JYLAMVO 2mg / ml oral solution medication leaflet

Jylamvo 2 mg/ml oral solution

One ml of solution contains 2 mg methotrexate.

One ml of solution contains 2 mg methyl hydroxybenzoate (as the sodium salt), and 0.2 mg ethylhydroxybenzoate.

For the full list of excipients, see section 6.1.

Oral solution.

Clear yellow solution.

Jylamvo is for use in the following indications:

In rheumatological and dermatological diseases

* Active rheumatoid arthritis in adult patients.

* Polyarthritic forms of active, severe juvenile idiopathic arthritis (JIA) in adolescents andchildren aged 3 years and over when the response to non-steroidal anti-inflammatory drugs(NSAIDs) has been inadequate.

* Severe, treatment-refractory, disabling psoriasis which does not respond sufficiently to otherforms of treatment such as phototherapy, psoralen and ultraviolet A radiation (PUVA) therapyand retinoids, and severe psoriatic arthritis in adult patients.

In oncology

* Maintenance treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents andchildren aged 3 years and over

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

Rheumatological and dermatological diseases

Important warning about the dosage of Jylamvo (methotrexate)

In the treatment of rheumatological or dermatological diseases, Jylamvo (methotrexate) must only betaken once a week. Dosage errors in the use of Jylamvo (methotrexate) can result in serious adversereactions, including death. Please read this section of the summary of product characteristics verycarefully.

The prescriber should ensure that patients or their carers will be able to comply with the once weeklyregimen.

The prescriber should specify the day of intake on the prescription.

The dose and duration of treatment are determined individually on the basis of the patient’s clinicalpicture and the tolerability of methotrexate. Treatment of active rheumatoid arthritis, severe JIA,severe psoriasis and severe psoriatic arthritis represents a long-term treatment.

A weekly dose of 25 mg (12.5 ml) should not be exceeded. Doses exceeding 20 mg (10 ml)/week canbe associated with a substantial increase in toxicity, especially bone marrow depression.

Concurrent folic acid supplementation of 5 mg twice weekly (except on the day of administration) isindicated additionally.

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg (3.75 ml) methotrexate once weekly.

Depending on the individual activity of the disease and tolerability by the patient, the dose may beincreased gradually by 2.5 mg (1.25 ml) per week.

Response to treatment can be expected after approximately 4-8 weeks.

After the desired treatment outcome is achieved, the dose should be reduced gradually to the lowestpossible effective maintenance dose.

Symptoms may return after treatment discontinuation.

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

Patients with JIA should always be referred to a rheumatology unit specialising in the treatment ofchildren/adolescents.

The recommended dose is 10-15 mg (5-7.5 ml)/m² body surface area (BSA)/week. Intherapy-refractory cases the weekly dosage may be increased to 20 mg (10 ml)/m² BSA/week.

However, an increased monitoring frequency is indicated if the dosage is increased.

Dosage in adults with severe forms of psoriasis and adult patients with psoriatic arthritis

It is recommended that a test dose of 2.5-5 mg (1.25-2.5 ml) be administered one week prior toinitiation of therapy, in order to detect early occurring adverse reactions. If, one week later,appropriate laboratory tests are normal, treatment may be initiated. The recommended initial dose is7.5 mg (3.75 ml) methotrexate once weekly. The dose should be increased gradually but should not, ingeneral, exceed a weekly dose of 25 mg of methotrexate. The usual dose is 10 mg-25 mg (5 ml-12.5 ml) taken once weekly. Doses exceeding 20 mg (10 ml) per week can be associated withsignificant increase in toxicity, especially bone marrow suppression.

Response to treatment can generally be expected after approximately 4-8 weeks. After the desiredtreatment outcome is achieved, the dose should be reduced gradually to the lowest possible effectivemaintenance dose.

Oncology

Dosage in acute lymphoblastic leukaemia

Low-dose methotrexate is used in the maintenance treatment of ALL in children aged 3 years andover, adolescents and adults within complex protocols in combination with other cytostatic medicinalproducts. Treatment should follow current therapy protocols.

Common accepted single doses lie in the range of 20-40 mg (10-20 ml)/m² body surface area.

If methotrexate is administered in combination with chemotherapy regimens, the dosage should takeinto consideration any overlapping toxicity of the other medicinal product components.

Higher dosages should be given parenterally.

Methotrexate should be used with caution in paediatric patients. Treatment should follow currentlypublished therapy protocols for children (see section 4.4).

Doses are usually based on the patient’s BSA and maintenance treatment represents a long-termtreatment.

Methotrexate should be used with caution in patients with impaired renal function (see section 4.4).

