Source: Υπουργείο Υγείας (CY) Revision Year: 2016 Publisher: Medililink Pharmaceuticals Ltd, 30 Armenias Street, 2003 Strovolos, Nicosia, Cyprus, Tel.: +357 22319282, Fax: +357 22319290
Difene Dual Release 100mg is not suitable for children and adolescents under 18 years because the content of active substance is too high.
The administration of Difene Dual Release 100mg associated with NSAIDs, including selective cyclo‑oxygenase‑2 inhibitors, should be avoided.
Undesirable effects can be reduced by taking the lowest effective dose for the shortest period needed to control symptoms (see section 4.2 and gastrointestinal and cardiovascular risks further below).
With elderly patients undesirable effects are more common under NSAID therapy, especially gastrointestinal bleeding and perforation, sometimes fatal (see section 4.2).
Gastrointestinal bleeding, ulcers or perforations, sometimes fatal, have been reported with all NSAIDs. They have occurred with and without previous warning symptoms or any history of serious gastrointestinal events, and at any point in the treatment.
The risk of gastrointestinal bleeding, ulceration or perforation is greater the higher the dose of the NSAID and in patients with a history of ulcers, especially with complications involving bleeding or perforation (see section 4.3), and in elderly patients. These patients should start the treatment at the lowest available dose.
For these patients, and also for patients who need concomitant treatment with low‑dose acetylsalicylic acid (ASA) or other medicinal products which can increase the gastrointestinal risk (see section 4.5), a combination treatment with protective medicinal products (e.g. misoprostol or a proton pump inhibitor) should be considered (see below and section 4.5).
Patients with a history of gastrointestinal toxicity, especially those of advanced age, should report any unusual abdominal symptoms (above all gastrointestinal bleeding), especially at the start of treatment.
Caution is advised if the patients are concurrently taking medicinal products which can increase the risk of ulcers or bleeding, such as oral corticosteroids, anticoagulants like warfarin, selective serotonin reuptake inhibitors or platelet aggregation inhibitors like ASA (see section 4.5).
If gastrointestinal bleeding or ulcers occur in patients taking Difene Dual Release 100mgthe treatment must be stopped.
NSAIDs should be given only with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as their condition can worsen (see section 4.8).
Patients with a history of hypertension and/or mild to moderate decompensated cardiac impairment require appropriate supervision and advice, because fluid retention and oedema have been reported in association with NSAID treatment.
Clinical trials and epidemiological data suggest that the use of diclofenac, especially at a high dose (150 mg daily) and for long‑term treatment, is possibly associated with a slightly raised risk of arterial thrombotic events (such as myocardial infarction and stroke).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically.
Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens‑Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome) have very rarely been reported with NSAID treatment (see section 4.8). The highest risk of such reactions seems to be at the start of treatment, as in most cases these reactions occurred in the first month of treatment. Difene Dual Release 100mg should be discontinued at the first signs of skin rashes, mucosal lesions or other signs of a hypersensitivity reaction.
It is imperative to exercise caution before starting to treat patients with hepatic dysfunction, because their condition could worsen under diclofenac treatment. If Difene Dual Release 100mg is taken for a long time or repeatedly, regular monitoring of liver function is indicated as a precaution. If clinical signs of liver disease are found, Difene Dual Release 100mg should be stopped immediately.
Difene Dual Release 100mg should be given only after carefully evaluating the risk/benefit ratio:
Especially careful medical supervision is required:
Severe acute hypersensitivity reactions (such as anaphylactic shock) are observed very rarely. At the first signs of a hypersensitivity reaction after taking Difene Dual Release 100mg the treatment must be stopped. Medically necessary procedures appropriate to the symptoms must be initiated by persons with specialist knowledge.
Diclofenac can temporarily inhibit platelet aggregation. Patients with coagulation disorders should therefore be carefully monitored.
As with other NSAIDs, the pharmacodynamic properties of diclofenac can mask the signs and symptoms of an infection.
The patient must therefore be recommended to see the doctor immediately if signs of an infection start or worsen while Difene Dual Release 100mg is being taken. It is necessary to check whether anti‑infective/antibiotic therapy is indicated.
With long‑term use of Difene Dual Release 100mg regular monitoring of renal function and of the blood count is required.
