Namaxir 25 mg Injektionsvätska, lösning i förfylld spruta

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

21-04-2018

Aktiva substanser:
metotrexat
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
L04AX03
INN (International namn):
methotrexate
Dos:
25 mg
Läkemedelsform:
Injektionsvätska, lösning i förfylld spruta
Sammansättning:
metotrexat 25 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Förfylld spruta, 4 x 1 st (med fast injektionsnål) (med automatiskt nålskydd och spritsudd); Förfylld spruta, 1 st (med fast injektionsnål) (med automatiskt nålskydd och spritsudd); Förfylld spruta, 1 st (med fast injektionsnål) (med automatiskt nålskydd); Förfylld spruta, 1 st (med fast injektionsnål) (med spritsudd); Förfylld spruta, 1 st (med fast injektionsnål); Förfylld spruta, 4 x 1 st (med fast injektionsnål) (med automatiskt nålskydd); Förfylld spruta, 4 x 1 st (med fast injektionsnål) (med spritsudd); Förfylld spruta, 4 x 1 st (med fast injektionsnål)
Bemyndigande status:
Godkänd
Godkännandenummer:
52555
Tillstånd datum:
2015-11-12

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Namaxir 2.5 mg solution for injection in pre-filled syringe

Namaxir 7.5 mg solution for injection in pre-filled syringe

Namaxir 10 mg solution for injection in pre-filled syringe

Namaxir 12.5 mg solution for injection in pre-filled syringe

Namaxir 15 mg solution for injection in pre-filled syringe

Namaxir 17.5 mg solution for injection in pre-filled syringe

Namaxir 20 mg solution for injection in pre-filled syringe

Namaxir 22.5 mg solution for injection in pre-filled syringe

Namaxir 25 mg solution for injection in pre-filled syringe

Namaxir 27.5 mg solution for injection in pre-filled syringe

Namaxir 30 mg solution for injection in pre-filled syringe

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Namaxir 2.5 mg:

Each pre-filled syringe of 0.33 ml contains 2.5 mg methotrexate.

Namaxir 7.5 mg:

Each pre-filled syringe of 0.30 ml contains 7.5 mg methotrexate.

Namaxir 10 mg:

Each pre-filled syringe of 0.40 ml contains 10 mg methotrexate.

Namaxir 12.5 mg:

Each pre-filled syringe of 0.31 ml contains 12.5 mg methotrexate.

Namaxir 15 mg:

Each pre-filled syringe of 0.38 ml contains 15 mg methotrexate.

Namaxir 17.5 mg:

Each pre-filled syringe of 0.44 ml contains 17.5 mg methotrexate.

Namaxir 20 mg:

Each pre-filled syringe of 0.50 ml contains 20 mg methotrexate.

Namaxir 22.5 mg:

Each pre-filled syringe of 0.56 ml contains 22.5 mg methotrexate.

Namaxir 25 mg:

Each pre-filled syringe of 0.63 ml contains 25 mg methotrexate.

Namaxir 27.5 mg:

Each pre-filled syringe of 0.69 ml contains 27.5 mg methotrexate.

Namaxir 30 mg:

Each pre-filled syringe of 0.75 ml contains 30 mg methotrexate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (solution for injection).

Clear, yellowish-orange solution free from visible particles.

Osmolality: 280 – 320 mOsm/kg.

pH: 7.0 – 9.0.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Namaxir is indicated for the treatment of

active rheumatoid arthritis in adult patients,

polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to

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

severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of

therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult

patients,

mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult

patients refractory or intolerant to thiopurines.

4.2

Posology and method of administration

Important warning about the dosage of Namaxir (methotrexate)

In the treatment of arthritis, psoriasis and Crohn’s disease, Namaxir (methotrexate)

must only be used

once a week.

Dosage errors in the use of Namaxir (methotrexate) can result in serious adverse

reactions, including death. Please read this section of the summary of product characteristics very

carefully.