The dose should be adjusted as follows for patients with rheumatoid arthritis, juvenile arthritis,psoriasis and psoriatic arthritis. For the oncology indication recommendations in published protocolsshould also apply.

Creatinine clearance % of dose to be administered(ml/min)>60 10030- 59 50<30 Jylamvo must not be administered.

Methotrexate should be administered only with the greatest caution, if at all, in patients withsignificant existing or previous liver disease, especially if due to alcohol. If bilirubin levels are>5 mg/dl (85.5 µmol/l), methotrexate is contraindicated (see sections 4.3 and 4.4).

Use in children under 3 years of age is not recommended as insufficient data on efficacy and safety areavailable for this patient group

Dose reduction should be considered in elderly patients (65 years and over) due to reduced liver andkidney function as well as low folic acid reserves which occur with increased age. In addition, closemonitoring of patients for possible early signs of toxicity is recommended (see sections 4.4, 4.5, pct. 4.8and 5.2).

Patients with pathological fluid accumulations (pleural effusion, ascites)

As the half-life of methotrexate can be prolonged four-fold in patients with pathological fluidaccumulations, it may be necessary to reduce the dose and in some cases even to discontinuemethotrexate (see sections 4.4 and 5.2). The amount of dose reduction should be decided on a case bycase basis.

Jylamvo is for oral use only.

The medicinal product can be taken with or without food.

The solution is provided ready for use, and it must be swallowed with some water to remove anymethotrexate residue from the oral cavity.

A 10 ml oral dosing syringe is provided for accurate measurement of the prescribed dose (see Package

Leaflet).

If the oral route is ineffective, a change to a parenteral dosage form is indicated. This can be done withmethotrexate as an intramuscular or subcutaneous administration and is recommended for patientswho exhibit inadequate absorption of the oral form of methotrexate or who do not tolerate oraladministration well.

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

* Hepatic impairment (bilirubin levels are >5 mg/dl [85.5 µmol/l], see section 4.2)

* Alcohol abuse

* Severe renal impairment (creatinine clearance less than 30 ml/min, see section 4.2)

* Pre-existing blood disorders such as bone marrow hypoplasia, leukopenia, thrombocytopenia orsignificant anaemia

* Immunodeficiency

* Severe, acute or chronic infections such as tuberculosis and HIV

* Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcers

* Breast-feeding (see section 4.6)

* Concurrent vaccination with live vaccines

Additionally for non-oncological indications

* Pregnancy (see section 4.6)

The oral solution contains 2 mg of methotrexate in each ml of solution; the scaling of the dosingsyringe is in ml and not mg; care should be taken that the correct dosing volume is prescribed.

Patients with rheumatological or dermatological diseases must be informed unequivocally thattreatment is to be taken just once a week and not daily. Incorrect use of methotrexate can result insevere and even fatal adverse reactions. Medical staff and patients must be clearly instructed.

The prescriber should specify the day of intake on the prescription.

The prescriber should make sure patients understand that Jylamvo (methotrexate) should only be takenonce a week.

Patients should be instructed on the importance of adhering to the once-weekly intakes.

Patients must be appropriately monitored during treatment so that signs of possible toxic effects oradverse reactions can be detected and evaluated with minimal delay.

Therefore, methotrexate should only be administered by, or under the supervision of, doctors whoseknowledge and experience includes treatment with antimetabolites.

Especially strict monitoring of the patient is indicated following prior radiotherapy (especially of thepelvis), functional impairment of the haematopoietic system (e.g., following prior radio- orchemotherapy), impaired general condition as well as advanced age and in very young children.

Because of the possibility of severe or even fatal toxic reactions, patients should be extensivelyinformed by the treating doctor of the risks involved (including early signs and symptoms of toxicity)and the recommended safety measures. Patients should be informed that they must notify the doctorimmediately if any symptoms of an overdose occur and that the symptoms of the overdose need to bemonitored (including regular laboratory tests).

Doses exceeding 20 mg (10 ml)/week can be associated with a substantial increase in toxicity,especially bone marrow depression.

Because of the delayed excretion of methotrexate in patients with impaired kidney function, theyshould be treated with particular caution and only with low doses of methotrexate (see section 4.2).

Methotrexate should be used only with great caution, if at all, in patients who have a significant liverdisease, particularly if this is/was alcohol-related.

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

Teratogenicity - Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, thepossible effects on reproduction, pregnancy loss and congenital malformations should be discussedwith female patients of childbearing age (see section 4.6).

In non-oncologic indications, the absence of pregnancy must be confirmed before Jylamvo is used. Ifwomen of child bearing potential are treated, effective contraception must be used during treatmentand for at least six months after.

For contraception advice for men see section 4.6.

