LEVIADEX 20CPR 25MG

DEXKETOPROFENE PHARMACARE 25 MG COMPRESENT RIVES WITH FILM

active ingredients

Each tablet contains: dexketoprofene 25 mg as dexketoprofene tromethylamolo. Excipients with known effects: 6.3 mg of sodium (as sodium starch glyculate). For the full list of excipients, see paragraph 6.1.

Excellent

Eccipients of the nucleus: Corn starch Cellulose microcrystalline Sodium glyculate starch Glicerol Exciting coating Ipromellose (E-464) Titanium Dioxide (E-171) Macrogol 400.

Therapeutic indications

Syntomatic treatment of mild to moderate pain, such as musculoskeletal pain, dysmenorrhea and dental pain.

Contraindications

Dexketoprofene Pharmacare tablets should not be administered in the following cases: • patients with hypersensitivity to the active ingredient, other NSAIDs, or any of the excipients listed in paragraph 6.1; • patients who have developed asthma, bronchospasm, acute rhinitis, nasal polyps, hives or angiourotic edema after exposure to active ingredients from the similar mechanism of action (e.g. acetyllic acid, or other NSAIDs); • patients with photoallergic or phototoxic reactions known during treatment with ketoprofen or fibres; • patients with bleeding anamnesis or gastrointestinal perforation related to a previous therapy with NSAIDs; • patients with active peptic ulcer/gastrointestinal bleeding in place or any previous anamnestic bleeding, ulceration or gastrointestinal perforation; • patients with chronic dyspepsia; • patients who have other bleeding in place or clotting disorders; • patients with Crohn disease or ulcerative colitis; • patients with severe heart failure; • patients with moderate to severe renal insufficiency (clearance of creatinine

Population

Population Adults Depending on the nature and intensity of 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 can be minimized using the minimum effective dose for the shortest duration necessary to control symptoms (see paragraph 4.4). Dexketoprofene Pharmacare Tablets is not intended for long-term use and treatment is limited to symptomatic period only. Pediatric population Dexketoprofene Pharmacare was not studied in children and adolescents. Therefore, safety and effectiveness in children and adolescents were not established and the product should not be used in children and adolescents. Seniors In older patients it is recommended to start therapy with the lowest therapeutic dose (50 mg of total daily dose). The dosage can be increased so as to reach the recommended one for the general population only after a good general tolerance has been established. Epathetic Comprogation Patients with mild to moderate liver impairment should start therapy at reduced doses (50 mg of total daily dose) under strict medical control. Dexketoprofene Pharmacare tablets should not be used in patients with severe liver failure. Renal Compromise In patients with mild renal impairment (cantonance of creatinine 60 - 89 ml/min) the initial dosage must be reduced to 50 mg of total daily dose (see paragraph 4.4). Dexketoprofene Pharmacare tablets should not be used in patients with mild to severe renal impairment (cancer ≤59 ml/min) (see paragraph 4.3). Method of administration The tablets must be swallowed whole 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 the pharmacokinetic properties), so in case of acute pain it is recommended to administer the drug at least 30 minutes before meals.

Conservation

Do not store at temperature above 25°C. Store blister packs in the external packaging to protect the medicine from light.

