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 Pharmaceutical Particulars
6.1 List of excipients
Printing Ink
Titanium Dioxide E171
Shellac
Propylene Glycol
Soya Leichin
Dimeticone
Total systemic clearance of diclofenac in plasma is 263+/-56mL/min (mean value +/-SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.
Section 6.3 Shelf life
Shelf life: changed from 3.5 years to 30 months.
Section 10. Date of (Partial) Revision of Text
Updated from July 2007 to July 2008
Difene 25mg Capsules 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 NSAID 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.
Warnings:
“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).
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
Difene Capsules 25mg SPC Changes
This is a new individual SPC (was previously included in a combined SPC). New individual SPCs have also been written for Difene Capsules 50mg, 75mg DR, 100mg DR, Suppositories, Gel and Ampoules. All details for these formulations have been removed from the sections listed below:
1. Name of the Medicinal Product
2. Qualitative and Quantitative Composition
3. Pharmaceutical Form
4.1. Therapeutic Indications
4.2. Posology and method of administration
4.3. Contraindications
4.4. Special warnings and precautions for use
4.5. Interaction with other medicinal products and other forms of interaction
4.7. Effects on ability to drive and use machines
4.8. Undesirable effects
4.9. Overdosage
5.2. Pharmacokinetic Properties
6.1. List of excipients
6.2. Incompatibilities
6.3. Shelf life
6.5. Nature and Contents of Container
6.6. Instructions for Use and Handling
8. Marketing Authorisation Number(s)
9. Date of First Authorisation/Renewal of the Authorisation
An individual SPC is also available for Difene Spray Gel.
Text inserted: “For excipients, see 6.1”.
4.2 Posology and method of administration
Text inserted: Elderly.. “See also Special warnings and special precautions for use.”
4.4 Special warnings and special precautions for use
This section has been harmonised with the reference product - i.e. expanded and divided into the following headings and subheadings:
Warnings
Gastro-intestinal
Hepatic:
Hypersensitivity reactions
Precautions
Renal
Hepatic
Haematological
Long-term treatment
In addition the following text has been inserted:
“Hypersensitivity reactions: As with other nonsteroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.
Like other NSAIDs, Difene may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.”
4.5 Interaction with other medicaments and other forms of interaction
This section has been harmonised with the reference product – i.e. expanded, re-worded and the arrangement reorganised.
The following new text has been inserted:
“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 a high dose can reversibly inhibit platelet aggregation.
Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDS. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.
NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking Difene concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.”
4.8 Undesirable effects
This section has been harmonised with the reference product i.e.:
A description of frequency estimate has been inserted:
“Frequency estimate: frequent > 10%, occasional >1%-10%, rare >0.001%-1%, isolated cases <0.001%.”
The subheading of “Other organ systems” has been re-classified to “Hypersensitivity” and “Cardiovascular system”.
New undesirable effects added: aseptic meningitis, congestive heart failure, vasculitis, pneumonitis
Undesirable effect removed: impotence
5.2 Pharmacokinetic Properties
This section has been harmonised with the reference product – i.e. expanded and divided into the following subheadings:
Absorption:
Bioavailability:
Distribution:
Metabolism:
Elimination:
Characteristics in patients Elderly; Patients with renal impairment; Patients with hepatic disease;
Peak plasma levels have been changed from “within 30mins” to “2 hours”.
6.5 Nature and Contents of Container
The following text has been inserted: “Not all pack sizes may be marketed.”
7. Marketing Authorisation Holder
Changed from Fujisawa Deutschland GmbH, Germany to Astellas Pharma Co. Ltd, Dublin 22, Ireland
8. Marketing Authorisation Number
P.A. number changed to 1241/12/1
9. Date of First Authorisation/Renewal of Authorisation
Date of renewal changed from 28th August 2000 to 28th August 2005.
10. Date of revision of the text
Changed to June 2006