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a

full understanding of the risks of methotrexate therapy. The administration should routinely be done

by health professionals. If the clinical situation permits the treating physician can, in selected cases,

delegate the subcutaneous administration to the patient her/himself. When self-administering

methotrexate patients must be educated and trained in the proper injection technique. The first

injection of Namaxir should be performed under direct medical supervision.

Namaxir is injected

once weekly

The patient is to be explicitly informed about the fact of administration

once weekly

. It is advisable to

determine a fixed, appropriate weekday as day of injection.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural

effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction

or, in some cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate

once weekly

, administered subcutaneously.

Depending on the individual activity of the disease and tolerability by the patient, the initial dose may

be increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be

exceeded. However, doses exceeding 20 mg/week are associated with significant increase in toxicity,

especially bone marrow suppression

.

Response to treatment can be expected after approximately 4 –

8 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to

the lowest possible effective maintenance dose.

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

arthritis

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

once weekly,

administered

subcutaneously. In therapy-refractory cases the weekly dosage may be increased up to 20 mg/m

body

surface area/

once weekly

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

increased.

Patients with JIA should always be referred to a rheumatology specialist

in the treatment of

children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is

available for this population (see section 4.4).

Dosage in patients with psoriasis vulgaris and psoriatic arthritis

It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to

therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of

methotrexate

once weekly

, administered subcutaneously. The dose is to be increased gradually but

should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per

week can be associated with significant increase in toxicity, especially bone marrow suppression.

Response to treatment can generally be expected after approximately 2 – 6 weeks. Upon achieving the

therapeutically desired result, the dose should be reduced gradually to the lowest possible effective

maintenance dose.

Dosage in patients with Crohn’s disease

Induction treatment:

25 mg/week administered subcutaneously.

Response to treatment can be expected after approximately 8 to 12 weeks.

Maintenance treatment:

15 mg/week administered subcutaneously.

There is not sufficient experience in the paediatric population to recommend Namaxir for the

treatment of Crohn’s disease in this population.

Maximum weekly dose

The dose should be increased as necessary but should in general not exceed the maximum

recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically

justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will

markedly increase.

Patients with renal impairment

Namaxir should be used with caution in patients with impaired renal function. The dose should be

adjusted as follows:

Creatinine clearance (ml/min)

Dose

≥ 60

100 %

30 – 59

50 %

< 30

Namaxir must not be used

See section 4.3.

Patients with hepatic impairment

Methotrexate should be administered with great caution, if at all, to patients with significant current or

previous liver disease, especially if due to alcohol. If bilirubin is

5 mg/dl (85.5 µmol/l), methotrexate

is contraindicated.

For the full list of contraindications, see section 4.3.

Use in elderly patients

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as

well as lower folate reserves which occur with increased age.

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

As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess

a third distribution space dose reduction or, in some cases, discontinuation of methotrexate

administration may be required (see section 5.2 and 4.4).

Method of administration

The medicinal product is for single use only.

Namaxir solution for injection can be given by subcutaneous route.

The overall duration of the treatment is decided by the physician.

For additional instructions for use and other handling see section 6.6.

Note:

If changing from oral application to parenteral administration a reduction of the dose may be required

due to the variable bioavailability of methotrexate after oral administration.

Folic acid supplementation may be considered according to current treatment guidelines.

4.3

Contraindications

Namaxir is contraindicated in the case of

hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

severe liver impairment (see section 4.2),

alcohol abuse,

severe renal impairment (creatinine clearance less than 30 ml/min., see section 4.2 and

section 4.4),

pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia,

or significant anaemia,

serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency

syndromes,

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

pregnancy and breast-feeding (see section 4.6),

concurrent vaccination with live vaccines (see sections 4.4 and 4.5).

4.4

Special warnings and precautions for use

Patients must be clearly informed that the therapy has to be administered

once a week

, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic

effects or adverse reactions may be detected and evaluated with minimal delay. Therefore

methotrexate should be only administered by, or under the supervision of physicians whose knowledge

and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even

fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the

recommended safety measures.

