NORDIMET 22.5mg injection for pre-filled pen medication leaflet

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

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.

Solution for injection (injection)

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

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 tononsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

- moderate to severe plaque psoriasis in adults who are candidates for systemic therapy, andsevere psoriatic arthritis in adult patients,

- induction of remission in moderate steroid-dependent Crohn's disease in adult patients, incombination with corticosteroids and for maintenance of remission, as monotherapy, inpatients who have responded to methotrexate.

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate anda full understanding of the risks of methotrexate therapy.

Patients must be educated and trained in the proper injection technique when self-administeringmethotrexate. The first injection of Nordimet should be performed under direct medical supervision.

Important warning about the dosage of Nordimet

In the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis, psoriaticarthritis and Crohn’s disease requiring dosing once a week. Nordimet must only be used once aweek. Dosage errors in the use of Nordimet can result in serious adverse reactions, including death.

Please read this section of the summary of product characteristics very carefully.

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

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

The overall duration of treatment is decided by the doctor.

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once weekly, administeredsubcutaneously. Depending on the individual activity of the disease and patient tolerability, theinitial 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, especiallybone 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 thelowest possible effective maintenance dose. Symptoms may return after treatment discontinuation.

Methotrexate treatment of rheumatoid arthritis represents long-term treatment.

Dosage in patients with plaque psoriasis and psoriatic arthritis

It is recommended that a test dose of 5-10 mg be administered subcutaneously one week prior toinitiation of therapy, in order to detect idiosyncratic adverse effects. The recommended initial doseis 7.5 mg methotrexate once weekly. The dose is to be increased gradually but should not, ingeneral, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can beassociated with significant increase in toxicity, especially bone marrow suppression. Response totreatment can generally be expected after approximately 2-6 weeks. Depending on the clinicalpicture 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 thelowest possible effective maintenance dose. In a few exceptional cases a higher dose than 25 mgmight be clinically justified, but should not exceed a maximum weekly dose of 30 mg ofmethotrexate as toxicity will markedly increase.

Methotrexate treatment of moderate to severe plaque psoriasis and severe psoriatic arthritisrepresents long-term treatment.

Dosage in adult patients with Crohn's disease:

Induction treatment25 mg/week administered subcutaneously.

Once patients have adequately responded to combination therapy, the corticosteroids should betapered. Response to treatment can be expected after 8 to 12 weeks.

Maintenance treatment15 mg/week administered subcutaneously, as monotherapy, if the patient has entered remission.

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

Methotrexate should be used with caution in patients with impaired renal function (see sections 4.3and 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

Methotrexate should be administered with great caution, if at all, to patients with significant currentor previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated ifbilirubin 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 whopossess a third distribution space, dose reduction or, in some cases, discontinuation of methotrexateadministration may be required (see sections 5.2 and 4.4).

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

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. Parenteraladministration is limited to subcutaneous injection. Patients with JIA should always be referred to arheumatology unit specializing in the treatment of children/adolescents.

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

It must be explicitly pointed out to the patient that Nordimet is applied only once a week. It isrecommended 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, theaffected parts are to be rinsed immediately with plenty of water (see section 6.6).

Please refer to the package leaflet for instructions on how to use the pre-filled pen or pre-filledsyringe.

- 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.

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

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

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

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

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

Fertility and reproduction

Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea inhumans, 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. These effectsappear to be reversible on discontinuing therapy.

Teratogenicity - reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possiblerisks of effects on reproduction, pregnancy loss and congenital malformations should be discussedwith female patients of childbearing potential (see section 4.6). The absence of pregnancy must beconfirmed before Nordimet is used. If women of child bearing potential are treated, effectivecontraception must be used during treatment and for at least six months after.

For contraception advice for men, see section 4.6.

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, serumalbumin, chest X-ray and renal function tests must be conducted. If clinically indicated, excludetuberculosis and hepatitis.

During therapy

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

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

Examination of the oral cavity and throat for mucosal change.

Complete blood count with differential blood count and platelets

Haematopoietic suppression induced by methotrexate may occur abruptly and at apparently safedoses. In the event of any significant drop in leukocytes or platelets, treatment must be discontinuedimmediately and appropriate supportive therapy instituted. Patients must be instructed to report allsigns and symptoms suggestive of infection. In patients concomitantly taking haematotoxicmedicinal products (e.g. leflunomide), the blood count and platelets should be closely monitored.

