Descrizione Clinica
ENANTYUM RIVESTATE COMPRESENTS WITH FILM
active ingredients
Each tablet contains: dexketoprofene 12.5 mg or 25 mg as dexketoprofene tromethylamolo. For the full list of excipients, see paragraph 6.1.Excellent
microcrystalline microcrystalline corn starch acid glycerol distearate ipromellose titanium propylene glycol macrogol 6000Therapeutic indications
Syntomatic treatment of painful affections of mild to moderate intensity, such as musculoskeletal pain, dysmenorrhea, dental pain.Contraindications
Enantyum tablets should not be used in the following cases: - patients with hypersensitivity to the active ingredient, or other NSAIDs, or any of the excipients listed in paragraph 6.1; - patients in which active ingredients to similar action (e.g. acetylsalicylic acid, or other NSAIDs) trigger asthma, bronchospasm, acute rhinitis, or are the cause of nasal polyps, urticaria or angioneurotic edema; - photoallergic or phototoxic reactions known during treatment with ketoprofen or fibres; - patients with history of bleeding or gastrointestinal perforation in relation to previous NSAID therapy; - patients with active peptic ulcer/gastrointestinal hemorrhage or positive anamnesi for bleeding, ulceration or gastrointestinal perforation; - patients with chronic dyspepsia; - patients who have other active bleeding or clotting disorders; - patients with Crohn disease or ulcerative colitis; - patients with severe heart failure; - patients with moderate to severe renal dysfunction (creatiny cleavage ≤ 59 ml/min); - patients with severe impairment of liver function ( Child-Pugh score 10 - 15); - patients with hemorrhagic dialysis and other clotting disorders; - patients with severe dehydration (caused by vomiting, diarrhea or insufficient liquid intake); - during the third trimester of pregnancy and nursing (see paragraph 4.6).Population
Population Adults Depending on the nature and severity of the pain, the recommended dose is generally 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 minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).Enantyum tablets are not indicated for long-term treatment and administration should be limited to the symptomatic period only. Seniors In the elderly patient it is recommended to start therapy at the lower limit of the dosage range (50 mg of total daily dose). The dosage can be increased so as to reach the one used for the general population only after a good general tolerance has been established. Epathetic insufficiency Patients with mild to moderate liver failure should start therapy at reduced doses (50 mg of total daily dose) and should be subjected to strict medical control. Enantyum tablets should not be used in patients with severe liver failure. Renal insufficiency In patients with mild kidney damage (cancer 60 - 89 ml/min), the initial dosage must be reduced to 50 mg of total daily dose (see paragraph 4.4). Enantyum tablets should not be used in patients with severe renal damage (cancerance of creatinine ≤ 59 ml/min) (see paragraph 4.3). Paediatric population Enantyum tablets has not been studied in children and adolescents. Therefore, safety and effectiveness have not been established and the product should not be used in children and adolescents. Method of administration The tablet must be swallowed with a sufficient amount of liquid (e.g. a glass of water). The concomitant administration of food delays the rate of absorption of the drug (see “Property Pharmacokinetics”), therefore in case of acute pain it is recommended that the administration take place at least 30 minutes before meals.Conservation
Keep the blister in the outer packing to keep it safe from the light.Warnings
Use with precaution in patients with history of allergic conditions. Concurrent use of Enantyum and other NSAIDs, including selective cycloxygenase 2 inhibitors must be avoided. Undesirable effects can be minimized with the use of the lowest effective dose for the shortest possible duration of treatment needed to control symptoms (see paragraph 4.2, and the paragraphs below on gastrointestinal and cardiovascular risks). Gastrointestinal safety Gastrointestinal bleeding, ulceration or perforation, which may be fatal, have 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, the treatment should be discontinued.The risk of gastrointestinal bleeding, ulceration or perforation increases 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.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).These patients should start treatment on the lowest possible dose.As with all NSAIDs, before initiating treatment with dexketoprofen, previous histories of oesophagitis, gastritis and/or peptic ulcer should be enquired about and ensure that they have completely healed.Patients with gastrointestinal symptoms or a history of gastrointestinal disorders should be carefully observed for 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 receiving concomitant low dose acetylsalicylic acid or other drugs likely to increase gastrointestinal risk (see below and section 4.5).Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.Caution is 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 acetylsalicylic acid (see section 4.5). Kidney safety To be used with caution in patients with impairment of kidney function. In these patients, the use of NSAIDs can cause a worsening of kidney function, fluid retention and edema. Caution is also required in patients under diuretic therapy or in patients who may develop hypovolemia, due to an increased risk of nephrotoxicity. During treatment an adequate supply of liquids must be ensured to prevent dehydration associated with a possible increase in kidney toxicity. Like all NSAIDs, the drug can cause an increase in azotemia and creatininemia. As with other prostaglandin synthesis inhibitors, it can be associated with adverse effects to the kidney that can lead to glomerular nephritis, interstitial nephritis, kidney papillar necrosis, nephrosic syndrome and acute kidney failure. Older patients tend more easily to have reduced kidney function (see paragraph 4.2). Epathetic safety To be used with caution in patients with impaired liver function.Like other NSAIDs, the medicinal product may cause slight transient increases in some liver parameters and also significant increases in AST and ALT.If a significant increase in these parameters occurs, treatment must be discontinued.Elderly patients are more likely to suffer from reduced liver function (see section 4.2). Cardiovascular and cerebrovascular safety Adequate monitoring and appropriate instructions are necessary in patients with history of hypertension and/or mild or moderate heart failure. Special caution is required in patients with history of heart disease, especially those with previous episodes of heart failure. In these patients, there has been an increase in the risk of triggering heart failure, as retention of fluids and edema were found in association with the NSAIDs. Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially high doses and long-term treatments) may be associated with a modest increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There is no sufficient data to exclude a similar risk for dexketoprofene. Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischemic cardiopathy, peripheral arterial disease and/or cerebrovascular disease should be treated with dexketoprofen only after careful evaluation. Analogue considerations must be made before starting a long-term treatment in patients with risk factors for cardiovascular diseases (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking). All non-selective NSAIDs are able to inhibit piastrinic aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. Therefore, the use of dexketoprofen in patients receiving other treatments that interfere with hemostasis, such as warfarin or other cumarinics or eparine is not recommended (see paragraph 4.5). Older patients tend more easily to have reduced cardiovascular function (see paragraph 4.2). Skin reactions Severe skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis were reported very rarely in association with the use of NSAIDs. Patients seem to be more at risk of such reactions at the beginning of therapy, as the appearance of reactions occurs in most cases within the first month of treatment. Treatment with Enantyum must be stopped at the first appearance of skin rashes, mucosal lesions or any other sign of hypersensitivity. Other information Particular caution is required in patients: - with a congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria) - with dehydration - immediately after major surgery If the physician considers long-term therapy with dexketoprofen necessary, liver and kidney function and blood counts should be monitored regularly.Severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed very rarely.Treatment should be stopped at the first signs of severe hypersensitivity following intake of Enantyum.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 rest of the population.Administration of this medicinal product may cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs (see section 4.3).Exceptionally, chickenpox may be the cause of serious skin complications and mild tissue infections.To date, the contribution of NSAIDs in the worsening of these infections cannot be excluded.Therefore, it is advisable to avoid the use of Enantyum in case of chickenpox.Enantyum should be administered with caution in patients suffering from haematopoietic disorders, systemic lupus erythematosus or in the presence of connective tissue diseases.As with other NSAIDs, dexketoprofen may mask the symptoms of infectious diseases. Paediatric population Safety of use in children and adolescents has not been established.Interactions
