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Enantyum 12.5 Mg Granules For Oral Solution

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

ENANTYUM 12.5 mg granules for oral solution.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet of granules for oral solution contains dexketoprofen 12.5 mg, as dexketoprofen trometamol.

Excipients:

Sucrose: 1.25 g.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules for oral solution, sachet lemon yellow coloured granules.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Short term symptomatic treatment of acute pain of mild to moderate intensity, such as acute musculo-skeletal pain, dysmenorrhoea and dental pain.

4.2 Posology and method of administration

Adults:

According to the nature and severity of pain, the recommended dosage 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 is only intended for short term use and the treatment must be limited to the symptomatic period.

Concomitant administration with food delays the absorption rate of the drug (see Pharmacokinetic Properties), thus in case of acute pain it is recommended that administration is at least 15 minutes before meals.

Special populations

Elderly:

In elderly patients it is recommended to start the therapy at the lower end of the dosage range (50 mg total daily dose). The dosage may be increased to that recommended for the adult only after good general tolerance has been ascertained. Due to the possible adverse effect profile (see section 4.4), elderly individuals should receive particularly close monitoring.

Hepatic dysfunction:

Patients with mild to moderate hepatic dysfunction should start therapy at reduced doses (50 mg total daily dose) and be closely monitored. ENANTYUM should not be used in patients with severe hepatic dysfunction.

Renal dysfunction:

The initial dosage should be reduced to 50 mg total daily dose in patients with mildly impaired renal function. ENANTYUM should not be used in patients with moderate to severe renal dysfunction.

Children and adolescents:

ENANTYUM granules has not been studied in children and adolescent. Therefore, safety and efficacy have not been established and the product should not be used in children and adolescent.

4.3 Contraindications

ENANTYUM granules must not be administered in the following cases:

- patients hypersensitive to dexketoprofen, to any other NSAID, or to any of the excipients of the product.

- patients in whom substances with a similar action (e.g. acetylsalicylic acid, or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema.

- known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates

- patients with history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. - patients with active, or history of recurrent peptic ulcer/gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding disorders).

- patients with chronic dyspepsia or suspected peptic ulcer/ haemorrhage.

- patients who have other active bleedings or bleeding disorders.

- patients with Crohn’s disease or ulcerative colitis.

- patients with severe heart failure.

- patients with moderate to severe renal dysfunction.

- patients with severely impaired hepatic function.

- patients with haemorrhagic diathesis and other coagulation disorders.

- patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)

- during the third trimester of pregnancy and lactation period.

4.4 Special warnings and precautions for use

The safe use in children and adolescents has not been established.

Administer with caution in patients with a history of allergic conditions.

The concomitant use of ENANTYUM with other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

Gastrointestinal safety

Gastrointestinal bleeding, ulceration or perforation

Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving ENANTYUM, the treatment should be withdrawn.

The risk of gastrointestinal bleeding, ulceration or perforation is higher 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 commence treatment on the lowest dose available.

As with all NSAIDs, any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with dexketoprofen trometamol. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding.

NSAIDs should be given with care 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 requiring concomitant low dose aspirin, 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 should be 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 aspirin (see section 4.5).

Renal Safety

Caution should be exercised in patients with impairment of renal functions. In these patients, the use of NSAIDs may result in deterioration of renal function, fluid retention and oedema. Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity.

Adequate fluid intake should be ensured during treatment to prevent dehydration and possibly associated increased renal toxicity.

As with all NSAIDs, it can increase plasma urea nitrogen and creatinine. As with other inhibitors of prostaglandin synthesis, it can be associated with adverse effects on the renal system which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure.

Elderly patients are more likely to be suffering from impaired renal function (see section 4.2).

Liver Safety

Caution should be exercised in patients with impairment of hepatic functions. As with other NSAIDs, it can cause transient small increases in some liver parameters, and also significant increases in SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued.

Elderly patients are more likely to be suffering from impaired hepatic function (see section 4.2).

