SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Diklofenak T Actavis 25 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Diclofenac potassium 25 mg For the full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablets. Pink, round, biconvex tablets, 6 mm in diameter 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of acute inflammatory disease in the musculoskeletal system, primary dysmenorrhoea and symptomatic treatment of acute migraine attacks with or without aura. Paediatric population: Symptomatic, short-term treatment in children and adolescents, aged 9 years or older, of - pain related to inflammatory infections of the ear, nose or throat, e.g. pharyngotonsillitis, otitis (ENT). In keeping with general therapeutic principles, the underlying disease should be treated with anti-infective basic therapy, as therapeutically appropriate. Fever alone without inflammatory component is not an indication. - acute post-operative pain after minor surgery (POP). 4.2 Posology and method of administration Posology Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use). Adult dose in acute inflammatory cases: mg/day divided into 2-3 doses. Adult dose in case of migraine: 50 mg at the first sign of migraine. Another 50 mg can be taken if the strength of the attack does not abate within two hours. The daily dose should not exceed 150 mg. Paediatric population Children aged 9 years (minimum 35 kg bodyweight) or over and adolescents should be given up to 2 mg/kg body weight per day in 3 to 4 divided doses, depending on the severity of the disorder. This only applies to the approved paediatric indications listed in section 4.1. See table 1 below with examples of doses based on body weight and corresponding age. Table 1: Dose recommendations for the acute paediatric indications POP and ENT Body weight Corresponding age Maximum daily dose kg 9-11 years 25 mg tablet three times a day 2

3 45-55 kg years 25 mg tablet three to four times a day Elderly Administer the lowest effective dose to weak older patients or patients with a low body weight. Renal and hepatic impairment Dose reduction does not seem to be warranted in patients with mild to moderate renal or hepatic impairment. Severe impairment is a contraindication. Patients with moderate renal impairment should be monitored closely during diclofenac treatment. The lowest effective dose should be administered. (See 4.3.) Method of administration Tablets should be swallowed whole with water, preferably before a meal. 4.3 Contraindications - Hypersensitivity to the active substance, peanuts, soya or to any of the excipients listed in section Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease. - Active gastric or intestinal ulcer, bleeding or perforation. - History of gastrointestinal bleeding or perforation, related to previous non-steroidal antiinflammatory drugs (NSAIDs) therapy. - Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). - Asthma, urticaria or acute rhinitis precipitated by salicylates or other NSAIDs. - Severe hepatic failure. - Severe renal failure. - Third trimester of pregnancy. 4.4 Special warnings and precautions for use The concomitant use of Diclofenac Rapid Actavis with systemic NSAIDs including cyclooxygenase-2-selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effect. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and the below sections on gastrointestinal and cardiovascular risks). NSAID may reduce the diuretic effect and enhance the efficacy of potassium-saving diuretics. Monitoring of serum potassium is therefore necessary. As with other NSAIDs, allergic reactions of varying degree, including anaphylactic/anaphylactoid reactions may occur during diclofenac treatment in patients who are hypersensitive to acetylsalicylic acid or other NSAIDs without earlier exposure to the drug. Consequently, detailed patient history is necessary to identify previous allergic reactions. Since diclofenac may suppress signs and symptoms of infections due to its pharmacodynamic properties, it should be administered cautiously in patients in risk of infections. Elderly Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight. The elderly have an increased frequency of adverse reations to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). 3