With long‑term use of analgesics headaches can occur which must not be treated with increased doses of the medicinal product.
Generally speaking, habitual intake of analgesics, especially when several analgesic active substances are combined, can lead to lasting kidney damage with the risk of renal failure (analgesic nephropathy).
Taking NSAIDs at the same time as alcohol can potentiate the undesirable effects caused by the active substance, especially those affecting the gastrointestinal tract or the central nervous system.
Regarding fertility in women, see section 4.6.
Taking several NSAIDs concurrently can raise the risk of gastrointestinal ulcers and bleeding because of a synergistic effect. The concomitant administration of diclofenac and other NSAIDs is not therefore recommended (see section 4.4).
Taking Difene Dual Release 100mg associated with digoxin, phenytoin or lithium can raise the concentration of these medicinal products in the blood. Monitoring the serum lithium levels is necessary. Monitoring the serum digoxin and the serum phenytoin levels is recommended.
Non‑steroidal antirheumatic agents can attenuate the effect of diuretics and antihypertensive agents. In patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function) the concurrent administration of an ACE inhibitor or an angiotensin II antagonist with a medicinal product which inhibits cyclo‑oxygenase can further impair renal function, or even possibly lead to acute renal failure, which is usually reversible. A combination of this kind should therefore be given only with caution, especially to elderly patients. The patients must be urged to drink adequate fluid and regular monitoring of the renal values should be considered once a combination therapy has begun. The administration of Difene Dual Release 100mg simultaneously with potassium‑sparing diuretics can lead to hyperkalaemia. The potassium level should be monitored when such treatments are concurrent.
Increased risk of gastrointestinal ulcers or bleeding (see section 4.4).
Increased risk of gastrointestinal bleeding (see section 4.4).
Giving Difene Dual Release 100mg less than 24 hours before or after the administration of methotrexate can raise the concentration of methotrexate in the blood and increase its toxic effect.
NSAIDs (like diclofenac sodium) can raise the renal toxicity of cyclosporin.
NSAIDs can potentiate the effect of anticoagulants such as warfarin (see section 4.4).
Medicinal products which contain probenecid or sulphinpyrazone can delay the excretion of diclofenac.
The inhibition of prostaglandin synthesis can have a negative effect on the pregnancy and/or embryo/foetal development. Data from epidemiological studies indicate an increased risk of miscarriage and also of cardiac malformation and gastroschisis after the use of a prostaglandin inhibitor in early pregnancy. It is assumed that the risk rises with the dose and the duration of treatment.
It has been shown in animals, that the administration of a prostaglandin synthesis inhibitor leads to increased pre‑implantation and post‑implantation losses and embryo/foetal death. There have also been reports of increased incidence of various malformations, including cardiovascular malformations, in animals that received a prostaglandin synthesis inhibitor during the phase of organogenesis.
During the first and second trimester of pregnancy diclofenac should be given only if absolutely necessary. If a woman who is trying to become pregnant takes diclofenac or if it is taken in the first or second trimester of pregnancy, the dose should be kept as low as possible, and the duration of treatment as short as possible.
During the third trimester of pregnancy all prostaglandin synthesis inhibitors can:
Diclofenac is therefore contraindicated during the third trimester of pregnancy.
Small amounts of the active substance diclofenac and its breakdown products pass into the mother’s milk. As no harmful effects on the baby are yet known it is not usually necessary to interrupt lactation with short‑term use. However, if longer‑term use or high doses are prescribed to treat rheumatic disorders, early weaning from the breast should be considered.
The use of Difene Dual Release 100mg, as with other medicinal products which are known to inhibit cyclo‑oxygenase/prostaglandin synthesis, can impair female fertility and is not therefore recommended for women who wish to become pregnant. For women who have difficulty becoming pregnant or who are undergoing investigations for infertility, discontinuing Difene Dual Release 100mg should be considered.
As undesirable effects on the central nervous system like fatigue and dizziness can occur when Difene Dual Release 100mgis used, especially at high dosage, in isolated cases the reaction time can be altered and the ability to drive and use machines impaired. This applies particularly when there is an interaction with alcohol.
The following categories are used as a basis for evaluating undesirable effects: 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).