Treatment should not be initiated or should be discontinued if there are persistent or significantabnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liverbiopsies.

Temporary increases in transaminases to two or three times the upper limit of normal have beenreported in patients at a frequency of 13-20 %. Persistent elevation of liver enzymes and/or decreasein serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increasein liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liverfunction tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition toliver function tests. Liver biopsy should be considered on an individual basis taking into account thepatient’s comorbidities, medical history and the risks related to biopsy. Risk factors forhepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes,history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity andprevious contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment.

Additional hepatotoxic medicinal products should not be given during treatment with methotrexateunless clearly necessary.Alcohol consumption should be avoided (see sections 4.3 and 4.5). Closermonitoring of liver enzymes should be undertaken in patients concomitantly taking otherhepatotoxic medicinal products.

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, asduring methotrexate therapy, liver cirrhosisdeveloped in isolated cases without any elevation oftransaminases.

Renal function should be monitored via renal function tests and urinanalysis (see sections 4.2 and4.3). If serum creatinine is increased, the dose should be reduced. As methotrexate is predominantlyexcreted 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 elderlypatients), closer monitoring is required. This particularly applies to the co-administration ofmedicinal products which affect methotrexate excretion, cause kidney damage (e.g. NSAIDs) or canpotentially lead to haematopoietic disorders. In patients with impaired renal function, concomitantadministration of NSAIDs is not recommended. Dehydration may also potentiate the toxicity ofmethotrexate.

Assessment of respiratory system

Questioning the patient with regard to possible pulmonary dysfunctions, if necessary, lung functiontest. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occurand deaths have been reported. Symptoms typically include dyspnoea, cough (especially a drynon-productive cough), thoracic pain and fever for which patients should be monitored at eachfollow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact theirdoctor immediately should they develop persistent cough or dyspnoea.

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used inrheumatologic and related indications. This event may also be associated with vasculitis and othercomorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhageis suspected to confirm the diagnosis.

Methotrexate should be discontinued in patients with pulmonary symptoms and a thoroughinvestigation (including chest x-ray) should be made to exclude infection and tumours. Ifmethotrexate induced lung disease is suspected, treatment with corticosteroids should be initiatedand 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 oftherapy, 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 jirovecipneumonia, which may take a lethal course. If a patient presents with pulmonary symptoms, thepossibility of pneumocystis jiroveci pneumonia should be taken into account.

Special caution is required in patients with impaired pulmonary function.

General safety measures

Methotrexate may, due to its effect on the immune system, impair the response to vaccinations andinterfere with the result of immunological tests. Concurrent vaccination using live vaccines mustnot be carried out.

Particular caution should be exercised in the presence of inactive, chronic infections (e.g. herpeszoster, 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 ofcytotoxic therapy is required.

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

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

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy,otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

If haematemesis, black discoloration of the stool or blood in stool occur, therapy is to beinterrupted.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patientsreceiving methotrexate, mostly in combination with other immunosuppressive medication. PML canbe fatal and should be considered in the differential diagnosis in immunosuppressed patients withnew onset or worsening neurological symptoms.

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

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety areavailable for this population. (see section 4.2).

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in someindividuals taking methotrexate (see section 4.8). Exposure to intense sunlight or UV rays should beavoided unless medically indicated. Patients should use adequate sun-protection to protectthemselves from intense sunlight.

Radiation induced dermatitis and sunburn can reappear during methotrexate therapy (recallreactions). Psoriatic lesions can worsen during UV radiation and co-administration of methotrexate.

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

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

Sodium contents

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially‘sodium-free’.

NSAIDs including salicylic acid

In animal experiments NSAIDs including salicylic acid caused reduction of tubular methotrexatesecretion and consequently increased its toxic effects. However, in clinical studies, where NSAIDsand salicylic acid were given as concomitant medicinal products to patients with rheumatoidarthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with suchmedicinal products can be continued during low-dose methotrexate therapy but only under closemedical supervision.

Regular alcohol consumption and administration of additional hepatotoxic medicinal productsincrease the probability of hepatotoxic effects of methotrexate. Alcohol consumption must beavoided during treatment with methotrexate.

Patients taking potentially hepatotoxic and haematoxic medicinal products during methotrexatetherapy (e.g. leflunomide, azathioprine, sulphasalazine, and retinoids) should be closely monitoredfor possibly increased hepatotoxicity.