4 Gastrointestinal effects Gastrointestinal (GI) bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. Diclofenac should be withdrawn if gastric ulcer or gastrointestinal haemorrhaging occurs during treatment. As with all NSAIDs, including diclofenac, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of GI or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. To reduce the risk of GI toxicity in these patients, the treatment should be initated and maintained at the lowest effective dose. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA)/aspirin, or other medicinal products likely to increase gastrointestinal risk (see below section 4.5). Patients with a history of GI toxicity, particular the elderly, should report any unusual abdominal symptoms (especially GI bleeding). Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid (see section 4.5). Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn s disease, as their condition may be exacerbated (see 4.8). Hepatic effects Close medical surveillance is required when prescribing diclofenac to patient with impaired hepatic function, as their condition may be exacerbated. As with other NSAIDs, an increase in liver enzymes may occur. Diclofenac Rapid tablets are not recommended for long-term treatment. However, if long-treatment is warranted, the hepatic function should be monitored regularly and blood counts made as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), treatment should be discontinued. Hepatitis may develop with or without prodromal symptoms. Caution should be exercised in treating hepatic porphyria patients since diclofenac may trigger an attack. Renal effects As fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state. Haematological effects During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended. As with other NSAIDs, diclofenac may temporarily inhibit blood platelet aggregation. Patients with defects of haemostasis and patients treated with anticoagulants should be monitored carefully. Caution should be exercised in treating patients with haematopoietic. Cardiovascular and cerebrovascular influences 4

5 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. Patients with a history of hypertension should be monitored and counselled adequately since fluid retention and oedemas have been reported in connection with the use of NSAIDs. Skin reactions of NSAIDs Serious skin reactions, 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 NSAIDSs (see section 4.8). Patients appear to be at 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. Diclofenac Rapid Actavis should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Pre-existing asthma In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so-called intolerance to analgesics / analgesics-asthma), Quincke s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria. 4.5 Interaction with other medicinal products and other forms of interaction Pharmacodynamic interactions Anticoagulants and anti-platelet agents Caution is recommended since concomitant administration could increase the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended. Selective serotonin re-uptake inhibitors (SSRIs) Increased risk of gastrointestinal bleeding (see section 4.4). Diuretics and antihypertensive agents NSAIDs may reduce the effect of diuretics and other antihypertensive drugs (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors). 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. Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. Concomitant treatment with potassium-sparing drugs may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4). Ciclosporin and tacrolimus Due to the effect NSAIDs have on prostaglandins, the nephrotoxic effect of ciclosporin and tacrolimus may increase. Therefore, diclofenac should be given at doses lower than those that would be used in patients not receiving ciclosporin and tacrolimus. 5

6 Other NSAIDs Concomitant treatment with other systemic NSAIDs should generally be avoided due to the increased risk of undesirable effects. Quinolone antibiotics Seizures may occur due to interaction between quinolone antibiotics and NSAIDs. This may occur in patients with or without a history of epilepsy or seizures. Caution should therefore be exercised in considering the use of a quinolone in patients who are already being treated with an NSAID. Antidiabetics Clinical trials have shown diclofenac not to affect the efficacy of oral antidiabetics. However, there are isolated reports on hypoglycaemic and hyperglycaemic effects, warranting a dose adjustment of the antidiabetics substance during treatment with diclofenac. For this reason, monitoring of the blood blucose level is recommended as a precautionary measure during concomitant therapy. Glucocorticoids Concomitant administration of NSAIDs and glucocorticoids may increase the risk of gastrointestinal undesirable effects (see section 4.4). Pharmacokinetic interactions Methotrexate Caution should be exercised when NSAID is administered less than 24 hours before or after the administration of methotrexate. The methotrexate plasma concentration and toxicity may increase as a consequence of reduced tubular renal clearance of methotrexate when NSAID is present. Combination with methotrexate in high (oncological) doses should be avoided. Lithium or digoxin NSAIDs inhibit the renal secretion of digoxin and lithium and may therefore increase the plasma concentration of these medicinal products. Monitoring of the plasma concentration is recommended during diclofenac treatment. Colestipol and cholestyramine These agents can induce a delay or decrease in aborption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/cholestyramine. Phenytoin When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin. Potent CYP2CP inhibitors Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significnat increase in peak plasma concentration and exposure to diclofenac due to inhibition of diclofenac metabolism. 4.6 Fertility, pregnancy and lactation Pregnancy The prostaglandin synthesis inhibitive effect of diclofenac may have a negative impact on pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of abortion and cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiac malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with increased dose and duration of treatment. In animals, the administration of a prostaglandin synthesis inhibitor has shown to cause failure of preand post-implantation and embryo-foetal lethality. In addition, an increased incidence of various 6