Recommended examinations and safety measures

Before beginning treatment or resuming treatment after a recovery period

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serumalbumin, chest X-ray and renal function tests. If clinically indicated, tuberculosis and hepatitis B and Cshould be excluded.

The tests below must be conducted weekly in the first two weeks, then every two weeks for a month;thereafter, depending on the leucocyte count and the stability of the patient, at least once a monthduring the next six months and then at least every three months.

An increased monitoring frequency should be considered when the dose is increased. In particular,elderly patients should be monitored at short intervals for early signs of toxicity (see section 4.2).

- Examination of the mouth and throat for mucosal changes.

- Complete blood count with differential blood count and platelets. Methotrexate-inducedhaematopoietic suppression may occur abruptly and with apparently safe dosages. Any seriousdecrease in leucocyte or platelet counts indicates the immediate discontinuation of treatmentand appropriate supportive therapy. Patients should be encouraged to report all signs andsymptoms suggestive of infection to their doctor. In patients simultaneously takinghaematotoxic medicinal products (e.g. leflunomide), blood count and platelets should be closelymonitored.

- Liver function tests

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, orliver biopsies.

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/ordecrease in serum albumin may be indicative for severe hepatotoxicity. In the event of apersistent increase in liver enzymes, consideration should be given to reducing the dose ordiscontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormalliver function tests. There are instances in cirrhosis where transaminases are normal. Therefore,non-invasive diagnostic methods for monitoring of liver condition should be considered, inaddition to liver function tests. Liver biopsy should be considered on an individual basis takinginto account the patient’s comorbidities, medical history and the risks related to biopsy. Riskfactors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation ofliver enzymes, history of liver disease, family history of hereditary liver disorders, diabetesmellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolongedmethotrexate treatment.

Additional hepatotoxic medicinal products should not be given during treatment withmethotrexate unless clearly necessary. Alcohol consumption should be avoided (see sections 4.3and 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantlytaking other hepatotoxic medicinal products.

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

- Renal function should be monitored by renal function tests and urinalyses. If serum creatininelevels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min,treatment with methotrexate should not be given (see sections 4.2 and 4.3).

Treatment with moderately high and high doses of methotrexate should not be initiated aturinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pHmonitoring (value greater than or equal to 6.8) for at least the first 24 hours after theadministration of methotrexate is started.

- Respiratory tract examination - patients must be monitored for symptoms of a lung functiondisorder and lung function tests performed if necessary. Lung-related symptoms (particularly adry, non-productive cough) or non-specific pneumonitis that occurs during treatment withmethotrexate can be a sign of potentially dangerous damage and require the discontinuation oftreatment and careful monitoring. Although the clinical presentation is variable, patients withmethotrexate-induced lung diseases typically suffer from fever, cough, dyspnoea orhypoxaemia. A chest X-ray must be taken in order to be able to exclude an infection. Acute orchronic interstitial pneumonia, often in association with blood eosinophilia, may occur anddeaths have been reported. Patients should be informed of the risks of pneumonia and advised tocontact their doctor immediately if they develop a persistent cough or persistent dyspnoea.

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

Methotrexate should be discontinued in patients with pulmonary symptoms and an immediateexamination (including chest X-ray) should be performed to exclude infection and tumours. Ifmethotrexate-induced lung disease is suspected, treatment with corticosteroids should beinitiated and treatment with methotrexate should not be restarted.

Pulmonary symptoms require a rapid diagnosis and discontinuation of methotrexate therapy.

Methotrexate-induced lung diseases such as pneumonitis can occur acutely and at any timeduring treatment, are not always completely reversible and have already been observed at alldoses (including low doses of 7.5 mg (3.75 ml)/week).

Opportunistic infections can occur during treatment with methotrexate, including Pneumocystisjiroveci pneumonia, which can also have a fatal outcome. If a patient develops pulmonarysymptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered.

Particular caution is required in patients with impaired pulmonary function.

Particular caution is also required in the presence of inactive chronic infections (e.g. herpeszoster, tuberculosis, hepatitis B or C) as it is possible that activation of these infections mayoccur.

Renal impairment and patients at risk of renal impairment

As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected inthe presence of renal impairment, which may result in severe adverse reactions.

If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place atshorter intervals. This applies in particular when medicinal products that affect the elimination ofmethotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment ofhaematopoiesis, are administered concomitantly.

If risk factors such as renal function disorders, including mild renal impairment, are present, combinedadministration with NSAIDs is not recommended. Dehydration may also intensify the toxicity ofmethotrexate.(See renal function monitoring)

Immune system

Due to its effect on the immune system, methotrexate may impair the response to vaccinations andaffect the results of immunological tests. Concurrent vaccination using live vaccines should not begiven.