Warnings

Use carefully in patients with anamnesi of allergic conditions. Concurrent use of Dexketoprofene Pharmacare with other NSAIDs, including selective cyclooxygenase-2 inhibitors must be avoided. Undesirable effects can be minimized using the lowest effective dose for the time strictly necessary to control symptoms (see paragraph 4.2 and gastrointestinal and cardiovascular risks below). Gastrointestinal safety Blood, ulceration or potentially fatal gastrointestinal perforation have been reported with all NSAIDs, at any time during treatment, with or without premonitory symptoms or previous anamnes of serious gastrointestinal events. When in patients with Dexketoprofene Pharmacare, bleeding or gastrointestinal ulceration occurs, therapy must be stopped. The risk of bleeding, ulceration or gastrointestinal perforation increases with the increase of the dosage of NSAIDs in patients with pregress ulcer, especially if complicated by hemorrhage or perforation (see paragraph 4.3) and in the elderly. The elderly have a greater frequency of adverse reactions to the NSAIDs, especially bleeding and gastrointestinal perforation that can be fatal (see paragraph 4.2). These patients must begin treatment with the minimum dose available. As with all NSAIDs, before starting treatment with dexketoprofene, it is necessary to investigate esophagitis, gastritis and/or peptic ulcers and ensure their total healing. Patients with gastrointestinal or anamnesi symptoms of gastrointestinal disease must be carefully monitored for the appearance of digestive disorders, especially gastrointestinal bleeding. NSAIDs should be given with caution to patients with anamnes of gastrointestinal pathologies ( ulcerative colitis, Crohn's disease), since such conditions may be exacerbated (see paragraph 4.8). Concurrent use of protective agents (e.g. misoprostol or protonic pump inhibitors) must be considered for these patients and patients who receive at the same time a low dose of acetylsalicylic acid or other drugs that may increase gastrointestinal risk (see below and paragraph 4.5). Patients with gastrointestinal toxicity anamnesis, especially if elderly, must report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially in the early stages of treatment. Precaution is recommended in patients who are administered at the same time drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, and anti-aggregating agents such as acetylsalicylic acid (see paragraph 4.5). Renal safety Caution should be used 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. It is also necessary in patients in diuretic therapy or who risk developing hypovolemia for an increase in the risk of nephrotoxicity. During treatment it is necessary to ensure adequate intake of liquids 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, undesirable effects can occur on the kidney system that can lead to glomerular nephritis, interstitial nephritis, kidney papillar necrosis, nephrosic syndrome and acute kidney failure. Senior patients are the most exposed to the risk of kidney failure (see paragraph 4.2). Epathetic safety Caution is needed in patients with impairment of liver function. Like other NSAIDs, the drug can cause slight transient increments of certain parameters of liver function, and also significant increases of AST and ALT. In the event of a significant increase in these parameters, therapy must be interrupted. Senior patients are the most exposed at risk of liver failure (see paragraph 4.2). Cardiovascular and cerebrovascular safety For patients with an anamnesi of hypertension and/or mild to moderate heart failure, appropriate monitoring is required. Particular caution should be given in patients with history of heart disease, especially in those with previous episodes of heart failure. In these patients, an increase in the risk of heart failure was reported, as fluid retention and edema were reported in association with 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 slight increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There is no sufficient data to exclude such risk for dexketoprofene. Therefore patients with uncontrolled hypertension, congestive heart failure, established ischemic cardiopathy, peripheral arteriopathy and/or cerebrovascular pathologies should be treated with dexketoprofen only after careful evaluation. Analogue attention should be paid before starting long-term treatment in patients with risk factors for cardiovascular disease (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. The use of dexketoprofen is therefore not recommended in patients receiving another therapy that interferes with hemostasis, such as warfarin or other cumarinics or eparine (see paragraph 4.5). Older patients are more likely to have alterations in the cardiovascular function (see paragraph 4.2). Skin reactions Severe skin reactions, some of which fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and epidermal toxic necrolysis, have been reported very rarely in association with the use of NSAIDs (see paragraph 4.8). In the early stages of therapy patients seem to be more at risk of reaction onset, as the appearance of reactions occurs in most cases within the first month of treatment. At the first appearance of skin rash, mucosa lesions or any other symptom of hypersensitivity, the therapy with Dexketoprofene Pharmacare must be interrupted. Masking the symptoms of underlying infections Dexketoprofen can mask the symptoms of infection, which may delay the start of proper treatment and thus worsen the outcome of the infection. This was observed in bacterial pneumonia acquired in communities and bacterial complications of chickenpox. When Dexketoprofene Pharmacare is administered for pain relief related to infection, it is recommended to monitor the infection. In non-hospital contexts, the patient should contact the doctor if symptoms persist or worsen. In exceptional cases chickenpox can be associated with skin complications and light infectious complications of soft tissues. A role of NSAIDs in the aggravation of such infections cannot be excluded to this day. Therefore it is advisable to avoid the use of dexketoprofen in patients with chickenpox. Other information Particular caution is required in patients with: - congenital abnormalities of porphyrin metabolism (e.g. acute intermittent porphyria); - dehydration; - immediately after a major surgery. If the doctor considers long-term therapy necessary with dexketoprofene, hepatic, kidney and hemochrome should be checked regularly. Serious reactions from acute hypersensitivity (e.g. anaphylactic shock) have been observed very rarely. Treatment should be stopped at the first symptoms of severe hypersensitivity after taking dexketoprofene. Depending on the symptoms, the necessary medical procedures must be initiated. Patients with asthma associated with chronic rhinitis, chronic sinusitis and/or nasal polypoxes have a greater risk of allergy to acetylsalicylic acid and/or NSAIDs than the rest of the population. The administration of this medicine may cause asthma or bronchospasm attacks, especially in allergic to acetylsalicylic acid or NSAIDs (see paragraph 4.3). Dexketoprofene Pharmacare tablets should be administered with caution in patients suffering from hematopoietic disorders, systemic lupus erythematous or in the presence of connective tissue pathologies. Pediatric population Safety of use in children and adolescents has not been established. This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially without sodium.

