ENANTYUM FILM-COATED TABLETS

Symptomatic treatment of painful conditions of mild to moderate intensity, such as musculoskeletal pain, dysmenorrhoea, dental pain.

Therapeutic indications

Symptomatic treatment of painful conditions of mild to moderate intensity, such as musculoskeletal pain, dysmenorrhoea, dental pain.

Dosage and method of use

Posology Adults Depending on the nature and intensity of the pain, the recommended dose is usually 12.5 mg every 4-6 hours or 25 mg every 8 hours. The total daily dose should not exceed 75 mg. Undesirable effects may be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.4). Enantyum tablets are not indicated for long-term treatments and the administration should be limited to the symptomatic period only. Elderly In elderly patients it is recommended to start therapy at the lower end of the dose range (50 mg total daily dose). The dosage may be increased to that used for the general population only after good general tolerability has been established. Hepatic insufficiency Patients with mild to moderate hepatic insufficiency should start therapy at low doses (50 mg total daily dose) and should be closely monitored. Enantyum tablets should not be used in patients with severe hepatic impairment. Renal impairment In patients with mild renal impairment (creatinine clearance 60 - 89 ml/min), the initial dosage should be reduced to 50 mg total daily dose (see section 4.4). Enantyum tablets should not be used in patients with moderate to severe renal impairment (creatinine clearance ≤ 59 ml/min) (see section 4.3). Pediatric population Enantyum tablets have not been studied in children and adolescents. Therefore, safety and efficacy have not been established and the product should not be used in children and adolescents. Method of administration The tablet should be swallowed with a sufficient amount of liquid (eg a glass of water). Concomitant administration of food delays the absorption rate of the drug (see section "Pharmacokinetic properties"), therefore in case of acute pain it is recommended that administration takes place at least 30 minutes before meals.

Contraindications

Enantyum tablets should not be used in the following cases: - patients with hypersensitivity to the active substance, or to other NSAIDs, or to any of the excipients listed in section 6.1; - patients in whom active ingredients with similar action (eg acetylsalicylic acid, or other NSAIDs) trigger asthma attacks, bronchospasm, acute rhinitis, or are the cause of nasal polyps, urticaria or angioneurotic oedema; known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates; - patients with a history of gastrointestinal bleeding or perforation in relation to previous NSAID therapy; - patients with active peptic ulcer/gastrointestinal haemorrhage or a history of gastrointestinal bleeding, ulceration or perforation; - patients with chronic dyspepsia; - patients who have other active bleeding or bleeding disorders; - patients with Crohn's disease or ulcerative colitis; - patients with severe heart failure; - patients with moderate to severe renal dysfunction (creatinine clearance ≤ 59 ml/min); - patients with severe hepatic impairment (Child-Pugh score 10 - 15); - patients with bleeding diathesis and other coagulation disorders; - patients with severe dehydration (caused by vomiting, diarrhea or insufficient fluid intake); - during the third trimester of pregnancy and lactation (see section 4.6).

Side effects

The table below, divided by system organ classification and listed in order of frequency, shows the adverse events, probably related to dexketoprofen, which occurred during the course of clinical trials and after marketing of Enantyum tablets:

The most common side effects are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, especially in the elderly, may occur (see section 4.4). Following administration, nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported (see section 4.4 "Special warnings and precautions for use"). Less frequently gastritis has been observed. Oedema, hypertension and heart failure have been reported in association with NSAID therapy. As with other NSAIDs, the following undesirable effects may occur: aseptic meningitis, which can predominantly occur in patients with systemic lupus erythematosus or connective tissue disease; haematological reactions (purpura, aplastic and haemolytic anemia, and rarely agranulocytosis and marrow hypoplasia). Bullous reactions including Stevens Johnson syndrome and toxic epidermal necrolysis (very rare). Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see section 4.4). paragraph 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization 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 at http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.