Cardiovascular and cerebrovascular safety

Appropriate monitoring and advice are required for patients with history of hypertension and/or mild to moderate heart failure. Special caution should be exercised in patients with a history of cardiac disease, in particular those with previous episodes of heart failure as there is an increased risk of triggering heart failure, since fluid retention and oedema have been reported in association with NSAIDs therapy.

Clinical trial and epidemiological data suggest that 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 (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Dexketoprofen Trometamol.

Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Dexketoprofen Trometamol after careful consideration. Similar consideration should be made before initiating longer-term treatment of the patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

All non-selective NSAIDs can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, the use of dexketoprofen trometamol in patients who are receiving other therapy that interferes with haemostasis, such as warfarin or other coumarins or heparins is not recommended (see Section 4.5).

Elderly patients are more likely to be suffering from impaired 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 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. ENANTYUM should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Other information

Particular caution is required in patients with:

- congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)

- dehydration

Directly after major surgery

If the physician considers long-term Dexketoprofen therapy to be necessary, hepatic and renal function and the blood count should be regularly checked.

Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been observed on very rare occasions. Treatment must be discontinued at the first signs of severe hypersensitivity reactions following intake of Enantyum Depending on the symptoms, any medically required procedures must be initiated by specialist healthcare professionals.

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of Enantyum in case of varicella.

ENANTYUM should be administered with caution to patients suffering from haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disease.

As other NSAIDs, dexketoprofen can mask the symptoms of infectious diseases.

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general:

Inadvisable combinations:

- Other NSAIDs, including high doses of salicylates (> 3 g/day): administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect.

- Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, 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, close clinical observation and monitoring of laboratory values should be carried out.

- Heparins: increased risk of haemorrhage (due to the inhibition of platelet function and damage to the gastroduodenal mucosa). If the combination cannot be avoided, close clinical observation and monitoring of laboratory values should be carried out.

- Corticosteroids: there is an increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

- Lithium (described with several NSAIDs): NSAIDs increase blood lithium levels, which may reach toxic values (decreased renal excretion of lithium). This parameter therefore requires monitoring during the initiation, adjustment and withdrawal of treatment with dexketoprofen.

- Methotrexate, used at high doses of 15 mg/week or more: increased haematological toxicity of methotrexate via a decrease in its renal clearance NSAIDs in general.

- Hydantoines and sulphonamides: the toxic effects of these substances may be increased.

Combinations requiring precautions:

- Diuretics, ACE inhibitors, antibacterial aminoglycosides and angiotensin II receptor antagonists: Dexketoprofen may reduce the effect of diuretics and antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the coadministration of agents that inhibit cyclo-oxygenase and ACE inhibitors angiotensin II receptor antagonists or antibacterial aminoglycosides may result in further deterioration of renal function, which is usually reversible. In case of combined prescription of dexketoprofen and a diuretic, it is essential to ensure that the patient is adequately hydrated and to monitor renal function at the start of the treatment and periodically thereafter. Co-administration of Enantyum and potassium-sparing diuretics can lead to hyperkalaemia. Monitoring of blood potassium concentrations is required. (see section 4.4).

- Methotrexate, used at low doses, less than 15 mg/week: increased haematological toxicity of methotrexate via a decrease in its renal clearance by antiinflammatory agents in general. Weekly monitoring of blood count during the first weeks of the combination. Increased surveillance in the presence of even mildly impaired renal function, as well as in the elderly.

- Pentoxyfilline: increased risk of bleeding. Increase clinical monitoring and check bleeding time more often.

- Zidovudine: risk of increased red cell line toxicity via action on reticulocytes, with severe anaemia occurring one week after the NSAID is started. Check CBC and reticulocyte count one to two weeks after starting treatment with the NSAID.

- Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of sulfonylureas by displacement from plasma protein binding sites.

Associations needing to be taken into account:

- Beta-blockers: treatment with a NSAID may decrease their antihypertensive effect via inhibition of prostaglandin synthesis.

- Cyclosporin and tacrolimus: nephrotoxicity may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combination therapy, renal function has to be measured.

