Ebetrex

- 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.

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 Ebetrex 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 Ebetrex 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

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

The dose should be adjusted as follows:

Patients with hepatic impairment

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

Patients with pathological fluid accumulation

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

Elderly

Ebetrex 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

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

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.

Ebetrex is contraindicated in pregnancy.

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

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

Warnings

Ebetrex 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.

Ebetrex should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection.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

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

Ebetrex 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 Ebetrex 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 Ebetrex (primarily at high dose), may elevate and prolong serum levels of Ebetrex and/or its metabolite hydroxyEbetrex, possibly leading to Ebetrex toxicities. In two of these cases, delayed Ebetrex elimination was observed when high-dose Ebetrex was co-administered with PPIs, but was not observed when Ebetrex was co-administered with ranitidine. However, no formal drug interaction studies of Ebetrex with ranitidine have been conducted.

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

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

In the treatment of psoriasis, Ebetrex 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, Ebetrex should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

2. Ebetrex 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, Ebetrex 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. Ebetrex 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 Ebetrex.

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 Ebetrex in patients with renal impairment. High doses may cause the precipitation of Ebetrex 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. Ebetrex 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. Ebetrex 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 Ebetrex administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

7. Ebetrex has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of Ebetrex 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 Ebetrex therapy.

9. Deaths have been reported with the use of Ebetrex. Serious adverse reactions including deaths have been reported with concomitant administration of Ebetrex (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 Ebetrex therapy.

13 If acute Ebetrex 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 Ebetrex and recovery ensured mostly after discontinuation of the therapy.

Precautions

Ebetrex 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 Ebetrex therapy or reinstituting Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex, 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 Ebetrex to be free of carcinogenic potential. Although Ebetrex 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 Ebetrex, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

Ebetrex 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, Ebetrex 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 Ebetrex 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, Ebetrex 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 Ebetrex 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.

Ebetrex 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 Ebetrex.

Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex 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.

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

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with Ebetrex which have 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 Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex increases the incidence of leukoencephalopathy.

Additional reactions related to or attributed to the use of Ebetrex 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 Ebetrex 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

Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral Ebetrex 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 Ebetrex 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 Ebetrex 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 Ebetrex and should be administered as soon as possible; preferably within the first hour and dosing continued until the serum levels of Ebetrex 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 Ebetrex and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve Ebetrex elimination. Effective clearance of Ebetrex has been reported with acute, intermittent haemodialysis using a high flux dialyser.

Pharmacotherapeutic group: Other immunosuppressive agents, ATC code: L04AX03

Ebetrex 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 Ebetrex interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of Ebetrex. It also inhibits antibody synthesis.

Ebetrex 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.

In doses of 0.1 mg (of Ebetrex) per kg, Ebetrex 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 Ebetrex may be slightly lower than those following I.V. injection.

Ebetrex 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. Ebetrex 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. Ebetrex 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, Ebetrex 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.

Ebetrex 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. Ebetrex has a biphasic excretion pattern. If Ebetrex 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 Ebetrex clearance.

Not applicable

Not applicable

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