Zexate

- Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy and PUVA, and severe psoriatic arthritis.

- Active rheumatoid arthritis in adult patients.

Zexate PEN 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.

This medicine should be taken once a week.

Do not exceed the weekly dose of this medicine due to toxicity hazards in psoriasis and rheumatoid arthritis.

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

Psoriasis

Before starting treatment it is advisable to give the patient a test dose of 2.5-5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated.

The usual dose is 5-25 mg taken once weekly, starting with a low dose and increasing as necessary.

The planned weekly dose may be administered in three divided doses at 12 hour intervals over 24 hours.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting Zexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of Zexate may permit the return to conventional topical therapy which should be encouraged.

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses at 12 hour intervals over 24 hours. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 20 mg.

Patients with renal impairment

Zexate should be used with caution in patients with impaired renal function.

The dose should be adjusted as follows:

Patients with hepatic impairment

Zexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Zexate in contraindicated if bilirubin values are > 5 mg/dl (85.5 μmol/l).

Patients with pathological fluid accumulation

Zexate elimination is reduced in patients with pathological fluid accumulation (third space fluids) such as ascites or pleural effusions that may lead to prolonged Zexate plasma elimination half-life and unexpected toxicity. Pleural effusions and ascites should be drained prior to initiation of Zexate treatment. Zexate dose should be reduced according to the serum Zexate concentrations.

Elderly

Zexate should be used with extreme caution in elderly patients. Dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Children

Zexate is not recommended for children under 3 years as insufficient data on efficacy and safety is available for this population

Zexate PEN should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal product and its mode of action. Patients must be educated to use the proper injection technique. The first injection of Zexate PEN should be performed under direct medical supervision. Zexate PEN is injected once weekly.

The patient must be explicitly informed about the fact that Zexate PEN is administered once a week only. It is advisable to determine an appropriate fixed day of the week for the 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.

Posology

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. Depending on the individual activity of the disease and 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. 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.

Paediatric population

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

The recommended dose is 10 - 15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory cases the weekly dosage may be increased up to 20 mg/m² body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is increased.

Due to limited data availability about intravenous use in children and adolescents, parenteral administration is limited to subcutaneous injection.

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.

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.

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.

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 Zexate PEN for the treatment of Crohn's disease in this population.

Patients with renal impairment

Zexate PEN should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

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.

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, ascites)

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.

Method of administration

The medicinal product is for single use only.

Zexate PEN solution for injection in pre-filled pen can only be given by subcutaneous route.

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

Guidance on how to use Zexate PEN solution for injection in pre-filled pen can be found in section 6.6.

Please note that all of the contents have to be used.

Note:

If changing the 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.

Active infections;

Overt or laboratory evidence of immunodeficiency syndrome(s);

Renal insufficiency

Liver insufficiency

Alcohol abuse

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

Zexate is contraindicated in pregnancy.

Due to the potential for serious adverse reactions from Zexate in breast fed infants, breast feeding is contra-indicated in women taking Zexate.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Zexate PEN 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 ,

- alcohol abuse,

- severe renal impairment ,

- 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, breast-feeding ,

- concurrent vaccination with live vaccines.

Warnings

Zexate must be used only by physicians experienced in antimetabolite chemotherapy.

Concomittant administration of hepatotoxic or haematotoxic DMARDs (e.g. leflunomide) is not advisable.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

Zexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection. If Zexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with Zexate should not be restarted.

When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.

Zexate has the potential for serious, sometimes fatal toxicity. The toxic effects may be related in frequency and severity to the dose or frequency of administration but have been seen at all doses. Because the toxic reactions can occur at any time during therapy, the patients have to be observed closely and must be informed of early signs and symptoms of toxicity.

Use caution when administering high-dose Zexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with Zexate (primarily at high dose), may elevate and prolong serum levels of Zexate and/or its metabolite hydroxyZexate, possibly leading to Zexate toxicities. In two of these cases, delayed Zexate elimination was observed when high-dose Zexate was co-administered with PPIs, but was not observed when Zexate was co-administered with ranitidine. However, no formal drug interaction studies of Zexate with ranitidine have been conducted.