Malignant lymphomas

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapymust be discontinued. If the lymphomas fail to regress spontaneously, cytotoxic treatment must beinitiated.

Pleural effusions or ascites

Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (seesection 4.2).

Conditions that cause dehydration such as vomiting, diarrhoea or stomatitis

Conditions that cause dehydration such as vomiting, diarrhoea or stomatitis can increase toxicity as aresult of raised active substance levels. In this case, treatment with methotrexate must be discontinueduntil the symptoms have disappeared.

It is important to determine any increase in active substance levels within 48 hours of therapy,otherwise irreversible methotrexate toxicity may occur.

Diarrhoea and ulcerative stomatitis may be signs of toxic effects and require the discontinuation oftreatment, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Following the occurrence of haematemesis, black-coloured stools or blood in the stools, treatmentmust be discontinued.

Folic acid supplementation

If acute methotrexate toxicity occurs, patients may require treatment with folinic acid. In patients withrheumatoid arthritis or psoriasis, folic acid or folinic acid supplementation may reduce methotrexatetoxicity, such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes.

It is recommended to check levels of vitamin B12 prior to initiating folic acid supplementation,particularly in adults aged over 50 years, as folic acid intake may mask a vitamin B12 deficiency.

Vitamin products

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives maydecrease the effectiveness of methotrexate (see sections 4.2 and 4.5).

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individualstaking methotrexate (see section 4.8). Exposure to intense sunlight or UV rays should be avoidedunless medically indicated. Patients should use adequate sun-protection to protect themselves fromintense sunlight.

Radiation-induced dermatitis and sunburn can reappear during methotrexate therapy (recall reactions).

Psoriatic lesions can worsen during UV radiation and co-administration of methotrexate.

Skin toxicity

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell’ssyndrome) or Stevens-Johnson syndrome have been reported after single or multiple doses ofmethotrexate.

Encephalopathy/leukoencephalopathy

Since cases of encephalopathy/leukoencephalopathy have occurred in cancer patients treated withmethotrexate, this cannot be ruled out either for patients with non-cancer indications.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receivingmethotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal andshould be considered in the differential diagnosis in immunosuppressed patients with new onset orworsening neurological symptoms.

Excipient warnings

This medicinal product contains sodium methyl parahydroxybenzoate (E219) and ethylparahydroxybenzoate (E214). It may cause allergic reactions (possibly delayed).

The risk of an interaction between NSAIDs and methotrexate should be considered in patients with alow methotrexate dose, particularly in the case of impaired kidney function. If combined treatment isrequired, the blood count and renal function should be monitored. Caution should be exercised if

NSAIDs and methotrexate are administered within 24 hours, since in this case methotrexate plasmalevels can rise and toxicity be increased as a result. Animal studies showed that the administration of

NSAIDs including salicylic acid resulted in reduced tubular methotrexate secretion and accordinglypotentiated its toxic effects. However, in clinical trials in which NSAIDs and salicylic acid wereadministered adjuvantly to patients with rheumatoid arthritis, no increase in adverse reactions wasobserved. Treatment of rheumatoid arthritis with such medicinal products can be continued duringtherapy with low-dose methotrexate, but only under close medical supervision.

Patients taking potentially hepatotoxic medicinal products during treatment with methotrexate (e.g.leflunomide, azathioprine, sulfasalazine and retinoids) should be monitored closely for increasedhepatotoxicity. The consumption of alcohol should be avoided during treatment with methotrexate(see section 4.4). Regular alcohol consumption and administration of additional hepatotoxic medicinalproducts increase the likelihood of hepatotoxic adverse reactions to methotrexate.

Administration of additional haematotoxic medicinal products increases the likelihood of severehaematotoxic 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.

Pharmacokinetic interactions between methotrexate, anticonvulsants (reduced serum methotrexatelevels) and 5-fluoruracil (increased half-life of 5-fluoruracil) must be borne in mind.

Salicylates, phenylbutazone, diphenylhydantoin (= phenytoin), barbiturates, tranquillisers, oralcontraceptives, tetracyclines, amidopyrine derivatives, sulphonamides, thiazide diuretics, oralhypoglycaemics, doxorubicin and p-aminobenzoic acid displace methotrexate from serum albuminbinding and thus increase bioavailability and hence toxicity (indirect dose increase).

Probenecid and weak organic acids can also reduce the tubular secretion of methotrexate and thuslikewise cause an indirect increase in dose.

Antibiotics such as penicillins, glycopeptides, sulphonamides, ciprofloxacin and cefalotin can inindividual cases reduce the renal clearance of methotrexate, so that increased serum methotrexateconcentrations can occur, accompanied by haematological and gastrointestinal toxicity.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibioticsmay reduce intestinal absorption of methotrexate or interfere with the enterohepatic circulation byinhibiting intestinal flora or suppressing bacterial metabolism.