The following interactions are characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs) in general: Non-advisable associations: - Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high doses of salicylates (≥ 3 g/day): the concomitant administration of several NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect;- Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4) due to the high plasma protein binding of dexketoprofen and the inhibition of platelet function and damage to the gastroduodenal mucosa.If the combination cannot be avoided, careful clinical observation and monitoring of laboratory parameters should be performed;- Heparins: increased risk of haemorrhage (due to inhibition of platelet function and damage to the gastroduodenal mucosa).If the combination cannot be avoided, careful clinical observation and monitoring of laboratory parameters should be performed;- Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4);- Lithium (described with several NSAIDs): NSAIDs increase blood levels of lithium which may reach toxic levels (decreased renal excretion of lithium).This parameter therefore requires careful monitoring during the institution, adjustment and interruption 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 sulfonamides: the toxic effects of these substances may be potentiated. Associations that require caution: - Diuretics, ACE inhibitors, aminoglycosidic antibiotics and antagonists of angiotensin receptor II: dexketoprofen can reduce the effect of diuretics and other antihypertensive drugs. In some patients with reduced kidney function (e.g. dehydrated patients or elderly patients with impaired kidney function), the concomitant administration of agents that inhibit cycloxygenase and ACE inhibitors, antagonists of angiotensin II receptor or aminoglycosidic antibiotics may cause further deterioration of kidney function, which is usually reversible. In case of a combined prescription of dexketoprofen with a diuretic, it is essential to ensure that the patient is properly hydrated and monitor the kidney function at the beginning of the treatment (see paragraph 4.4 Special warnings and precautions of use). - Metotrexate, used at doses less than 15 mg/week: increased hematological toxicity of metotrexate due to a decrease in its kidney clearance caused by anti-inflammatory drugs generally. It counts weekly blood in the first weeks of the association. Increased surveillance, as well as for the elderly patient, in case of even mild kidney failure. - Pentoxyphylline: increased risk of hemorrhage. Increase clinical monitoring and control bleeding time more frequently. - Zidovudina: risk of increased toxicity on the erythrocyte line due to action on reticulocytes, with occurrence of severe anemia a week after the start of treatment with NSAIDs. Check the complete hemochrome and reticulocytes every one or two weeks during treatment with NSAIDs. - Sulphonluree: NSAIDs can increase the hypoglycemic effect of sulphonluree by spying on plasma protein binding sites. Combinations to be taken into account: - Beta-blockers: Treatment with NSAIDs can decrease their antihypertensive effect due to the inhibition of prostaglandin synthesis. - Ciclosporine and tacrolimus: NSAIDs can enhance nephrotoxicity due to the effects mediated by kidney prostaglandins. During association therapy, renal function must be kept under control. - Trombolitics: increased risk of hemorrhage. - Serotonin reuptake selective agents and inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see paragraph 4.4). - Probenecid: it can increase the plasma concentrations of dexketoprofen; this interaction can be due to an inhibitory mechanism at the level of the secretion of the renal tubule and glucuronoconjugation and requires a adjustment of the dose of dexketoprofene. - Cardioactive glycosides: NSAIDs can increase plasma concentrations of glycosides. - Mifepristone: there is the theoretical risk that prostaglandin-synthesis inhibitors may alter the effectiveness of mifepristone. Limited evidence suggests that the concomitant administration of NSAIDs on the same day of prostaglandine administration does not adversely affect the effects of mifepristone or prostaglandins on cervical maturation or uterine contractility and does not reduce the clinical effectiveness of the medical interruption of pregnancy. - Chinolonic antibiotics: animal studies indicate that high doses of chinolone in combination with NSAIDs can increase the risk of convulsion occurrence. - Tenofovir: Concurrent use with NSAIDs can increase atathemia and creatinine, so the kidney function must be monitored to control a possible synergistic influence on the kidney function. - Deferasirox: Concurrent use with NSAIDs can increase the risk of gastrointestinal toxicity. When administering deferasirox with these substances it is necessary to carry out rigorous clinical monitoring. - Pemetrexed: Concurrent use with NSAIDs can reduce the elimination of pemetrexed, therefore it is necessary to exercise caution in administering higher doses of NSAIDs; in patients with mild to moderate renal failure (clearance of creatinine between 45 and 79 ml/min), the concomitant administration of pemetrexed with NSAID should be avoided for 2 days before and 2 days after administration.Effects