Special warnings

Use with caution in patients with a history of allergic conditions. Concomitant use of Enantyum and other NSAIDs, including selective cyclooxygenase 2 inhibitors should be avoided. Undesirable effects may be minimized by using the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see section 4.2, and sections on gastrointestinal and cardiovascular risks below). Gastrointestinal safety Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at various stages of treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. If gastrointestinal bleeding or ulceration occurs in patients receiving Enantyum, treatment should be discontinued. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID doses, in patients with a history of ulcer, especially if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. Elderly: The elderly have an increased frequency of undesirable reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal (see section 4.2). These patients should start treatment with the lowest possible dose. As with all NSAIDs, before starting treatment with dexketoprofen, it is necessary to investigate previous histories of oesophagitis, gastritis and/or peptic ulcers and ensure their total recovery. Patients with gastrointestinal symptoms or a history of gastrointestinal disturbances should be closely monitored for the appearance of digestive disturbances, especially gastrointestinal bleeding. NSAIDs should be administered with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8). Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients concomitantly taking low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk (see below and paragraph 4.5). Patients with a history of gastrointestinal toxicity, particularly if elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. Caution is advised in patients receiving concomitant treatments that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid (see section 4.5). Renal Safety To be used with caution in patients with impaired renal function. In these patients, the use of NSAIDs can cause deterioration of renal function, fluid retention and oedema. Caution is also required in patients receiving diuretic therapy or in those patients who may develop hypovolaemia, due to an increased risk of nephrotoxicity. Adequate fluid intake should be ensured during treatment to prevent dehydration associated with a possible increase in renal toxicity. Like all NSAIDs, the medicine can cause an increase in blood urea nitrogen and creatininemia. As with other prostaglandin synthesis inhibitors, it may be associated with adverse effects on the kidney which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. Elderly patients are more likely to have impaired renal function (see section 4.2). Hepatic Safety To be used with caution in patients with impaired hepatic function. Like other NSAIDs, the medicine can cause transient slight increases in some liver parameters and also significant increases in AST and ALT. In the event of a significant increase in these parameters, the treatment must be discontinued. Elderly patients are more likely to suffer from impaired liver function (see section 4.2). Cardiovascular and cerebrovascular safety Appropriate monitoring and advice are required in patients with a history of hypertension and/or mild to moderate heart failure. Particular caution is needed in patients with a history of cardiac disease, especially those with a history of heart failure. In fact, an increased risk of triggering heart failure has been reported in these patients, since fluid retention and edema have been reported in association with treatment with NSAIDs. Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There are insufficient data to exclude a similar risk for dexketoprofen. Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with dexketoprofen after careful consideration. Similar considerations should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). All non-selective NSAIDs are able to inhibit platelet aggregation and prolong bleeding time by inhibition of prostaglandin synthesis. Therefore, the use of dexketoprofen in patients receiving other treatments that interfere with haemostasis, such as warfarin or other coumarins or heparins is not recommended (see section 4.5). Elderly patients are more likely to have decreased cardiovascular function (see section 4.2). Skin reactions 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 NSAIDs. Patients appear to be most at risk of such reactions early in therapy, as the onset of reactions occurs in the majority of cases within the first month of treatment. Treatment with Enantyum should be discontinued at the first appearance of skin rashes, mucosal lesions or any other sign of hypersensitivity. Other information Particular caution is required in patients: - with an inborn disorder of porphyrin metabolism (e.g. acute intermittent porphyria) - with dehydration - immediately after major surgery If the doctor considers long-term dexketoprofen therapy necessary, the functional liver and kidney and blood counts (blood counts) should be checked regularly. Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been observed very rarely. Treatment should be discontinued at the first signs of severe hypersensitivity following Enantyum intake. Any necessary medical procedures should be initiated by healthcare professionals based on symptoms. Patients with asthma associated with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than the general population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs (see section 4.3). Exceptionally, chickenpox can be the cause of serious skin complications and mild tissue infectious complications. To date, the contribution of NSAIDs in the worsening of these infections cannot be excluded. Therefore, it is advised to avoid using Enantyum in case of chicken pox. Enantyum should be administered with caution to patients suffering from haematopoietic disorders, systemic lupus erythematosus or connective tissue disease. As with other NSAIDs, dexketoprofen can mask the symptoms of infectious diseases. Pediatric population The safe use in children and adolescents has not been established.

Pregnancy and breastfeeding

Enantyum tablets are contraindicated during the third trimester of pregnancy and while breastfeeding. (see section 4.3). Pregnancy Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo/foetal development. Results of epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in the early stages of pregnancy. The absolute risk of cardiac malformations is increased from less than 1% to approximately 1.5%. The risk was thought to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period. However, animal studies with dexketoprofen have not indicated reproductive toxicity (see section 5.3). During the first and second trimester of pregnancy, dexketoprofen should not be administered unless strictly necessary. If dexketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose and duration of treatment should be kept as low as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the fetus to: - cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); - renal dysfunction, which can progress to renal failure with oligohydramnios; the mother and the newborn, at the end of pregnancy, to: - possible prolongation of bleeding time, an anti-aggregating effect which can occur even at very low doses; - inhibition of uterine contractions resulting in delayed or prolonged labour. Breast -feeding It has not been established whether dexketoprofen is excreted in breast milk. Enantyum is contraindicated during lactation (see section 4.3). Fertility As with other NSAIDs, the use of Enantyum may reduce female fertility and is not recommended in women attempting to conceive. Consideration should be given to discontinuing dexketoprofen treatment in women who are having difficulties conceiving or who are undergoing investigation of infertility.

Expiration and conservation

Do not store above 30°C. Keep the blister in the outer carton in order to protect from light.