In the event of (prior) treatment with medicinal products that can have adverse reactions on bonemarrow (e.g. sulphonamides, trimethoprim/sulphamethoxazole, chloramphenicol, pyrimethamine), thepossibility of haematopoietic disorders must be considered.

Concomitant therapy with medicinal products that can cause folic acid deficiency (e.g. sulphonamides,trimethoprim/sulphamethoxazole) can result in increased methotrexate toxicity. Accordingly,particular caution should be exercised in patients with pre-existing folic acid deficiency.

Conversely, co-administration of medicinal products containing folinic acid or vitamin preparationscontaining folic acid or derivatives may impair the efficacy of methotrexate.

The combination of methotrexate and sulfasalazine can enhance the effect of methotrexate, assulfasalazine causes inhibition of folic acid synthesis. This can result in an increased risk of adversereactions, although in several studies this was only observed in individual patients.

Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessiveimmunosuppression with risk of lymphoproliferation when the combination is used.

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yieldingincreased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case ofintrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can bereduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexateshould be avoided.

Co-administration of proton pump inhibitors such as omeprazole or pantoprazole can result ininteractions: co-administration of methotrexate and omeprazole has resulted in delayed renalelimination of methotrexate. In one case in which methotrexate was combined with pantoprazole,renal elimination of the metabolite 7-hydroxymethotrexate was inhibited and myalgia and shiveringoccurred.

The application of procarbazine during high-dose methotrexate therapy increases the risk ofimpairment or renal function

Excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeinatedbeverages, black tea) should be avoided during methotrexate therapy as the effect of methotrexate maybe reduced by the possible interaction between methotrexate and methylxanthines at the adenosinereceptors.

Combination therapy with methotrexate and leflunomide may increase the risk for pancytopenia.

Particularly in the case of orthopaedic surgery where the risk of infection is high, combination therapywith methotrexate and immunomodulatory medicinal products must be used with caution.

Cholestyramine can increase the non-renal elimination of methotrexate by interfering with theenterohepatic circulation.

The possibility of delayed methotrexate clearance should be considered in combination with othercytostatic medicinal products.

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

Methotrexate can reduce the clearance of theophylline. During concomitant therapy withmethotrexate, therefore, serum theophylline levels should be monitored.

Combined administration of mercaptopurine and methotrexate can increase the bioavailability ofmercaptopurine, possibly as a result of inhibition of the metabolism of mercaptopurine.

In view of its possible effects on the immune system, methotrexate can falsify vaccinal and test results(immunological procedures to assess the immune reaction). During methotrexate therapy, concurrentvaccination with live vaccines should be avoided (see sections 4.3 and 4.4).

Women must not get pregnant during methotrexate therapy, and effective contraception must be usedduring treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiatingtherapy, women of childbearing potential must be informed of the risk of malformations associatedwith methotrexate and any existing pregnancy must be excluded with certainty by taking appropriatemeasures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinicallyrequired (e.g. after any gap of contraception). Female patients of reproductive potential must becounselled 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 be excluded.

Limited clinical evidence does not indicate an increased risk of malformations or miscarriagefollowing paternal exposure to low-dose methotrexate (less than 30 mg [15 ml]/week). For higherdoses, there is insufficient data to estimate the risks of malformations or miscarriage followingpaternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended touse reliable contraception during treatment of the male patient and for at least 3 months after cessationof 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). Ifpregnancy occurs during treatment with methotrexate and up to six months thereafter, medical adviceshould be given regarding the risk of harmful effects on the child associated with treatment andultrasonography examinations should be performed to confirm normal foetal development. In animalstudies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetaldeath, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervoussystem 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 [15 ml]/week), compared to a reported rate of 22.5% indisease-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 [15 ml]/week) during pregnancy, compared to approximately 4% of livebirths in disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than30 mg (15 ml)/week, but higher rates of spontaneous abortions and congenital malformations areexpected, in particular at doses commonly used in oncologic indications

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

When used in oncological indications, methotrexate should not be administered during pregnancy inparticular during the first trimester of pregnancy. In each individual case the benefit of treatment mustbe weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if thepatient becomes pregnant while taking methotrexate the patient should be informed of the potentialrisk to the foetus.

As methotrexate passes into breast milk and may cause toxicity in breast-fed children, treatment iscontraindicated during the lactation period (see section 4.3). If use during the lactation period shouldbecome necessary, breast-feeding is to be stopped prior to treatment.

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans,methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. Theseeffects appear to be reversible after discontinuation of therapy in most cases. In oncologic indications,women who are planning to become pregnant are advised to consult a genetic counselling centre, ifpossible, prior to therapy and men should seek advice about the possibility of sperm preservationbefore starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).