Haematotoxic medicinal products

Administration of additional haematotoxic medicinal products increases the likelihood of severehaematoxic adverse reactions to methotrexate. Concurrent administration of metamizole andmethotrexate can increase the haematotoxic effect of methotrexate, especially in elderly patients.

Therefore, coadministration should be avoided.

One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsantmedicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t½ of5--fluorouracil).

Alterations in bioavailability of methotrexate

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

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

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

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

Colestyramine can increase the non-renal elimination of methotrexate by interrupting theenterohepatic circulation. Delayed methotrexate clearance should be considered in combinationwith other cytostatic medicinal products.

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

Substances that may have adverse effects on the bone marrow

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

Folate metabolism

Co-administration of medicinal products which cause folate deficiency (e.g. sulphonamides,trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular cautionshould 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 vitaminpreparations, which contain folic acid or derivatives, may impair methotrexate efficacy.

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yieldingincreased toxicity such as severe unpredictable myelosuppression and stomatitis. Whilst this effectcan be reduced by administering calcium folinate, the concomitant use of nitrous oxide andmethotrexate should be avoided.

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

Other antirheumatic agents

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

Cyclosporine

Cyclosporine may potentiate methotrexate efficacy and toxicity. There is an increased risk of renaldysfunction. In addition, there is a biological plausibility of excessive immunosuppression and itsassociated complications.

Theophylline and caffeine

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

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

Leflunomide

The combined use of methotrexate and leflunomide may increase the risk for pancytopenia.

Methotrexate leads to increased plasma levels of mercaptopurines. Therefore, the combination ofthese may require dose adjustment.

Immune-modulating medicinal products

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

Radiotherapy

Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.

Vaccines

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

Women must not get pregnant during methotrexate therapy, and effective contraception must beused during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior toinitiating therapy, women of childbearing potential must be informed of the risk of malformationsassociated with methotrexate and any existing pregnancy must be excluded with certainty by takingappropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated asclinically required (e.g. after any gap of contraception). Female patients of reproductive potentialmust be counselled regarding pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic inanimal studies, such that the risk of genotoxic effects on sperm cells cannot completely beexcluded. Limited clinical evidence does not indicate an increased risk of malformations ormiscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). Forhigher doses, there is insufficient data to estimate the risks of malformations or miscarriagefollowing paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommendedto use reliable contraception during treatment of the male patient and for at least 3 months aftercessation of methotrexate. Men should not donate semen during therapy or for 3 months followingdiscontinuation of methotrexate.

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3).

If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medicaladvice should be given regarding the risk of harmful effects on the child associated with treatmentand ultrasonography examinations should be performed to confirm normal foetal development.

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 beenreported to cause foetal death and/or congenital abnormalities (e.g. craniofacial, cardiovascular,central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions,intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dosemethotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexatetreatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births inin disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week,but higher rates of spontaneous abortions and congenital malformations are expected.

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

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 duringthe breast-feeding period should become necessary, breast-feeding is to be stopped prior totreatment.

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans,methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea.

These effects appear to be reversible after discontinuation of therapy in most cases.

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.

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

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

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

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 theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

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)

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferativedisorders (see “description below”).

Not known: Eosinophilia

Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Uncommon: Precipitation of diabetes mellitus.

Uncommon: Depression, confusion.

Rare: Mood alterations.

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness.

Very rare: Pain, muscular asthenia, paraesthesia/hypoaesthesia, changes in sense of taste (metallictaste), convulsions, meningism, acute aseptic meningitis, paralysis.

Not known: Encephalopathy/ Leukoencephalopathy.

Rare: Visual disturbances.

Very rare: Impaired vision, Retinopathy.

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Rare: Hypotension, thromboembolic events

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia.

Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, notproductive cough, shortness of breath and fever.

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

Not known: Epistaxis, pulmonary alveolar haemorrhage.

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 andbilirubin).

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

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitivity reactions , 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), increasedpigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Not known: Skin exfoliation/dermatitis exfoliative

Uncommon: Arthralgia, myalgia, osteoporosis.

Rare: Stress fracture.

Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders)

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

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

Not known: Proteinuria.

Uncommon: Inflammation and ulceration of the vagina.

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

Rare: Fever, wound-healing impairment.

Not known: Asthenia, injection site necrosis, oedema.