In the table below, divided by classification for systems and organs and listed in frequency order, are reported adverse events, probably related to dexketoprofen, verified during the course of clinical studies and after the marketing of Enantyum tablets:| CLASSIFICATION FOR SYSTEMS AND ORGANI | Common (≥1/100, | Not common (≥1/1.000, | Rare (≥1/10.000, | Very rare ( |
| Emolinfopoietic system pathologies | neutropenia thrombocytopenia | |||
| Immune system disorders | edema of larynx | anaphylactic reactions, including anaphylactic shock | ||
| Disorders of metabolism and nutrition | anorexia | |||
| Psychiatric disorders | insomnia; anxiety | |||
| Diseases of the nervous system | headache, dizziness, drowsiness | anger, syncope | ||
| Pathologies of the eye | sight blurring | |||
| Ear and labyrinth pathologies | dizziness | tinnitus | ||
| Heart disease | palpitations | tachycardia | ||
| Vascular diseases | heat flashes | hypertension | hypotension | |
| Respiratory, chest and mediastinic pathologies | bradypnea | bronchospasm, dispnea | ||
| Gastrointestinal diseases | nausea and/or vomiting, abdominal pain, diarrhoea, dyspepsia. | gastriti, stipsi, dry mouth, flatulence | peptic ulcer, peptic ulcer haemorrhage or peptic ulcer perforation (see section 4.4) | pancreatis |
| Hepatobiliary diseases | hepatocellular injury | |||
| Pathologies of skin and subcutaneous tissue | rash | hives, acne, increased sweating | stevens Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial edema, photosensitivity reaction, pruritus | |
| Diseases of musculoskeletal system and connective tissue | backache | |||
| Kidney and urinary pathologies | acute kidney failure, polyuria | nephritis or nephrosic syndrome | ||
| Reproductive system and breast disorders | menstrual disorders;prostate disorders | |||
| Systemic pathologies and conditions for administration | fatigue, pain, astenia, shivers, sense of malaise | peripheral edema | ||
| Diagnostic examinations | abnormalities in liver function tests |
Overdosing
The symptoms following overdose are unknown.Similar drugs have caused gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (drowsiness, dizziness, disorientation, headache) disorders.In case of accidental or excessive intake, immediately adopt an appropriate symptomatic therapy based on the clinical conditions of the patient.Activated charcoal should be administered within one hour if more than 5 mg/kg have been ingested by an adult or a child.Dexketoprofen can be eliminated by dialysis.Enantyum tablets is contraindicated during the third trimester of pregnancy and during lactation. (see paragraph 4.3).
Pregnancy
Inhibition of prostaglandin synthesis can negatively affect pregnancy and/or embryo/fetal development. Results of epidemiological studies suggest an increased risk of abortion and cardiac malformation and gastroschisis after the use of an inhibitor of prostaglandin synthesis in the early stages of pregnancy. The absolute risk of heart failure is increased from less than 1% to about 1.5%. It has been considered that the risk increases with dose and duration of therapy. In animals, the administration of prostaglandin synthesis inhibitors showed an increase in pre- and post-system loss and embryo-fetal mortality. In addition, an increase in the incidence of various malformations, including cardiovascular disease, was reported in animals that had been given inhibitors of prostaglandin synthesis during the organogenetic period. However, studies on animals with dexketoprofen did not indicate reproductive toxicity (see paragraph 5.3). During the first and second trimester of pregnancy, dexketoprofen should not be administered if not in strictly necessary cases. If dexketoprofene is used by a woman waiting for conception, or during the first and second trimester of pregnancy, the dose and duration of treatment must be kept as low as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose the fetus to: - cardiopulmonary toxicity (with premature closure of arterial duct and pulmonary hypertension); - kidney dysfunction, which can progress in kidney failure with oligoidramnios; the mother and the newborn, at the end of pregnancy, to: - possible prolongation of bleeding time, an anti-aggregating effect that can occur even at very low doses; - inhibition of uterine contractions resulting in delay or extension of labor.Breastfeeding
It has not been established whether dexketoprofen is secreted in human milk.Enantyum is contraindicated during breastfeeding (see section 4.3).Fertility
As with other NSAIDs, the use of Enantyum can reduce female fertility and is not recommended in women who intend to conceive. It should be considered the interruption of treatment with dexketoprofen in women who have difficulty in conception or subject to infertility investigations.Source: Farmadati