7 malformations, including cardiovascular malformations, have been reported in animals in which prostaglandin synthesis inhibitors were administered during organogenesis. Diclofenac should not be administered during the first and second trimester unless it is strictly necessary. If diclofenac is used by a woman wanting to become pregnant or in the first or second trimester of pregnancy, the dose should be kept as low as possible and the duration of treatment should be as short as possible. During the third trimester, all prostaglandin synthesis inhibitors may expose; the foetus to: - cardiopulmonary toxicity (with premature closure of ductus arteriosus and pulmonary hypertension) - renal dysfunction, which may develop into renal failure with oligohydramnios. the mother and the newborn infant at the end of pregnancy to: - possible prolongation of bleeding time, an anti-aggregating effectwhich may occur even at very low doses. - inhibition of uterine contraction resulting in delayed or prolonged labour. Consequently, diclofenac is contraindicated during the third trimester of pregnancy. Breastfeeding Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant. Fertility As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. 4.7 Effects on ability to drive and use machines Patients experiencing visual disturbances, dizziness, vertigo, somnolence or other central nervous system disturbances while taking diclofenac, should refrain from driving or using machines. 4.8 Undesirable effects Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension and heart failure have been reported in connection with administration of NSAIDs. 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). The following undesirable effects include those reported with either short-term or long-term use. Organ class Blood and lymphatic system Common ( 1/100 and <1/10): Uncommon ( 1/1,000 and <1/100) Rare ( 1/10,000 and <1/1,000 ) Thrombocytopeni a, leucopoenia, agranulocytosis, anaemia (including haemolytic and aplastic anaemia) Very rare (<1/10,000, including isolated reports) Not known: cannot be estimated from the available data 7

8 Immune system Psychiatric Nervous system Eye Ear and labyrinth Cardiac Vascular Respiratory, thoracic and mediastinal Gastrointestinal Headache and dizziness Vertigo Epigastric pain and other gastrointestinal (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia). Hypersensitivity reactions such as asthma, anaphylactic and anaphylactoid reactions (including hypotension and shock) Gastrointestinal haemorrhaging (haematemesis, melaena and bloody diarrhoea) Drowsiness Palpitations, chest pain and congestive heart failure. Hypertension, vasculitis Preumonitis, asthma (including dyspnoea) Gastritis, gastrointestinal ulcer (with or without bleeding or perforation), intestinal disturbances (such as nonspecific haemorrhagic colitis or deterioration of ulcerative colitis or Crohn s disease), stomatitis Angioneurotic oedema (including face oedema) Disorientation, depression, insomnia, nightmares, irritability, psychotic reactions Sensory dysfunctions, including paraesthesiae, memory disturbances, seizures, anxiety, tremor, taste dysfunctions, cerebrovascular accident and aseptic meningitis. Visual disturbance, blurred vision, diplopia Reduced hearing, tinnitus Myocardial infarction Pancreatitis Ischaemic colitis 8

9 Hepatobiliary Skin and subcutaneous tissue disorder Renal and urinary Reproductive system and breast General and administration site conditions Increase in serum transaminases (S-ALAT, S- ASAT) Hepatitis with or without jaundice (including aphthous stomatitis), glossitis, esophageal lesions, intestinal stenosis and constipation. Fatal fulminant hepatitis, jaundice, liver disorder Rash or itching Urticaria Bullous eruptions, eczema, erythema multiforme, Stevens- Johnson s syndrome, toxic epidermal necrolysis (Lyell s syndrome), exfoliative dermatitis, hair shedding, photosensitivity reactions, purpura, including allergic purpura Oedema Hepatic necrosis, hepatic failure Erythema Acute renal failure, urine abnormalities such as haematuria, proteinuria, interstitial nephritis, nephrotic syndrome and renal papilliary necrosis. Impotence (causative relation to diclofenac is uncertain) 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 the national reporting system listed in Appendix V. 4.9 Overdose Symptoms 9