Recommended examinations and safety measures

Before beginning or reinstituting methotrexate therapy after a rest period:

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum

albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (at least once a month during the first six months and every three months thereafter):

An increased monitoring frequency should be considered also when the dose is increased.

Examination of the mouth and throat for mucosal changes

Complete blood count with differential blood count and platelets. Haemopoietic suppression

caused by methotrexate may occur abruptly and with apparently safe doses. Any profound drop

in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and

appropriate supportive therapy. Patients should be advised to report all signs and symptoms

suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal

products (e.g. leflunomide) should be monitored closely with blood count and platelets.

Liver function tests: Particular attention should be given to the appearance of liver toxicity.

Treatment should not be instituted or should be discontinued if any abnormality of liver

function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should

return to normal within two weeks after which treatment may be recommenced at the discretion

of the physician. There is no evidence to support use of a liver biopsy to monitor hepatic

toxicity in rheumatological indications.

For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial.

Further research is needed to establish whether serial liver chemistry tests or propeptide of

type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case

by case and differentiate between patients with no risk factors and patients with risk factors such

as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver

disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of

significant exposure to hepatotoxic drugs or chemicals and prolonged methotrexate treatment or

cumulative doses of 1.5 g or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or

three times of the upper limit of normal have been reported by patients at a frequency of

13-20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or

discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should

not be taken during treatment with methotrexate

unless clearly necessary

and the consumption

of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver

enzymes should be exercised in patients taking other hepatotoxic medicinal products

concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous

administration of haematotoxic medicinal products (e.g. leflunomide).

Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2

and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be

expected in the case of renal impairment, which may result in severe undesirable effects.

Where renal function may be compromised (e.g. in the elderly), monitoring should take place

more frequently. This applies in particular, when medicinal products are administered

concomitantly, that affect the elimination of methotrexate, cause kidney damage (e.g. non-

steroidal anti-inflammatory medicinal products) or that can potentially lead to impairment of

blood formation. Dehydration may also intensify the toxicity of methotrexate.

Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if

necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation

of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-

specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially

dangerous lesion and require interruption of treatment and careful investigation. Acute or

chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths

have been reported. Although clinically variable, the typical patient with methotrexate-induced

lung disease presents with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray,

infection needs to be excluded. Pulmonary affection requires a quick diagnosis and

discontinuation of methotrexate therapy. This lesion can occur at all doses.

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in

rheumatologic and related indications. This event may also be associated with vasculitis and

other comorbidities. Prompt investigations should be considered when pulmonary alveolar

haemorrhage is suspected to confirm the diagnosis.

Methotrexate may, due to its effect on the immune system, impair the response to vaccination

results and affect the result of immunological tests. Particular caution is also needed in the

presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for

reasons of eventual activation. Vaccination using live vaccines must not be carried out under

methotrexate therapy (see sections 4.3 and 4.5).

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy

must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the

initiation of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been

reported to cause an acute megaloblastic pancytopenia in rare instances (see section 4.5).

Radiation induced dermatitis and sunburn can reappear under methotrexate therapy (recall-reaction).

Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of

methotrexate.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural

effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction

or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should

be drained prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise

haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may

decrease the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling

psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis

has been established by biopsy and/or after dermatological consultation.

Encephalopathy/leukoencephalopathy have been reported in oncologic patients receiving methotrexate

therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

Fertility and reproduction

Fertility

Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in

humans, during and for a short period after cessation of therapy, and to cause impaired fertility,

affecting spermatogenesis and oogenesis during the period of its administration – effects that appear to

be reversible on discontinuing therapy.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible

risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed

with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be

confirmed before Namaxir is used. If women of a sexually mature age are treated, effective

contraception must be performed during treatment and for at least six months after.

For contraception advice for men see section 4.6.

Paediatric population

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are

available for this population (see section 4.2).

Excipient(s)

Sodium

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

‘sodium-free ’.