Methotrexate has moderate influence on the ability to drive and use machines, since central nervoussystem disorders such as tiredness, dizzy spells or drowsiness can occur during treatment.

In general, the incidence and severity of side effects are considered to be dose-related.

In the antineoplastic treatment, myelosuppression and mucositis are the predominant dose-limitingtoxic effects of methotrexate. The severity of these reactions depends on the dose, mode and durationof application of methotrexate. Mucositis generally appears about 3 to 7 days after methotrexateapplication, leucopenia and thrombocytopenia follow a few days later. In patients with unimpairedelimination mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28days.

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 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 reactions areleukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitialalveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythemaand pruritus.

The occurrence and severity of adverse reactions depend on dosage level and frequency ofadministration of methotrexate. However, as severe adverse reactions may occur even at low doses, itis essential for the treating physician to monitor patients closely (see section 4.4).

Most adverse reactions are reversible if they are detected early. If such adverse reactions occur, thedose should either be reduced or treatment discontinued and appropriate countermeasures taken (seesection 4.9). Methotrexate therapy should only be resumed with particular caution, after carefulconsideration of the need for treatment and with increased vigilance for the possible recurrence oftoxicity.

Frequencies in the table are defined according to the MedDRA 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.

System organ Very Common Uncommon Rare Very rare Not knownclass common

Infections and Infections Opportunistic Herpes zoster Sepsis Nocardiosis,infestations infections Cytomegalovirus- Histoplasma(sometimes fatal) induced infections. andcryptococcusmycosis,

Disseminatedherpes simplex

Neoplasms Lymphoma1benign,malignant andunspecified(including cystsand polyps)

Blood and Leucocytopenia, Pancytopenia, Megaloblastic Bone marrow Haemorrhageslymphatic Thrombo- Agranulocytosis, anaemia depression (severesystem cytopenia, Haematopoietic courses),disorders Anaemia disorders Aplastic anaemia,

Lymphoproliferativedisorder2,

Eosinophilia,

Neutropenia,

Lymphadenopathy

Immune system Allergic reactions, Immuno-disorders Anaphylactic suppression,shock, Allergic vasculitis

Fever, (severe toxic

Chills symptom),

Hypogamma-globulinaemia

Metabolism and Diabetes mellitusnutritiondisorders

Psychiatric Depression Mood swings Insomniadisorders

Nervous system Headache, Convulsions, Hemiparesis, Cerebral oedema, Encephalop-disorders Fatigue, Vertigo, Paresis Acute aseptic athy/

Drowsiness Confusion meningitis with Leukoenceph-meningism alopathy(paralysis, vomiting),

Lethargy,

Transient subtlecognitivedysfunction,

Psychoses,

Aphasia,

Pain,

Muscularasthenia,Paraesthesia/hypoaesthesia,

Taste changes(metallic taste),

Irritation,

Dysarthria,

Unusual cranialsensations,

Tinnitus

Eye disorders Severe visual Retinopathy,disturbances Conjunctivitis

Cardiac Pericarditis,disorders Pericardialeffusion,

Pericardialtamponade

Vascular Thromboembolicdisorders reactions(including arterialand cerebralthrombosis,thrombophlebitis,deep leg veinthrombosis,retinal veinthrombosis,pulmonaryembolism),

Respiratory, Interstitial Pulmonary Respiratory Pneumocystis Pulmonarythoracic and alveolitis/ fibrosis paralysis, jiroveci pneumonia alveolarmediastinal pneumonia (can Bronchial and other lung haemorrhage3disorders be fatal) asthma-like infections,reactions such as Chronic obstructivecough, dyspnoea pulmonary disease,and pathological Pleural effusionchanges in lungfunction tests,

Pharyngitis

Gastrointestinal Loss of Diarrhoea Ulceration and Pancreatitis, Toxic megacolon,disorders appetite, bleeding of Enteritis, Haematemesis

Nausea, gastrointestinal Malabsorption,

Vomiting, tract Melaena,

Abdominal Gingivitispain,

Inflammationandulceration ofmucosa ofmouth andthroat,

Stomatitis,

Dyspepsia

Hepatobiliary Increase in Hepatic steatosis, Acute hepatitis Acute liver Hepatitis anddisorders liver-related fibrosis and and hepatotoxicity degeneration, liver failure4enzymes cirrhosis, Liver failure,(ALAT Decrease in serum Reactivation of[GPT], albumin chronic hepatitis,

ASAT[GOT],alkalinephosphataseandbilirubin)

