When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
6.5 Nature and Contents of Container
Changed from
Five colourless, Type I Ph.Eur. glass ampoules in a clear plastic tray, one or two trays per box.
To
Five colourless, Type I Ph.Eur. glass ampoules in an ampoule tray, one or two trays per box.
10. Date of (Partial) Revision of Text
Changed from July 2007 to February 2010
Difene Ampoules SPC
Version June 2006 v July 2007
Section 4.2 Posology and method of administration
New text inserted:
“Undesirable effects may be minimised by using the shortest duration necessary to control symptoms (see section 4.4).”
Section 4.3. Contraindications
New text inserted regarding gastrointestinal and heart failure contraindications:
“History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
Severe heart failure.”
Section 4.4. Special warnings and precautions for use
New text inserted regarding special warnings and precautions for use, as noted below.
Ø First three paragraphs are newly inserted.
Ø The section on gastrointestinal warnings has been expanded compared to previously.
Ø New sections for cardiovascular/ cerebrovascular and skin reactions, female fertility and concomitant medications have been inserted.
“Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).
The use of Difene Capsules with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
Warnings:
Gastro-intestinal: Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of previous GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5).
Patients with a history of GI toxicity especially when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
When GI bleeding or ulceration occurs in patients receiving Difene Capsules, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated (see section 4.8 – undesirable effects).
Cardiovascular and cerebrovascular effects
Caution and appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg initiating daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before longer- term treatment of patient with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
…….
Serious skin reaction, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 4.8). Patients appear to be at the highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Difene capsules should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
The use of Difene Capsules may impair the female fertility and is not recommended in women attempting to conceive. In woman who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Difene Capsules should be considered.
….
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).”
Section 4.5. Interaction with other medicinal products and other forms of interaction
Text has been updated regarding anti-coagulants and anti-platelet agents:
Deleted text:
“Anticoagulants: Although clinical investigations do not appear to indicate that Difene has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy. Therefore to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in high dose can reversibly inhibit platelet aggregation.”
New text:
“Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).
Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).”
New test inserted re corticosteroids: “Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).”
Section 4.8. Undesirable effects
Gastrointestinal tract: new events of abdominal pain and gastritis inserted.
Also within cardiovascular system, following new text inserted:
“Clinical and epidemiological data suggest that use of diclofenac, particularily at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).”
Date of revision of the text updated to July 2007