4.5

Interaction with other medicinal products and other forms of interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products

The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol

consumption and when other hepatotoxic medicinal products are taken at the same time (see

section 4.4). Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide)

should be monitored with special care. The same should be taken into account with the simultaneous

administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids,

sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide

is combined with methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of

hepatotoxicity.

Medicinal products with adverse reactions on the bone marrow

In the case of medication with medicinal products, which may have adverse reactions on the bone

marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine);

attention should be paid to the possibility of pronounced impairment of blood formation.

Interactions affecting the use of this medicinal product

Interactions which may increase methotrexate levels:

Nitrous oxide

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding

increased toxicity such as severe unpredictable myelosuppression and stomatitis. Whilst this effect can

be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate

should be avoided.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in

individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of

methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding

Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal

products such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins,

tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents,

which can lead to increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the

elimination of methotrexate and higher serum concentrations may be assumed inducing higher

haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate

and non-steroidal anti-inflammatory medicinal products or salicylates are combined.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulphonamides,

trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is

therefore advisable in the presence of existing folic acid deficiency.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to

interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal

elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the

metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Sulfasalazine

Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of

methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis

through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the

course of several studies.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Namaxir is

administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds,

penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, ciclosporin).

Interactions which may decrease methotrexate levels:

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may

decrease the effectiveness of methotrexate.

Caffeine- or theophylline-containing beverages

An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-

containing soft drinks, black tea) should be avoided during methotrexate therapy as the effect of

methotrexate may be reduced by the possible interaction between methotrexate and methylxanthines at

the adenosine receptors.

Other interactions:

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics

can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of

the bacterial metabolism.

Interactions affecting the use of other medicinal products

Live vaccines

In view of its possible effects on the immune system, methotrexate can falsify vaccinal and test results

(immunological procedures to assess the immune reaction). Vaccination using live vaccines must not

be carried out under methotrexate therapy (see sections 4.3 and 4.4).

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and

mercaptopurine may therefore require dose adjustment.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored

when used concurrently with methotrexate.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used

during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating

therapy, women of childbearing potential must be informed of the risk of malformations associated

with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate

measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically

required (e.g. after any gap of contraception). Female patients of reproductive potential must 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 in

animal 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 miscarriage

following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there

is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to

use reliable contraception during treatment of the male patient and for at least 6 months after cessation

of methotrexate. Men should not donate semen during therapy or for 6 months following

discontinuation of methotrexate.

Pregnancy

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, medical advice

should be given regarding the risk of harmful effects on the child associated with treatment and

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 be teratogenic to humans; it has been reported to

cause foetal death, miscarriages 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-dose

methotrexate 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 methotrexate

treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live

births in in 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.

Breast-feeding

As methotrexate passes into breast milk and may cause toxicity in breast-fed children, treatment is

contraindicated during the lactation period (see section 4.3). If use during the lactation period should

become necessary, breast-feeding is to be stopped prior to treatment.

Fertility

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.

4.7

Effects on ability to drive and use machines

Central nervous symptoms such as tiredness (commonly) and dizziness (uncommonly) can occur

during treatment, Namaxir has minor or moderate influence on the ability to drive and use machines.

Patients should be instructed to be cautious when starting treatment with Namaxir and if affected,

avoid potentially hazardous tasks such as driving and operating machines.

4.8

Undesirable effects

Summary of the safety profile

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity,

hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-

Johnson syndrome.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal

disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver

function tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently

(common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness,

drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral

ulcers, diarrhoea, exanthema, erythema and pruritus.

The most relevant undesirable effects are suppression of the haematopoietic system and

gastrointestinal disorders.