Lymphoma/Lymphoproliferative disorders

There have been reports of individual cases of lymphoma and other lymphoproliferative disorderswhich subsided in a number of cases once treatment with methotrexate had been discontinued.

The appearance and degree of severity of undesirable effects depends on the dosage level and thefrequency 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms of overdose

The adverse toxic effects of methotrexate mainly affect the haematopoietic and gastrointestinalsystem. Symptoms include leukocytopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia,bone marrow depression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinalulceration and gastrointestinal bleeding. Some patients showed no signs of overdose. There arereports 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. Inthe event of accidental overdose, a dose of calcium folinate equal to or higher than the offendingdose of methotrexate should be administered intravenously or intramuscularly within 1 hour, anddosing 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 preventprecipitation of methotrexate and/or its metabolites within the renal tubules. Neither haemodialysisnor peritoneal dialysis has been shown to improve methotrexate elimination. Effective methotrexateclearance has been reported with acute, intermittent haemodialysis using a high-flux dialyser.

In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis orplaque psoriasis, 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 isrecommended, since folic acid may mask an existing vitamin B12 deficiency, particularly in adultsover 50 years of age.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants. ATC code:

L04AX03

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

A study of weekly injections of methotrexate in a group of patients with chronically active Crohn’sdisease (despite at least three months of prednisone therapy), showed that methotrexate was moreeffective than placebo in improving symptoms and reducing requirements for prednisone. A total of141 patients were randomly assigned in a 2:1 ratio to methotrexate (25 mg weekly) or placebo.

After 16 weeks, 37 patients (39.4%) were in clinical remission in the methotrexate group, ascompared with 9 patients (19.4%, P=0.025;) in the placebo group. The patients in the methotrexategroup received less prednisone overall and their mean score on the Crohn’s Disease Activity Indexwas significantly lower than those in the placebo group (P=0.026 and P=0.002, respectively).[Feagan et al (1995)]

A study of patients, who had entered remission after 16 to 24 weeks of treatment with 25 mg ofmethotrexate, showed that a low dose of methotrexate maintains remission. Patients were randomlyassigned to receive either methotrexate at a dose of 15 mg I.M. once weekly or placebo for 40weeks. At week 40, 26 patients (65%) were in remission in the methotrexate group and fewerneeded prednisone for relapse (28%), as compared with the placebo group (39%; P=0.04 and 58%,

P=0.01, respectively). [Feagan et al (2000)]

The adverse events observed in the studies performed with methotrexate for Crohn’s disease atcumulative doses have not shown a different safety profile of methotrexate than the profile that isalready known. Therefore, similar cautions must be taken with the use of methotrexate for thetreatment of Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate(see sections 4.4 and 4.6).

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

Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into bodytissues, high concentrations particularly in liver, kidneys and spleen in form of polyglutamates canbe 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 bodyweight), concentrations between 4 and 7 µg/ml have been measured in the body fluids. Averageterminal half-life is 6-7 hours and demonstrates considerable variation (3-17 hours). Half-life maybe prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites).

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

Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration andactive 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 presenceof hepatic insufficiency is not known.

Methotrexate passes the placental barrier in rats and monkeys.

Chronic toxicity

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

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

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

6 PHARMACEUTICAL PARTICULARS

Sodium chloride

Sodium hydroxide (for pH adjustment)

Water for injections

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

2 years.

Store below 25°C.

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

Do not freeze.

Pre-filled pen

Pre-filled pen with a 1 mL type I glass syringe with attached stainless steel needle and a chlorobutylrubber 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 1.0 ml of solution for injection.

Each pack contains 1 pre-filled pen and one alcohol swab and multipacks containing 4 (4 packs of 1or 1 pack of 4), 6 (6 packs of 1) and 12 (3 packs of 4) pre-filled pens and 4, 6 and 12 alcohol swabsrespectively.

Pre-filled syringe1 mL type I glass syringe with attached stainless steel needle, a chlorobutyl rubber plunger stopperand 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 1.0 ml solution for injection.

Each pack contains 1 pre-filled syringe and two alcohol swabs and multipacks containing 4 (4 packsof 1), 6 (6 packs of 1) and 12 (12 packs of 1) pre-filled syringes and 8, 12 and 24 alcohol swabsrespectively.

Not all pack sizes may be marketed.

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

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 requirementsfor cytotoxic agents.