Interactions

The following interactions are characteristics of non-steroidal anti-inflammatory drugs (NSAID) in general: Unrecommended associations • Other NSAIDs (including selective cycloxygenase-2 inhibitors) and high doses of salicylates (≥3 g/die): simultaneous administration of several NSAIDs can increase the risk of gastrointestinal ulceration and bleeding due to a synergistic effect. • Antiagulants: NSAIDs can enhance the effects of anticoagulants, such as warfarin (see paragraph 4.4), due to the high plasma protein bond of dexketoprofene, inhibition of pyasternic function and damage to gastroduodenal mucosa. If it is not possible to avoid the association, rigorous clinical observation and monitoring of laboratory parameters are necessary. • Eparine: increased risk of hemorrhage (due to the inhibition of the pyasternic function and the damage to gastroduodenal mucosa). If it is not possible to avoid the association, rigorous clinical observation and monitoring of laboratory parameters are necessary. • Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see paragraph 4.4). • Lithium (described with many NSAIDs): NSAIDs increase blood levels of lithium that can reach toxic values (renal excretion of decreased lithium). Therefore, this parameter requires careful monitoring at the beginning, during adjustment and at the end of treatment with dexketoprofene. • Metotrexate, used at high doses (≥ 15 mg/week): increased hematological toxicity of metotrexate due to a decrease in its kidney clearance, in general with anti-inflammatory drugs. • Idantoins and sulfonamides: the toxic effects of these substances can be enhanced. Associations requiring caution • Diuretics, ACE inhibitors, aminoglycoside antibiotics and antagonists of angiotensin receptor II: dexketoprofen can reduce the effect of diuretics and antihypertensive drugs. In some patients with impaired kidney function (for example, dehydrated patients or elderly patients with impaired kidney function), concomitant administration of agents that inhibit cyclooxygenase and ACE inhibitors, antagonists of angiotensin II receptor or aminoglycoside antibiotics may cause further deterioration of kidney function, usually reversible. In case of concomitant prescription of dexketoprofen and diuretics, it is essential to ensure proper hydration of the patient and to control the kidney function at the beginning of the treatment (see paragraph 4.4 Special warnings and precautions of use). • Metotrexate used at low doses (Associations to be taken into account • Beta-blockers: treatment with NSAIDs can decrease their antihypertensive effect due to the inhibition of prostaglandin synthesis. • Ciclosporin and tacrolimus: NSAIDs can enhance nephrotoxicity due to the effects mediated by kidney prostaglandins. During therapy in combination, check the kidney function. • Trombolitics: increased risk of hemorrhage. • Anti-platelet agents and selective serotonin reuptake 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 dexketoprofen. • Cardioactive glycosides: NSAIDs can increase plasma concentrations of glycosides. • Mifepristone: there is a 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 chinolonic antibiotics in combination with NSAIDs can increase the risk of seizures. • 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), concomitant administration of pemetrexed with NSAIDs must be avoided for 2 days before and 2 days after administration of pemetre.

Effects

Adverse events reported as possibly linked to dexketoprofene in clinical trials, as well as adverse reactions reported after marketing dexketoprofene in tablets are included in the table below, classified by systems and organs and in frequency order:

CLASSIFICATION FOR SYSTEMS AND ORGANI	Common (≥1/100,	Not common (≥1/1.000,	Rare (≥1/10.000,	Very rare (
Emolinfopoietic system pathologies	---	---	---	Neutropenia, Trombocytopenia
Immune system disorders	---	---	Larynx Edema	Anaphylactic reactions, including anaphylactic shock
Disorders of metabolism and nutrition	---	---	Anorexia	---
Psychiatric disorders	---	Insomnia, anxiety	---	---
Diseases of the nervous system	---	Cephalea, dizziness, drowsiness	Parestesia, syncope	---
Pathologies of the eye	---	---	---	Unused vision
Ear and labyrinth pathologies	---	Dizziness	---	Tinnitus
Heart disease	---	Palpitations	---	Tachycardia
Vascular diseases	---	Heat flashes	Hypertension	Hypotension
Respiratory, chest and mediastinic pathologies	---	---	Bradipnea	Broncospasmo, dispnea
Gastrointestinal diseases	Nausea and/or vomiting, abdominal pain, diarrhea, dyspepsia	Gastrites, stips, dry mouth, flatulence	Peptic ulcer, hemorrhage or perforation from peptic ulcer (see paragraph 4.4)	Pancreatis
Hepatobiliary diseases	---	---	Hepatocellular lesion
Pathologies of skin and subcutaneous tissue	---	Skin rash	Orticaria, acne, increased sweating	Stevens-Johnson Syndrome, toxic epidermal necrolysis ( Lyell syndrome), angioedema, facial edema, photosensitivity reaction, itching
Diseases of musculoskeletal system and connective tissue	---	---	Backache	---
Kidney and urinary pathologies	---	---	Acute renal insufficiency, polyuria	Nephritis or nephrosic syndrome
Pathologies of the reproductive apparatus and of the breast	---	---	Menstrual disorders, prostate disorders	---
General system pathologies and conditions for the administration	---	Affection, pain, asthenia, feverish shivers, malaise	Peripheral edema	---
Diagnostic examinations	---	---	Anomaly in liver function tests	---

The most commonly observed side effects are gastrointestinal. Peptic ulcers, perforation or gastrointestinal bleeding may occur, sometimes fatal especially in the elderly (see paragraph 4.4). As a result of the administration, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, ematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see paragraph 4.4 Special warnings and precautions of use). Gastritis was detected with less frequency. In association with NSAID therapy, edema, hypertension and heart failure were reported. As with other NSAIDs, the following side effects may occur: aseptic meningitis, which can occur more in patients with systemic erythematous lupus or pathologies to the load of connective tissue; hematological reactions (porpora, aplastic anemia and hemolytics, and more rarely agranulocytosis and midollar hypoplasia). Bollose reactions including Stevens Johnson syndrome and toxic epidermal necrolysis (very rare). Clinical studies and epidemiological data suggest that the use of some NSAIDs (especially at high doses and long-term treatments) may be associated with a slight increase in the risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see paragraph 4.4). Reporting of suspicious adverse reactions The reporting of suspicious adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare workers are required to report any suspected adverse reaction via the national reporting system at the address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

Overdosing

Syntomatology derived from overdose is not known. Similar medicinal products have caused gastrointestinal disorders (vomite, anorexia, abdominal pain) and neurological disorders (sonnolence, dizziness, disorientation, headache). In case of accidental or excessive intake, immediately take appropriate symptomatic therapy according to the patient’s clinical conditions. Within an hour it is necessary to administer activated charcoal if more than 5 mg/kg were ingested by an adult or child. Dexketoprofen can be eliminated by dialysis.

Dexketoprofene Pharmacare tablets is contraindicated during the third trimester of pregnancy and lactation.

Pregnancy

The inhibition of prostaglandin synthesis can have negative effects on pregnancy and/or on the development of embryo or fetus. Results of epidemiological studies suggest an increased risk of spontaneous abortion and heart and gastroschisis malformation after the use of an inhibitor of prostaglandin synthesis in the early stages of pregnancy The absolute risk of heart failure had increased from less than 1% to about 1.5%. It is believed 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 disorders, was reported in animals that had been given inhibitors of prostaglandin synthesis during the organogenetic period. However, studies in animals have shown that dexketoprofen did not show reproductive toxicity (see paragraph 5.3). During the first and second trimester of pregnancy dexketoprofen should not be administered unless strictly necessary. 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 maintained 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 also occur at very low doses; • inhibition of uterine contractions, resulting in delay or extension of labor.

Food

It is not known whether dexketoprofene is excreted in breast milk. Dexketoprofene Pharmacare is contraindicated during lactation (see paragraph 4.3).

Fertility

As with other NSAIDs, the use of dexketoprofen can damage female fertility and it is not recommended that women wish to have a pregnancy. In the case of women with difficulties of conception or who are carrying out infertility examinations, assess the interruption of the administration of dexketoprofen.

Source: Farmadati