- Thrombolytics: increased risk of bleeding.

- Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

- Probenecid: plasma concentrations of dexketoprofen may be increased; this interaction can be due to an inhibitory mechanism at the site of renal tubular secretion and of glucuronoconjugation and requires adjustment of the dose of dexketoprofen.

- Cardiac glycosides: NSAIDs may increase plasma cardiac glycosides concentration.

- Mifepristone: There is a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone.

Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or theprostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

- Quinolone Antibiotics: Animal data indicate that high doses of quinolones in combination with NSAIDs can increase the risk of developing convulsions.

4.6 Pregnancy and lactation

ENANTYUM is contraindicated during pregnancy and lactation (see section 4.3).

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in 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 a prostaglandin synthesis inhibitor during the organogenetic period. Nevertheless, animal studies with dexketoprofen trometamol haven’t shown reproductive toxicity (see section 5.3). During the first and second trimester of pregnancy, dexketoprofen trometamol should not be given unless clearly necessary. If dexketoprofen trometamol is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short 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 may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Fertility

The use of ENANTYUM 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 dexketoprofen trometamol should be considered.

Lactation

It is not known whether dexketoprofen is excreted in human milk. ENANTYUM is contraindicated during breast-feeding (see section 4.3).

4.7 Effects on ability to drive and use machines

ENANTYUM granules may cause undesirable effects such as dizziness, visual disturbances or drowsiness. The ability to react and the ability to take part actively in road traffic and to operate machines may be impaired in these cases.

4.8 Undesirable effects

The adverse reactions reported as at least possibly related with dexketoprofen trometamol in clinical trials (tablet formulation), as well as the adverse reactions reported after the marketing of ENANTYUM granules are tabulated below, classified by system organ class and ordered by frequency:

Because Cmax plasma levels of dexketoprofen for the granule formulation are higher than those reported for the tablet formulation, a potentially increased risk for adverse (gastrointestinal) events cannot be excluded.

SYSTEM ORGAN CLASS	Common (□1/100 to <1/10)	Uncommon (□1/1,000 to <1/100)	Rare (□1/10,000 to <1/1,000)	Very rare / Isolated reports (<1/10,000)	Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders				Neutropenia, thrombocytopenia
Immune system disorders				Anaphylactic reaction, including anaphylactic shock	Laryngeal oedema
Metabolism and nutrition disorders			Anorexia

Psychiatric disorders	___	Insomnia, anxiety	---	---
Nervous system disorders		Headache, dizziness somnolence	Paraesthesia, syncope
Eye disorders	---	---	---	Blurred vision
Ear and labyrinth disorders		Vertigo		Tinnitus
Cardiac disorders	___	Palpitations	---	Tachycardia
Vascular disorders	---	Flushing	Hypertension	Hypotension
Respiratory, thoracic and mediastinal disorders			Bradypnoea	Bronchospasm, dyspnoea
Gastrointestinal disorders	Nausea and/or vomiting, abdominal pain, diarrhoea, dyspepsia	Gastritis, constipation, dry mouth, flatulence	Peptic ulcer, peptic ulcer haemorrhage or peptic ulcer perforation (see section 4.4)	Pancreatitis
Hepatobiliary disorders	---	---	Hepatic lesion	Hepatocellular injury	Hepatitis
Skin and subcutaneous tissue disorders		Rash	Urticaria, acne, sweating increased	Stevens Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial oedema, photosensitivity reaction, pruritus
Musculoskeletal and connective tissue disorders			Back pain
Renal and urinary disorders			Polyuria	Nephritis or nephrotic syndrome	Acute renal failure
Reproductive system and breast disorders			Menstrual disorder, prostatic disorder
General disorders and administration site conditions		Fatigue, pain, asthenia, rigors, malaise	Peripheral oedema
Investigations	---	---	Liver function test	---

abnormal

The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal 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 cardiac failure have been reported in association with NSAIDs treatment.

As with other NSAIDs the following undesirable effects may appear: aseptic meningitis, which might predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease; and haematological reactions (purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia).