It must be borne in mind that the following undesirable effects of the medicinal product are predominantly dose‑dependent and differ between individuals.
The undesirable effects most commonly observed affect the gastrointestinal tract. Peptic ulcers, perforations or haemorrhage, sometimes fatal, can occur, especially in elderly patients (see section 4.4). Nausea, vomiting, diarrhoea, bloating, constipation, indigestion, abdominal pain, tarry stool, haematemesis, ulcerative stomatitis, worsening of colitis and Crohn’s disease (see section 4.4) have been reported after use. Less commonly, gastritis has been observed.
Oedema, hypertension and cardiac impairment have been reported in association with NSAID treatment.
Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment. (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).
Very rare: palpitations, oedema, cardiac impairment, myocardial infarction.
Very rare: haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis), haemolytic anaemia.
The first signs can be: fever, sore throat, superficial lesions in the mouth, 'flu‑like symptoms, severe exhaustion, nosebleeds and bleeding into the skin.
With long‑term treatment, the blood count should be monitored regularly.
Common: central nervous system disorders such as headaches, dizziness, drowsiness, agitation, irritability or fatigue.
Very rare: impaired sensitivity, impaired sense of taste, impaired memory, disorientation, convulsions, tremor.
Very rare: visual impairment (blurred vision and diplopia).
Very rare: tinnitus, temporary impairment of hearing.
Very common: gastrointestinal problems such as nausea, vomiting and diarrhoea, also slight gastrointestinal blood loss, which in exceptional cases can cause anaemia.
Common: dyspepsia, flatulence, abdominal cramps, loss of appetite and gastrointestinal ulcers (in some circumstances with bleeding and perforation).
Uncommon: haematemesis, melaena or bloody diarrhoea.
Very rare: stomatitis, glossitis, oesophageal lesions, lower abdominal problems (such as bloody colitis or aggravation of ulcerative colitis/Crohn’s disease), severe constipation, pancreatitis.
The patient must be instructed to stop taking the medicinal product and see a doctor immediately if severe upper abdominal pain occurs or if there is melaena or haematemesis.
Very rare: diaphragm‑like intestinal strictures.
Uncommon: development of oedema, especially in patients with systemic hypertension or renal impairment.
Very rare: damage to renal tissue (interstitial nephritis, papillary necrosis), which can be accompanied by acute renal failure, proteinuria and/or haematuria. Nephrotic syndrome.
Renal function should be monitored regularly.
Uncommon: alopecia.
Very rare: exanthemata, eczema, photosensitivity, purpura (also allergic purpura) and bullous skin reactions such as Stevens‑Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome).
Very rarely, worsening of inflammations due to infection (e.g. the development of necrotising fasciitis) has been described as occurring within the same time‑frame as the systemic use of NSAIDs. This is possibly associated with the mechanism of action of the NSAID.
If signs of an infection start or worsen during the administration of Difene Dual Release 100mg, the patient is recommended to see the doctor without delay. It is necessary to check whether anti‑infective/antibiotic treatment is indicated.
Very rarely, symptoms of aseptic meningitis with neck stiffness, headaches, nausea, vomiting or clouding of consciousness have been observed while diclofenac is being administered. Patients with autoimmune disease (SLE, mixed connective tissue disease) seem to be predisposed.
Very rare: hypertension.
Common: hypersensitivity reactions such as skin rash and itching of the skin.
Uncommon: urticarial
The patient must be instructed to tell the doctor immediately in this case and to stop taking Difene Dual Release 100mg.
Very rare: severe general hypersensitivity reactions. They may manifest as facial oedema, swelling of the tongue, internal swelling of the larynx with constriction of the airways, dyspnoea, tachycardia, drop in blood pressure sometimes even to the point of anaphylactic shock.
If one of these symptoms occurs, which may be observed even at the first administration, Difene Dual Release 100mg should be stopped and immediate medical assistance sought.
Very rare: allergic vasculitis and allergic pneumonia.
Common: elevation of serum transaminases.
Uncommon: liver damage, especially with long‑term treatment, acute hepatitis with or without jaundice (very rarely with a fulminant course, even without prodromal symptoms).
Liver values should be regularly monitored during long‑term treatment.
Very rare: psychotic reactions, depression, feelings of anxiety, nightmares.
Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.
None known to date.
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