The carton and bottle label will state: “Check dose and frequency - Zexate is usually taken once a week.”

Deaths have been reported with the use of Zexate in the treatment of psoriasis.

In the treatment of psoriasis, Zexate 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.

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

Patients should be aware of importance of adhering to the once weekly intakes.

1. Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, Zexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Zexate may be hepatotoxic, particularly at high dosage or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy. If substantial hepatic function abnormalities develop, Zexate dosing should be suspended for at least 2 weeks. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of other drugs with hepatotoxic potential (including alcohol) should be avoided.

3. Zexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients should not receive Zexate.

4. Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. Reduce dose of Zexate in patients with renal impairment. High doses may cause the precipitation of Zexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 - 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a preventative measure. Zexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

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

6. Zexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of Zexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Zexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of Zexate should be taken into account when immune responses of patients are important or essential. Immunization with live virus vaccines is generally not recommended.

8. Pleural effusions and ascites should be drained prior to initiation of Zexate therapy.

9. Deaths have been reported with the use of Zexate. Serious adverse reactions including deaths have been reported with concomitant administration of Zexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

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

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

12 A chest X-ray is recommended prior to initiation of Zexate therapy.

13 If acute Zexate toxicity occurs, patients may require folinic acid.

14 Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g., toxic epidermic necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, vasculitis and extensive herpetiform skin eruptions) may occur after the administration of Zexate and recovery ensured mostly after discontinuation of the therapy.

Precautions

Zexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision. The physician should be familiar with the various characteristics of the drug and its established clinical usage.

Before beginning Zexate therapy or reinstituting Zexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. If any abnormality in liver function tests or liver biopsy is seen prior to initiation of treatment or develops during therapy, treatment with Zexate should not be instituted, or should be discontinued. Should such abnormalities return to normal within two weeks, treatment may be recommenced at the discretion of the physician.

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of Zexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Malignant Lymphomas may occur in patients receiving low dose Zexate, in which case therapy must be discontinued. Failure of the Lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity studies have demonstrated Zexate to be free of carcinogenic potential. Although Zexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with Zexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Zexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, Zexate causes embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see 'Warnings').

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic haematological studies are essential to the use of Zexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, Zexate should be used with caution, if at all.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving Zexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Liver biopsy may be considered after cumulative doses > 1.5g have been given, if hepatic impairment is suspected.

Zexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to Zexate.

Zexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Since it is reported that Zexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

In all instances where the use of Zexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Zexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity.

Zexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

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 treatment with methotrexate should only be initiated and supervised by 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.

1. Examination of the mouth and throat for mucosal changes

2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. 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.

3. 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. 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).

4. Renal function should be monitored by renal function tests and urinanalysis.

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.

5. 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. This lesion can occur at all doses.

6. 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.

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.

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

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.

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.

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

Sodium

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

Paediatric population

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is available for this population.

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with Zexate which have minor or moderate influence on the ability to drive and use machines.

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Zexate PEN has minor or moderate influence on the ability to drive and use machines.

The most common adverse reactions include ulcerative stomatitis, leukopenia, vasculitis, eye-irritation and loss of libido/impotence, nausea and abdominal distress. Although very rare, anaphylactic reactions to Zexate have occurred. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows:

Skin: Severe, occasionally fatal, dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, skin necrosis, exfoliative dermatitis, epidermal necrolysis.). Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

Central Nervous System: Headaches, drowsiness, blurred vision, aphasia cognitive disorder, unusual cranial sensations, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

Other reactions related to, or attributed to the use of Zexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

There have been reports of leukoencephalopathy following intravenous Zexate in high doses, or low doses following cranial-spinal radiation.

Cardiac disorders: Pericarditis, pericardial effusion

Ear disorders: Tinnitus

Eye disorders: Conjunctivitis

Infections and infestations: Opportunistic infections (sometimes fatal e.g. fatal sepsis) have also been reported in patients receiving Zexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include, pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, disseminated Herpes Simplex, hepatitis and cytomegalovirus infection, including cytomegaloviral pneumonia.