Tabulated list of adverse reactions

The following headings are used to organise the undesirable effects in order of frequency:

Very common (

1/10), common (

1/100 to <1/10), uncommon (

1/1,000 to <1/100), rare (

1/10,000

to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations

Uncommon:

Pharyngitis

Rare:

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

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

Very rare:

Lymphoma (see “description” below)

Blood and lymphatic system disorders

Common:

Leukopenia, anaemia, thrombopenia

Uncommon:

Pancytopenia

Very rare:

Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative

disorders (see “description” below)

Not known:

Eosinophilia

Immune system disorders

Rare:

Allergic reactions, anaphylactic shock, hypogammaglobulinaemia

Metabolism and nutrition disorders

Uncommon:

Precipitation of diabetes mellitus

Psychiatric disorders

Uncommon:

Depression, confusion

Rare:

Mood alterations

Nervous system disorders

Common:

Headache, tiredness, drowsiness

Uncommon:

Dizziness

Very rare:

Pain, muscular asthenia, paraesthesia/hypoaesthesia, changes in sense of taste

(metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis

Not known:

Encephalopathy/leukoencephalopathy

Eye disorders

Rare:

Visual disturbances

Very rare:

Impaired vision, retinopathy

Cardiac disorders

Rare:

Pericarditis, pericardial effusion, pericardial tamponade

Vascular disorders

Rare:

Hypotension, thromboembolic events

Respiratory, thoracic and mediastinal disorders

Common:

Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia.

Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry,

not productive cough, short of breath and fever

Rare:

Pulmonary fibrosis,

Pneumocystis jirovecii

pneumonia, shortness of breath and

bronchial asthma, pleural effusion

Not known:

Epistaxis, pulmonary alveolar haemorrhage

Gastrointestinal disorders

Very common:

Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain

Common:

Oral ulcers, diarrhoea

Uncommon:

Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis

Rare:

Gingivitis

Very rare:

Haematemesis, haematorrhea, toxic megacolon

Hepatobiliary disorders (see section 4.4)

Very common:

Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and

bilirubin)

Uncommon:

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

Rare:

Acute hepatitis

Very rare:

Hepatic failure

Skin and subcutaneous tissue disorders

Common:

Exanthema, erythema, pruritus

Uncommon:

Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes

zoster, vasculitis, herpetiform eruptions of the skin, urticaria

Rare:

Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis

Very rare:

Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased

pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia

Not known:

Skin exfoliation/dermatitis exfoliative

Musculoskeletal and connective tissue disorders

Uncommon:

Arthralgia, myalgia, osteoporosis

Rare:

Stress fracture

Not known:

Osteonecrosis of jaw (secondary to lymphoproliferative disorders)

Renal and urinary disorders

Uncommon:

Inflammation and ulceration of the urinary bladder, renal impairment, disturbed

micturition

Rare:

Renal failure, oliguria, anuria, electrolyte disturbances

Not known:

Proteinuria

Reproductive system and breast disorders

Uncommon:

Inflammation and ulceration of the vagina.

Very rare:

Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation,

vaginal discharge

General disorders and administration site conditions

Rare:

Fever, wound-healing impairment

Not known:

Asthenia, oedema, injection site necrosis

Description of selected adverse reactions

Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma

and other lymphoproliferative disorders which 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 dose level and the

frequency of administration. However, as severe undesirable effects can occur even at lower doses, it

is indispensable that patients are monitored regularly by the doctor at short intervals.

Generally, subcutaneous application of methotrexate is locally well tolerated. Usually, only mild local

skin reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching,

pain) were observed, decreasing during therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

Symptoms of overdose

Toxicity of methotrexate mainly affects the haematopoietic system.

Treatment measures in the case of overdose

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose

of methotrexate should be administered intravenously or intramuscularly within one hour and dosing

continued until the serum levels of methotrexate are below 10

mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent

precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor

peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of

methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents; immunosuppressants;

other immunosuppressants, ATC code: L04AX03

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and

polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for

the treatment of Crohn’s disease.

Mechanism of action

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as

antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus

inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the

management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn’s disease, is due to an

anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase

in extracellular adenosine concentration at inflamed sites contributes to these effects.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease

patients that are intolerant or have failed to respond to first-line immunomodulating agents as

azathioprine (AZA) or 6-mercaptopurine (6-MP).

