Methotrexate Orion 2.5 mg tablets

Amended recommendations for contraception in males.

During the PSUSA on amoxicillin, the inclusion in the product information of interactions between amoxicillin and methotrexate is recommended. The PRAC considered that these interactions should also be included in the product information of methotrexate products

In addition to those some minor other corrections and updates have been done on the PI texts

What Methotrexate Orion is and what it is used for: the information on the properties of methotrexate has been reworded and the wording relating to acute lymphoblastic leukaemia has been updated to include age groups.

Methotrexate Orion with food, drink and alcohol: the following is added:

Ensure that you drink a lot of fluids during treatment with Methotrexate Orion tablets because dehydration (the reduction of body water) can increase the side effects of methotrexate.

Therapeutic Indications: Wording on cytostatic indication (treatment of acute lymphoblastic leukaemia) updated to clarify age groups

Special warnings and precautions for use: Dosing in the treatment of rheumatoid arthritis, psoriasis and severe psoriatic arthritis updated to undeline importance on once weekly intake.

1. 4.4 Special warnings and precautions for use

Recommended examinations and safety measures -> during treatment

• Under Liver function tests
  • Inserted following paragraphs: “Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies. Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20%. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy. Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient’s comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment. Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided (see sections 4.3 and 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products. Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.”
  • Removed following: “Treatment should not be initiated or should be discontinued if there are any abnormalities in liver function tests or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal within two weeks, after which, treatment may be resumed at the discretion of the doctor.”
  • Removed following paragraph “Testing of serum liver enzymes Transient increases in transaminases to twice or three times normal occur in 13-20% of patients. Persistent abnormalities of liver enzymes and/or a decrease in serum albumin can indicate severe hepatotoxicity. In rheumatological indications, there is no evidence to support use of liver biopsies in monitoring hepatotoxicity. 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 function tests or determinations of propeptide of type III collagen are appropriate for detecting hepatotoxicity. This evaluation should 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 a hereditary liver disease, diabetes mellitus, obesity and history of significant exposure to hepatotoxic medicinal product or chemicals, as well as prolonged methotrexate treatment or a cumulative total dose of 1.5 g or more. If liver enzymes are constantly increased, a dose reduction or treatment discontinuation should be considered. Due to its potentially toxic effects on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless urgently necessary and the consumption of alcohol should be avoided or reduced (seesection 4.5). Closer monitoring of liver enzymes should be undertaken in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). This should also be considered during simultaneous administration of haematotoxic medicinal products. Increased caution is required in patients with insulin-dependent diabetes mellitus as hepatic cirrhosis has developed in individual cases without any elevation of transaminases during methotrexate treatment.”

• Under Progressive multifocal leukoencephalopathy (PML) (new entry)
  • Inserted following paragraph: “Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.”

10 Date of revision of text

• Changed to 31 March 2022

Section 2 - what you need to know before you take Methotrexate Orion - warning and precautions

• • Inserted new paragraph: “If you, your partner or your caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes contact your doctor immediately because these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).”
  • Inserted the word ‘other’ to  ‘Certain other brain disorders’
  • Removed paragraph: “Before the beginning of treatment Before treatment is started your doctor may carry out blood tests, and also to check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests.”
  • “Recommended follow-up examinations and precautions” paragraph amended from “Even when methotrexate is used at low doses, serious side effects can occur. Your doctor will carry out blood and urine tests to make sure that any side effects are identified quickly” to “ Even if methotrexate is used in low doses, serious side effects can occur. In order to detect them in time, your doctor must perform monitoring examinations and laboratory tests”.
  • New paragraph inserted “Prior to the start of therapy: Before you start treatment, your blood will be checked to see if you have enough blood cells. Your blood will also be tested to check your liver function and to find out if you have hepatitis. Furthermore, serum albumin (a protein in the blood), hepatitis (liver infection) status and kidney function will be checked. The doctor may also decide to run other liver tests, some of these may be images of your liver and others may need a small sample of tissue taken from the liver in order to examine it more closely. Your doctor may also check to see if you have tuberculosis and they may X-ray your chest or perform a lung function test.”
  • New paragraph inserted “During the treatment: Your doctor may perform the following examinations:
    • examination of the oral cavity and the pharynx for changes in the mucous membrane such an inflammation or ulceration
    • blood tests/ blood count with number of blood cells and measurement of serum methotrexate levels
    • blood test to monitor liver function
    • imaging tests to monitor liver condition
    • small sample of tissue taken from the liver in order to examine it more closely
    • blood test to monitor kidney function
    • respiratory tract monitoring and, if necessary, lung function test.
  • New paragraph inserted “It is very important that you appear for these scheduled examinations. If the results of any of these tests are conspicuous, your doctor will adjust your treatment accordingly.”
• Under Children, adolescents and elderly, paragraph has been amended from  “Children, adolescents and the elderly should be kept under particularly close medical surveillance during treatment with Methotrexate Orion, in order to identify possible side effects as early as possible” to “Children, adolescents and the elderly under treatment with methotrexate should be monitored closely by a physician so that possible side effects can be detected as early as possible.” Also added a new paragraph “Agerelated impairment of liver and kidney function as well as low body reserves of the vitamin folic acid in old age require a relatively low dosage of methotrexate. Use in children below 3 years of age is not recommended.”

6. Contents of the pack and other information

Added “ For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: Orion Pharma (Ireland) Limited, c/o Allphar Services Ltd, 4045 Kingswood Road, Citywest Business Park, Co Dublin.”

Date of revision

• Changed to 31 March 2022.

The contact phone number for Amdipharm has been updated.

The contact phone number for Amdipharm has been updated.

The contact phone number for Amdipharm has been updated.

Addition of additional pack sizes to the patient leaflet.

Addition of additional pack sizes to the Summary of Product Characteristics

Correction of typing errors

The date of revision of the text is updated following the renewal of the marketing authorisation.

The date of revision of the text is updated following the renewal of the marketing authorisation.

Addition of a blister pack of 4 tablets to pack sizes for Methotrexate Orion 10mg Tablets

The leaflet has been updated to include an alternative closure to the bottle.

The SPC has been updated to include an alternative closure to the bottle (section 6.5).

Checklist for Physicians who prescribe Methotrexate - Information to minimise the risk of potentially fatal dosing errors

Checklist for Community Pharmacists who dispense Methotrexate- Information to minimise the risk of potentially fatal dosing errors

Checklist for Hospital Pharmacists who dispense Methotrexate- Information to minimise the risk of potentially fatal dosing errors

The first publication of the SmPC for this formulation of Methotrexate Orion 2.5mg tablets.