Musculoskeletal and connective tissue disorders: Arthralgia/myalgia

Psychiatric disorders: Mood altered

Vascular disorders: Hypotension, thromboembolic events (e.g. thrombophlebitis, pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis).

Adverse reactions following intrathecal Zexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal Zexate increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of Zexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

A small number of cases of accelerated nodulosis have been reported in the literature it is unclear whether the development of accelerated nodulosis during Zexate therapy is a drug-related side effect or is part of the natural history of the rheumatoid disease.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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.

Tabulated list of adverse reactions

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

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

Blood and lymphatic system disorders

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

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

Not known: Eosinophilia

Immune system disorders

Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Metabolism and nutrition disorders

Uncommon: Precipitation of diabetes mellitus.

Psychiatric disorders

Uncommon: Depression, confusion.

Rare: Mood alterations.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness.

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

Not known: Encephalopathy/leukoencephalopathy.

Eye disorders

Rare: Visual disturbances.

Very rare: Impaired vision, Retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

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

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

Not known: Epistaxis.

Gastrointestinal disorders

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

Common: Oral ulcers, diarrhoea.

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

Rare: Gingivitis.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders

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, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.

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

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

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia, myalgia, osteoporosis.

Rare: Stress fracture.

Renal and urinary disorders

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

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

Not known: Proteinuria.

Reproductive system and breast disorders

Uncommon: Inflammation and ulceration of the vagina.

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

General disorders and administration site conditions

Rare: Fever, wound-healing impairment.

Not known: Asthenia.

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

Subcutaneous application of methotrexate is locally well tolerated. 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral Zexate have been reported. In these cases, symptoms that have been commonly reported are haematological and gastrointestinal reactions.

Calcium folinate (Calcium Leucovorin) is a potent agent for neutralizing the immediate toxic effects of Zexate on the haematopoietic system. It may be administered orally, intramuscularly or by an intravenous bolus injection or infusion. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. Where average doses of Zexate appear to have an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than, the offending dose of Zexate and should be administered as soon as possible; preferably within the first hour and dosing continued until the serum levels of Zexate are below 10^-7M.

Other supporting therapy such as blood transfusion and renal dialysis may be required. In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of Zexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve Zexate elimination. Effective clearance of Zexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

a) Symptoms of overdose

Toxicity of methotrexate mainly affects the haematopoietic system.

b) 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^-7 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.

Pharmacotherapeutic group: Other immunosuppressive agents, ATC code: L04AX03

Zexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by Zexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of Zexate. It also inhibits antibody synthesis.

Zexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.

Pharmacotherapeutic group: Folic acid analogues

ATC code: L01BA01

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.

In doses of 0.1 mg (of Zexate) per kg, Zexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. / I.M. or intra-arterial administration. Serum concentrations following oral administration of Zexate may be slightly lower than those following I.V. injection.

Zexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Zexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Zexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

In one study, Zexate had a serum half-life of 2-4 hours following I.M. administration. Following oral doses of 0.06 mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037 mg/kg were given.

Zexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Zexate has a biphasic excretion pattern. If Zexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress Zexate clearance.

Absorption

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are possible (25 - 100 %). Maximum serum concentrations are achieved after 1 - 2 hours.

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. 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).

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.

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to hepatic impairment is not known.

Not applicable

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

Not applicable

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

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

The manner of handling and disposal must be in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Zexate PEN.

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 should be disposed of in accordance with local requirements.

Instructions for subcutaneous use

The most appropriate zones for the injection are:

- upper thighs,

- abdomen except around the navel.

1. Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).

2. Pull the cap straight off.

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

4. The fold must be held pinched until the Zexate PEN is removed from the skin after the injection.

5. Push the Zexate PEN firmly into the skin at a 90degree angle in order to unlock the button. Then press the button (a click indicates the start of injection).

6. Do not remove the Zexate PEN from the skin before the end of the injection to avoid incomplete injection. This can take up to 5 seconds.

7. Remove the Zexate PEN from the skin at the same 90degree angle.

8. The protective shield automatically moves into place over the needle and is then locked.