The adverse events observed in the studies performed with methotrexate for Crohn’s disease at

cumulative doses have not shown a different safety profile of methotrexate than the profile it is already

known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of

Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4

and 4.6).

5.2

Pharmacokinetic properties

Absorption

Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly

100 %.

Distribution

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body

tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in

particular, which can be retained for weeks or months. When administered in small doses,

methotrexate passes into the cerebrospinal fluid in minimal amounts.

Biotransformation

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle

metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active

secretion in the proximal tubulus.

Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary. There is

pronounced enterohepatic circulation.

The terminal half-life is on average 6 - 7 hours and demonstrates considerable variation (3 – 17 hours).

The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution

space (pleural effusion, ascites).

Special populations

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard

to hepatic impairment is not known.

5.3

Preclinical safety data

Chronic toxicity

In chronic toxicity studies in mice, rats and dogs, toxic effects were seen in the form of gastrointestinal

lesions, myelosuppression and hepatotoxicity.

Mutagenic and carcinogenic potential

Long-term studies in rats, mice and hamsters revealed no evidence of a tumorigenic potential of

methotrexate. Methotrexate induces gene and chromosomal mutations

in vitro

in vivo

. There is a

suspected mutagenic effect in humans.

Reproductive toxicology

Teratogenic effects have been observed in four species (rats, mice, rabbits, cats). In rhesus monkeys,

no malformations comparable to those seen in humans occurred.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Sodium hydroxide for pH adjustment

Water for injections

6.2

Incompatibilities

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

products.

6.3

Shelf life

2 years

6.4

Special precautions for storage

Store below 25 °C.

Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5

Nature and contents of container

Nature of container

Pre-filled syringes of colourless glass (type I) of 1 ml capacity, with staked s.c. injection needle and

rigid needle shield. Plunger stoppers of chlorobutyl rubber (type I) and plastic plunger rods inserted on

the stopper to form the syringe plunger. <The pre-filled syringes are fitted with a safety system to help

prevent needle stick injuries after use.>

Pack sizes

Namaxir pre-filled syringes containing 0.33 ml (2.5 mg), 0.30 ml (7.5 mg), 0.40 ml (10 mg), 0.31 ml

(12.5 mg), 0.38 ml (15 mg), 0.44 ml (17.5 mg), 0.50 ml (20 mg), 0.56 ml (22.5 mg), 0.63 ml (25 mg),

0.69 ml (27.5 mg) or 0.75 ml (30 mg) solution.

Namaxir 2.5 mg, 7.5 mg, 10 mg, 12.5 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg and 30 mg

Packs of 1 and 4 syringes and multipacks containing 12 (3 packs of 4) syringes <with alcohol pads>.

Namaxir 15 mg

Packs of 1 and 4 syringes and multipacks containing 12 (3 packs of 4) and 6 (6 packs of 1) syringes

<with alcohol pads>.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in

accordance with local requirements. Pregnant healthcare personnel should not handle and/or

administer Namaxir.

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.

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements for cytotoxic agents.

Instructions for subcutaneous use

The best places for the injection are:

upper thighs,

abdomen except around the navel.

Clean the area around the chosen injection site <(e.g. by using the

enclosed alcohol pad)>.

Pull the protective plastic cap straight off.

Build a skin fold by gently squeezing the area at the injection site.

The fold must be held pinched until the syringe is removed from the skin after the injection.

To avoid the loss of medicinal product when using the prefilled syringe, do not expel the air

bubble from the syringe before the injection.

Push the needle fully into the skin at a 90-degree angle.

Inject the liquid underneath the skin by pushing the plunger slowly to the bottom of the syringe.

Remove the syringe from the skin at the same 90-degree angle. If the syringe is fitted with a

safety system, keep your finger on the plunger rod while removing the syringe.

Pre-filled syringes with safety system

: Orienting the needle away from you and others, activate

the safety system by firmly pushing the plunger. The protective sleeve will automatically cover

the needle and an audible ‘click’ will be heard to confirm shield activation.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}

<Date of latest renewal: {DD month YYYY}>

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2021-03-19

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