4.9 Overdose

The symptoms of overdose can include CNS-related symptoms such as headache, dizziness, lethargy, unconsciousness (in children also myclonic convulsions), abdominal pain, nausea, vomiting, gastrointestinal bleeding and hepatic and renal dysfunction. Hypotension, respiratory depression and cyanosis.

In case of accidental or excessive intake, immediately institute symptomatic therapy according to the patient’s clinical condition. Activated charcoal should be administered if more than 5 mg/kg has been ingested by an adult or a child within an hour.

Dexketoprofen trometamol may be removed by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: propionic acid derivatives ATC code: M01AE17.

Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid, an analgesic, anti-inflammatory and antipyretic drug, which belongs to the non-steroidal anti-inflammatory group of drugs (M01AE).

The mechanism of action of non-steroidal antiinflammatory drugs is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, PGF2a and PGD2 and also prostacyclin PGI2 and thromboxanes (TxA2 and TxB2). Furthermore, the inhibition of the synthesis of prostaglandins could affect other inflammation mediators such as kinins, causing an indirect action which would be additional to the direct action.

Dexketoprofen has been demonstrated to be an inhibitor for COX-1 and COX-2 activities in experimental animals and humans.

Clinical studies performed on several pain models demonstrated effective analgesic activity of dexketoprofen trometamol. The onset of the analgesic activity was obtained in some studies at 30 minutes post-administration. The analgesic effect persists for 4 to 6 hours.

5.2 Pharmacokinetic properties

Dexketoprofen trometamol is rapidly absorbed after oral administration, with maximum plasma concentrations achieved after 0.25-0.33 hours when administered as granules.

The comparison between the standard release dexketoprofen oral tablet and granules at the dose of 12.5 and 25 mg indicated that the two formulations were bioequivalent in terms of the extent of bioavailability (AUC). Peak concentrations (Cmax) weres approximately 30% higher after granules in comparison to the tablet .

The distribution half-life and elimination half-life values of dexketoprofen trometamol are 0.35 and 1.65 hours, respectively. As with other drugs with a high plasma protein binding (99%), its volume of distribution has a mean value below 0.25 l/kg. The main elimination route for dexketoprofen is glucuronide conjugation followed by renal excretion.

After administration of dexketoprofen trometamol only the S-(+) enantiomer is obtained in urine, demonstrating that no conversion to the R-(-) enantiomer occurs in humans.

In multiple-dose pharmacokinetic studies, it was observed that the AUC after the last administration is not different from that obtained following a single dose, indicating that no drug accumulation occurs.

When administered concomitantly with food, the AUC does not change, however the Cmax of dexketoprofen trometamol decreases and its absorption rate is delayed (increased tmax).

Preclinical safety data

5.3

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and immunopharmacology. The chronic toxicity studies carried out in mice and monkeys gave a No Observed Adverse Effect Level (NOAEL) of 3 mg/kg/day. The main adverse effect observed at high doses was gastrointestinal erosions and ulcers that developed dose-dependently.

As it has been recognised for the whole pharmacological class of NSAIDs, dexketoprofen trometamol may cause changes of embryo-foetal survival in animal models, both indirectly, through the gastrointestinal toxicity on the pregnant mothers, and directly upon the development of the foetus.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ammonium glycyrrhizinate Neohesperidin-dihydrochalcone Quinoline yellow (E-104)

Lemon aroma Sucrose

Silica, colloidal hydrated

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The granules for oral solution is provided in single dose, coating-aluminium-polyethylene, heat-sealed sachets.

ENANTYUM 12.5 mg - packs containing 2, 10, 20, 30, 40, 50, 100 and 500 sachets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Dissolve the whole contents of each sachet in a glass of water; shake well to help to dissolve.

The obtained solution should be immediately ingested after reconstitution.

7 MARKETING AUTHORISATION HOLDER

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare,

L-1611 Luxembourg

8 MARKETING AUTHORISATION NUMBER(S)

PL 16239/0035

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/04/2011

10 DATE OF REVISION OF THE TEXT

28/04/2011