/1124/019 - 4 pack

EU/1/16/1124/020 - 6 pack

Nordimet 22.5 mg solution for injection in pre-filled pen

EU/1/16/1124/007 - 1 pack

EU/1/16/1124/021 - 4 pack

EU/1/16/1124/022 - 6 pack

Nordimet 25 mg solution for injection in pre-filled pen

EU/1/16/1124/008 - 1 pack

EU/1/16/1124/023 - 4 pack

EU/1/16/1124/024 - 6 pack

Nordimet 7.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/025 - 1 pack

EU/1/16/1124/026 - 4 pack

EU/1/16/1124/027 - 6 pack

Nordimet 10 mg solution for injection in pre-filled syringe

EU/1/16/1124/028 - 1 pack

EU/1/16/1124/029 - 4 pack

EU/1/16/1124/030 - 6 pack

Nordimet 12.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/031 - 1 pack

EU/1/16/1124/032 - 4 pack

EU/1/16/1124/033 - 6 pack

Nordimet 15 mg solution for injection in pre-filled syringe

EU/1/16/1124/034 - 1 pack

EU/1/16/1124/035 - 4 pack

EU/1/16/1124/036 - 6 pack

Nordimet 17.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/037 - 1 pack

EU/1/16/1124/038 - 4 pack

EU/1/16/1124/039 - 6 pack

Nordimet 20 mg solution for injection in pre-filled syringe

EU/1/16/1124/040 - 1 pack

EU/1/16/1124/041 - 4 pack

EU/1/16/1124/042 - 6 pack

Nordimet 22.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/043 - 1 pack

EU/1/16/1124/044 - 4 pack

EU/1/16/1124/045 - 6 pack

Nordimet 25 mg solution for injection in pre-filled syringe

EU/1/16/1124/046 - 1 pack

EU/1/16/1124/047 - 4 pack

EU/1/16/1124/048 - 6 pack

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18 August 2016

10. Date of revision of the text

16 September 2017

Company Contact Details
Nordic Pharma Limited
Address

3 Commerce Park, Brunel Road, Theale, Reading, Berkshire, RG7 4AB

Fax

+44 (0) 118 207 9161

Medical Information e-mail
Stock Availability
Telephone

+44 (0) 118 207 9160

Medical Information Direct Line

+44 (0) 800 121 8924

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+44 (0) 44 1748 828801