Nordic Group B.V.

Siriusdreef 412132 WT Hoofddorp

The Netherlands

Nordimet 7.5 mg solution for injection in pre-filled pen

EU/1/16/1124/001 - 1 pre-filled pen

EU/1/16/1124/009 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/010 - multipack: 6 (6 packs of 1) pre-filled pens

EU/1/16/1124/057 - 4 pre-filled pens

EU/1/16/1124/058 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 10 mg solution for injection in pre-filled pen

EU/1/16/1124/002 - 1 pre-filled pen

EU/1/16/1124/011 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/012 - multipack: 6 (6 packs of 1) pre-filled pens

EU/1/16/1124/059 - 4 pre-filled pens

EU/1/16/1124/060 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 12.5 mg solution for injection in pre-filled pen

EU/1/16/1124/003 - 1 pre-filled pen

EU/1/16/1124/013 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/014 - multipack:6 (6 packs of 1) pre-filled pens

EU/1/16/1124/061 - 4 pre-filled pens

EU/1/16/1124/062 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 15 mg solution for injection in pre-filled pen

EU/1/16/1124/004 - 1 pre-filled pen

EU/1/16/1124/015 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/016 - multipack:6 (6 packs of 1) pre-filled pens

EU/1/16/1124/063 - 4 pre-filled pens

EU/1/16/1124/064 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 17.5 mg solution for injection in pre-filled pen

EU/1/16/1124/005 - 1 pre-filled pen

EU/1/16/1124/017 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/018 - multipack:6 (6 packs of 1) pre-filled pens

EU/1/16/1124/065 - 4 pre-filled pens

EU/1/16/1124/066 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 20 mg solution for injection in pre-filled pen

EU/1/16/1124/006 - 1 pre-filled pen

EU/1/16/1124/019 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/020 - multipack:6 (6 packs of 1) pre-filled pens

EU/1/16/1124/067 - 4 pre-filled pens

EU/1/16/1124/068 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 22.5 mg solution for injection in pre-filled pen

EU/1/16/1124/007 - 1 pre-filled pen

EU/1/16/1124/021 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/022 - multipack: 6 (6 packs of 1) pre-filled pens

EU/1/16/1124/069 - 4 pre-filled pens

EU/1/16/1124/070 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 25 mg solution for injection in pre-filled pen

EU/1/16/1124/008 - 1 pre-filled pen

EU/1/16/1124/023 - multipack: 4 (4 packs of 1) pre-filled pens

EU/1/16/1124/024 - multipack:6 (6 packs of 1) pre-filled pens

EU/1/16/1124/071 - 4 pre-filled pens

EU/1/16/1124/072 - multipack:12 (3 packs of 4) pre-filled pens

Nordimet 7.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/025 - 1 pre-filled syringe

EU/1/16/1124/026 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/027 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/049 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 10 mg solution for injection in pre-filled syringe

EU/1/16/1124/028 - 1 pre-filled syringe

EU/1/16/1124/029 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/030 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/050 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 12.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/031 - 1 pre-filled syringe

EU/1/16/1124/032 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/033 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/051 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 15 mg solution for injection in pre-filled syringe

EU/1/16/1124/034 - 1 pre-filled syringe

EU/1/16/1124/035 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/036 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/052 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 17.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/037 - 1 pre-filled syringe

EU/1/16/1124/038 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/039 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/053 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 20 mg solution for injection in pre-filled syringe

EU/1/16/1124/040 - 1 pre-filled syringe

EU/1/16/1124/041 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/042 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/054 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 22.5 mg solution for injection in pre-filled syringe

EU/1/16/1124/043 - 1 pre-filled syringe

EU/1/16/1124/044 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/045 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/055 - multipack: 12 (12 packs of 1) pre-filled syringes

Nordimet 25 mg solution for injection in pre-filled syringe

EU/1/16/1124/046 - 1 pre-filled syringe

EU/1/16/1124/047 - multipack: 4 (4 packs of 1) pre-filled syringes

EU/1/16/1124/048 - multipack: 6 (6 packs of 1) pre-filled syringes

EU/1/16/1124/056 - multipack: 12 (12 packs of 1) pre-filled syringes

Date of first authorisation: 18 August 2016

Date of latest renewal: 21 June 2021

Detailed information on this medicinal product is available on the website of the European

Medicines Agency (http://www.ema.europa.eu).