Interactions with other drugs

The following interactions are characteristic of non-steroidal anti-inflammatory drugs (NSAIDs) in general: Combinations not advisable : - Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high doses of salicylates (≥ 3 g/day): the concomitant administration of several NSAIDs can increase the risk of ulcers and gastrointestinal bleeding due to a synergistic effect; - Anticoagulants: NSAIDs may potentiate the effects of anticoagulants such as warfarin (see section 4.4) due to the high plasma protein binding of dexketoprofen and inhibition of platelet function and damage to the gastroduodenal mucosa. If the association cannot be avoided, careful clinical observation and laboratory monitoring should be performed; - Heparins: increased risk of bleeding (due to inhibition of platelet function and damage to the gastroduodenal mucosa). If the association cannot be avoided, careful clinical observation and laboratory monitoring should be performed; - Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4); - Lithium (described with various NSAIDs): NSAIDs increase blood levels of lithium which can reach toxic values ​​(decreased renal excretion of lithium). This parameter therefore requires careful monitoring during the establishment, adjustment and discontinuation of treatment with dexketoprofen; - Methotrexate, used at high doses such as 15 mg/week or more: increased haematological toxicity of methotrexate due to a decrease in its renal clearance, caused by anti-inflammatory drugs in general; - Hydantoins and sulphonamides: the toxic effects of these substances can be enhanced. Combinations requiring caution : - Diuretics, ACE inhibitors, aminoglycoside antibiotics and angiotensin II receptor antagonists: dexketoprofen can reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), the concomitant administration of agents that inhibit cyclo-oxygenase and ACE inhibitors, angiotensin II receptor blockers or aminoglycoside antibiotics may cause further deterioration of kidney function, which is usually reversible. In case of combined prescription of dexketoprofen with a diuretic, it is essential to ensure that the patient is adequately hydrated and to monitor renal function at the start of treatment (see section 4.4 Special warnings and precautions for use). - Methotrexate, used at doses lower than 15 mg/week: increased haematological toxicity of methotrexate due to a decrease in its renal clearance caused by anti-inflammatory drugs in general. Weekly blood count in the first weeks of the association. Increased surveillance, as well as for the elderly patient, in the event of even mild renal insufficiency. - Pentoxifylline: increased risk of bleeding. Increase clinical monitoring and check bleeding time more frequently. - Zidovudine: risk of increased erythrocyte lineage toxicity due to action on reticulocytes, with onset of severe anemia one week after starting treatment with NSAIDs. Check complete blood count and reticulocytes every one to two weeks during treatment with NSAIDs. - Sulphonylureas: NSAIDs may increase the hypoglycaemic effect of sulphonylureas by displacement from plasma protein binding sites. Combinations to be taken into consideration : - Beta-blockers: treatment with NSAIDs can decrease their antihypertensive effect due to inhibition of prostaglandin synthesis. - Cyclosporine and tacrolimus: NSAIDs can enhance their nephrotoxicity due to effects mediated by renal prostaglandins. Renal function should be monitored during combination therapy. - Thrombolytics: increased risk of haemorrhage. - Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4). - Probenecid: may increase plasma concentrations of dexketoprofen; this interaction may be due to an inhibitory mechanism at the level of renal tubular secretion and glucuronoconjugation and requires an adjustment of the dexketoprofen dose. - Cardiac glycosides: NSAIDs can increase the plasma concentrations of glycosides. - Mifepristone: There is a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone. Limited evidence suggests that concomitant administration of NSAIDs on the same day as prostaglandin administration does not adversely affect the effects of mifepristone or prostaglandins on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy. - Quinolone antibiotics: Animal studies indicate that high doses of quinolones in combination with NSAIDs may increase the risk of convulsions. - Tenofovir: Concomitant use with NSAIDs may increase blood urea nitrogen and creatinine, consequently renal function should be monitored to control a possible synergistic influence on renal function. - Deferasirox: Concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Strict clinical monitoring should be performed when deferasirox is administered with these substances. - Pemetrexed: concomitant use with NSAIDs may reduce the elimination of pemetrexed, therefore caution should be exercised when administering higher doses of NSAIDs; in patients with mild to moderate renal impairment (creatinine clearance between 45 and 79 mL/min), co-administration of pemetrexed with NSAIDs should be avoided for 2 days before and 2 days after pemetrexed administration.

Overdose

The symptoms following an overdose are not known. Similar drugs have produced gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (drowsiness, dizziness, disorientation, headache) disturbances. In case of accidental or excessive intake, immediately adopt adequate symptomatic therapy based on the patient's clinical conditions. Activated charcoal should be administered within one hour if more than 5 mg/kg has been ingested by an adult or child. Dexketoprofen can be removed by dialysis.

Active principles

Each tablet contains: dexketoprofen 12.5 mg or 25 mg as dexketoprofen trometamol. For the full list of excipients, see section 6.1.

Excipients

maize starch microcrystalline cellulose sodium starch glycolate glycerol distearate hypromellose titanium dioxide propylene glycol macrogol 6000