10 There is no typical clinical image of diclofenac overdose. Overdose can cause symptoms such as nausea, vomiting, gastrointestinal haemorrhage, diarrhoea and tinnitus. Cerebral symptoms may include dizziness and ataxia developing into a state of coma or seizures. Impact on the hepatic and renal function, hypotension, respiratory depression, possibly coagulation disturbances. In the event of significant poisoning, acute renal failure and liver damage are possible. Therapeutic measures In case of serious overdose, a specialised hospital must be contacted immediately. The following therapeutic precautions should be initiated in case of overdose: Absorption from the digestive tract should be prevented as quickly as possible using activated charcoal. Gastric decontamination (e.g. vomiting, gastric lavage) may be considered after ingestion of a potentially life threatening overdose. Management of acute poising with NSAIDs, including diclofenac, essentially consists of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be initiated to avoid complications such as hypotension, renal failure, seizures, gastrointestinal irritation and respiratory depression. Special treatment such as forced diuresis, dialysis or haemoperfusion is likely to be without importance for the elimination of NSAID due to the high degree of protein-binding and distinct metabolism. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Non-steroid anti-inflammatory drug/antirheumatic, NSAID, ATC code: M01AB05 Mechanism of action Inhibits the prostaglandin synthesis. Pharmacodynamic effect The anti-inflammatory effect of diclofenac and other NSAIDs is partially due to inhibition of the prostaglandin synthesis and release of prostaglandin in connection with inflammation. Prostaglandins are involved in the development of inflammation, pain and fever. The analgetic effect of diclofenac also seems to be primarily caused by the inhibition of prostaglandin synthesis. Prostaglandins seem to make pain receptors sensitive to mechanical stimulation and other chemical mediators (e.g. bradykinin, histamine). As with other NSAIDs, diclofenac may relieve pain by inhibiting the prostaglandin synthesis peripherally and possibly centrally. Clinical effect Has an analgetic effect on moderate to severe pain. Reduces spontaneous pain and motor pain in posttraumatic and postoperative inflammatory cases. Inflammatory swelling and wound oedema is reduced. Alleviates migraine attacks and the associated symptoms of nausea and vomiting. Prostaglandins are involved in ovulation, meaning that administration of prostaglandin synthesis inhibitors may affect the fertility in women (see 4.4 and 4.6). Pain relief and reduced menstrual bleeding have been shown in clinical studies of primary dysmenorrhoea. 5.2 Pharmacokinetic properties Absorption Absorbed quickly and completely from the intestinal tract. Medium plasma concentration is 1.2 mg/ml (3.8 mmol/l), and is achieved minutes after administration of 50 mg. The absorbed quantity is linearly correlated to the dose size. Ventricular passage is quickest when the dose is taken before a meal, 10

11 but the absorbed quantity is the same. Since approximately half is metabolised on first passage through the liver, AUC is approximately half of the similar dose administered parenterally after oral or rectal administration. Distribution The pharmacological properties do not change on repeated administration, and the recommended dose interval does not accumulate. The plasma concentration in children is as in adults, provided that an equivalent dose (mg/kg) is administered. The protein-binding degree is 99.7%; half-life is 1-2 hours. Approximately 60% is excreted renally as glucuronide conjugate and as metabolites. Less than 1% is excreted unchanged. The remaining is excreted biliarily. Elimination At creatinine clearance < 10 ml/min, the plasma concentration of hydroxyl metabolites is approximately 4 times higher than in normal subjects. However, the metabolites are ultimately eliminated biliarily. 5.3 Preclinical safety data There are no preclinical data available deemed relevant to clinical safety besides the data described in other sections of this summary of product characteristics. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Silica colloidal anhydrous Sodium starch glycollate Povidone Maize starch Anhydrous calcium hydrogen phosphate Magnesium stearate (E470b) Polyvinyl alcohol Titanium dioxide (E171). Talcum (E553b) Soyalecithin (E322) Red iron oxide (E172) Xanthane rubber (E415) Yellow iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage None. 6.5 Nature and contents of container Blister pack (aluminium/aluminium): 6, 10, 12, 20, 30, 50 or 100 tablets. PP container with LDPE lid and drying agent: 10, 20, 30, 50 and 100 tablets. 11

12 Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special precautions are required. 7. MARKETING AUTHORISATION HOLDER [To be completed nationally] 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION [To be completed nationally] 10. DATE OF REVISION OF THE TEXT