Skin and Erythema, Severe toxic Increased nail Acute paronychia, Skinsubcutaneous Exanthema, manifestations: pigment changes, Furunculosis, exfoliation/tissue disorders Pruritus vasculitis, Onycholysis, Telangiectasis, dermatitisherpetiform skin Acne, Hidradenitis exfoliativeeruptions, Petechiae,

Stevens-Johnson Bruising,syndrome, toxic Erythemaepidermal multiforme,necrolysis (Lyell’s Cutaneoussyndrome), erythematous

Increased eruptions,rheumatic Lesions ofnodules, psoriasis may

Painful erosions worsen withof psoriatic concomitant UVplaque, therapy,

Photosensitivity Radiationreactions, dermatitis and

Increased skin sunburn may bepigmentation, “recalled”

Hair loss,

Impaired woundhealing,

Urticaria

Musculoskeletal Osteoporosis, Stress fracture Osteonecrosisand connective Arthralgia, of jawtissue disorders Myalgia, (secondary tolymphoprolifer

- ativedisorders)

Renal and Nephropathy Renal failure, Proteinuriaurinary Inflammation and Oliguria,disorders ulceration of Anuria,urinary bladder Azotaemia(possibly withhaematuria),

Dysuria

Reproductive Vaginal Oligospermia, Infertility,system and Inflammation and Menstrual Loss of libido,breast disorders ulceration dysfunction Impotence,

Vaginal discharge,

Gynaecomastia

General Fever Oedemadisorders andadministrationsite conditions1 can be reversible - see 4.42 Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and otherlymphoproliferative disorders which subsided in a number of cases once treatment with methotrexate had been discontinued.3 has been reported for methotrexate used in rheumatologic and related indications4 see remarks on liver biopsy in section 4.4

Frequency, type and severity of adverse reactions in children and adolescents are expected to be thesame as in adults.

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 symptoms following oral overdose predominantly affect the haematopoietic and gastrointestinalsystems.

Symptoms include leucocytopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia,myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulcerationand bleeding.

Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead ofweekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported arehematological and gastrointestinal reactions.

There are reports of deaths from sepsis, septic shock, renal failure and aplastic anaemia.

Therapeutic management 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 offending doseof methotrexate should be administered intravenously or intramuscularly within 1 hour, and dosingcontinued until serum level of methotrexate are below 10-7 mol/L.

In the event of a massive overdose, hydration and alkalinisation of the urine may be required toprevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysisnor peritoneal dialysis has been shown to improve the elimination of methotrexate. Effective clearanceof methotrexate is reported to be achieved with acute intermittent haemodialysis using a high-fluxdialyser.

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

Methotrexate is a folic acid antagonist that, as an antimetabolite, belongs to the class of cytotoxicactive substances. It acts by competitive inhibition of the enzyme dihydrofolate reductase and thusinhibits DNA synthesis.

It has not yet been possible to date to clarify whether the efficacy of methotrexate in the managementof psoriasis, psoriatic arthritis and chronic polyarthritis is due either to an anti-inflammatory orimmunosuppressive effect, or to what extent a methotrexate-induced increase in extracellularadenosine concentration at inflamed sites contributes to this effect.

Highly proliferating tissue such as malignant cells, bone marrow, foetal cells, skin epithelium andmucosa is generally more sensitive to this effect of methotrexate. Cell proliferation is usually greaterin malignant tumours than in normal tissue and methotrexate can therefore exert a sustained effect onmalignant growth without causing irreversible damage to normal tissue.

In psoriasis, cell proliferation of the epithelium is markedly increased compared with normal skin.

This difference in cell proliferation rate is the starting point for the use of methotrexate in particularlysevere, generalised, treatment-resistant psoriasis and psoriatic arthritis.

After oral administration, methotrexate is absorbed from the gastrointestinal tract. When administeredin low doses (7.5 mg/m2 to 80 mg/m2 body surface area), the mean bioavailability of methotrexate isapproximately 70%, but considerable inter- and intra-individual variations are possible (25-100%).

Peak serum concentrations are attained within 1-2 hours.

Data from a randomised trial in patients with juvenile rheumatoid arthritis (aged 2.8 to 15.1 years)indicated greater oral bioavailability of methotrexate in the fasting state. In children with JIA, the dosenormalized area under the plasma concentration versus time-curve (AUC) of methotrexate increasedwith the age of the children and was lower than that found in adults. The dose normalized AUC of themetabolite 7-hydroxymethotrexate was not dependent on age.

Methotrexate is approximately 50% bound to serum proteins. After distribution, it collectspredominantly in the liver, kidneys and spleen in the form of polyglutamates, which can be retainedfor weeks or months.

The mean terminal half-life is 6-7 hours and demonstrates considerable variations (3-17 hours). Thehalf-life may be prolonged up to four-fold in patients with a third distribution compartment (pleuraleffusion, ascites).

Approximately 10% of the administered methotrexate dose is metabolised in the liver. The mainmetabolite is 7-hydroxymethotrexate.

Excretion occurs predominantly in the unchanged form by glomerular filtration and active secretion inthe proximal tubule via the kidneys.

Approximately 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is eliminated in the bile.

There is a pronounced enterohepatic circulation.

Elimination in patients with impaired renal function is markedly delayed. Impaired elimination inpatients with hepatic impairment is not known at present.

Methotrexate crosses the placental barrier in rats and monkeys.

Chronic toxicity

In chronic toxicity studies in mice, rats and dogs, toxic effects were seen in the form of gastrointestinallesions, myelosuppression and hepatotoxicity.

Long-term studies in rats, mice and hamsters revealed no evidence of a tumorigenic potential ofmethotrexate. Methotrexate induces gene and chromosomal mutations in vitro and in vivo. There is asuspected mutagenic effect in humans.

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

Macrogol 400

Glycerol

Orange flavour

Sucralose

Ethyl parahydroxybenzoate (E214)

Sodium methyl parahydroxybenzoate (E219)

Citric acid monohydrate

Tri-sodium citrate

Purified water

Not applicable.

Unopened bottle18 months.

After first opening3 months.

Do not store above 25ºC.

Keep the bottle tightly closed (see section 6.6).

75 ml amber type III glass bottle with tamper evident child-resistant closure (polypropylene withexpanded polyethylene liner) containing 60 ml of oral solution.

Each pack contains one bottle, an LDPE bottle adaptor and a 10 ml white polypropylene dosingsyringe (with major graduations at every 1 ml and minor graduations at every 0.25 ml).

Safe handling

Anyone handling methotrexate should wash their hands before and after administering a dose. Todecrease the risk of exposure, parents and care givers should wear disposable gloves when handlingmethotrexate.

Contact with the skin or mucous membrane must be avoided. If methotrexate comes into contact withskin or mucosa, it should be washed immediately and thoroughly with soap and water.

Spillages must be wiped immediately.

Women who are pregnant, planning to be or breast-feeding should not handle methotrexate.

Parents, care givers and patients should be advised to keep methotrexate out of the reach of children,preferably in a locked cupboard.

Accidental ingestion can be lethal for children.

Keep the bottle tightly closed to protect the integrity of the product and minimise the risk of accidentalspillage.

The usual caution should be exercised in handling cytostatics.

Instructions for use of the syringe provided in the pack1. Put on disposable gloves before handling.2. Shake the bottle.3. Remove the bottle cap and push the adaptor firmly into the top of the bottle.4. Push the tip of the dosing syringe into the hole in the adaptor.5. Turn the bottle upside down.6. Pull the syringe plunger back SLOWLY so that the medicine is drawn from the bottle into thesyringe until the WIDEST part of the white syringe plunger is lined up to the black syringemarking of the dose required. DO NOT measure to the narrow tip of the plunger. If there areair bubbles in the syringe, repeat until bubbles are eliminated.

7. Turn the bottle back the right way up and carefully remove the syringe from the adaptor,holding the syringe by the barrel rather than the plunger.

8. Confirm that the dose in the syringe is correct.9. Ensure that the patient is sitting up or standing before giving the medicine.10 Gently place the tip of the syringe into the patient’s mouth and direct it to the inside of thecheek.11. Slowly and gently push the plunger down to gently squirt the medicine into the inside of thecheek. DO NOT push down the plunger too hard or squirt the medicine to the back of the mouthor throat as this may cause choking. The plunger should be pushed back gently to the seatedposition until it clicks into place.

12. Remove the syringe from the patient’s mouth.13. Ask the patient to swallow the medicine and then to drink some water, making sure no medicineis left in the mouth.14. Put the cap back on the bottle with the adaptor left in place. Ensure that the cap is tightly closed.15. Wash the syringe immediately after use with fresh warm, soapy water and rinse well. Thesyringe should be held under water and the plunger drawn in and out several times until alltraces of medicine are removed from inside the syringe including the tip. The plunger and barrelshould then be separated and both washed thoroughly in the warm soapy water. They shouldthen be rinsed thoroughly under COLD water and excess water shaken off before wiping drywith a clean paper towel. The plunger and barrel should be stored in a clean dry container withthe medicine and reassembled before next use. All parts of the syringe should be completely drybefore using it for the next dose.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements for cytotoxic products.

Oresund Pharma ApS

Orient Plads 12150 Nordhavn

Denmark

EU/1/17/1172/001

Date of first authorisation: 29 March 2017

Date of latest renewal: 22 November 2021

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

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