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ENANTYUM

Main information

  • Trade name:
  • ENANTYUM Tablets 25 Milligram
  • Available from:
  • Laboratorios Menarini S.A.
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
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Documents

Localization

  • Available in:
  • ENANTYUM Tablets 25 Milligram
    Ireland
  • Language:
  • English

Other information

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Status

  • Source:
  • IMB
  • Authorization date:
  • 03-04-1998
  • Last update:
  • 09-08-2016

Summary of Product characteristics

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

ENANTYUM 25 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: Dexketoprofen trometamol 36.9 mg corresponding to dexketoprofen 25 mg.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film coated tablets.

White, round, scored film-coated tablets. The tablets can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Symptomatic treatment of pain of mild to moderate intensity, such as musculo-skeletal pain, dysmenorrhoea, 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 tablets are not intended for long 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 30 minutes before meals.

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 general population only after good general tolerance has

been ascertained.

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 tablets 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

(creatinine clearance 50 – 80 ml / min) (see section 4.4). ENANTYUM tablets should not be used in patients with

moderate to severe renal dysfunction (creatinine clearance <50 ml / min) (see section 4.3).

Children and adolescents:

ENANTYUM tablets have not been studied in children and adolescents. Therefore, safety and efficacy have not been

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4.3 Contraindications

ENANTYUM tablets 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.

- patients with active or suspected peptic ulcer/haemorrhage or history of recurrent peptic ulcer/haemorrhage (two or

more distinct episodes of proven ulceration or bleeding) or chronic dyspepsia.

- patients with history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

- patients who have gastrointestinal bleeding or other active bleedings or bleeding disorders.

- patients with Crohn’s disease or ulcerative colitis.

- patients with a history of bronchial asthma.

- patients with severe heart failure.

- patients with moderate to severe renal dysfunction (creatinine clearance <50 ml/min).

- patients with severely impaired hepatic function (Child-Pugh score 10 - 15).

- patients with haemorrhagic diathesis and other coagulation disorders.

- during the third trimester of pregnancy and lactation period (see section 4.6).

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 use of Enantyum with concomitant other NSAIDs including cyclooxygenase-2 selective inhibitors should be

avoided.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control

symptoms (see section 4.2, and GI and cardiovascular risks below).

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-

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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).

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.

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.

ENANTYUM tablets 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.

Caution should be exercised in patients with impairment of hepatic and/or renal functions as well as in patients with a

history of hypertension and/or heart failure. 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. 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.

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

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 (see section 4.8). Patients

appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the

majority of cases within the first month of treatment. ENANTYUM should be discontinued at the first appearance of

skin rash, mucosal lesions, or any other sign of hypersensitivity.

As with other NSAIDS, the use of dexketoprofen trometamol 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. Dexketoprofen should not be used during

first and second trimester of pregnancy unless clearly necessary.

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate

congestive heart failure as 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.

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).

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

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- 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 by antiinflammatory agents 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 (see section 4.4 Special warnings and special precautions for use).

- 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 complete blood count 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.

Combinations 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 glycoside concentration.

- Mifepristone: Because of a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of

mifepristone, NSAIDs should not be used for 8-12 days after mifepristone administration.

- Quinolone antibiotics: Animal data indicate that high doses of quinolones in combination with NSAIDs can

increase the risk of developing convulsions.

4.6 Fertility, pregnancy and lactation

ENANTYUM tablets are contraindicated during the third trimester of pregnancy and lactation (see section 4.3).

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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 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.

It is not known whether dexketoprofen is excreted in human milk.

4.7 Effects on ability to drive and use machines

ENANTYUM tablets can cause minor or moderate influence on the ability to drive and use machines due to the

possibility of dizziness or drowsiness occurring.

4.8 Undesirable effects

The adverse events reported as at least possibly related with dexketoprofen trometamol in clinical trials, as well as the

adverse reactions reported after the marketing of ENANTYUM tablets are tabulated below, classified by system organ

class and ordered by frequency:

SYSTEM

ORGAN CLASS Common

(1-10%) Uncommon

(0.1-1%) Rare

(0.01-0.1%) Very rare /

Isolated reports

(<0.01%)

Blood and

lymphatic

system disorders Neutropenia

thrombocytopenia

Immune system

disorders Laryngeal oedema Anaphylactic

reaction, including

anaphylactic shock

Metabolism and

nutrition

disorders Anorexia

Psychiatric

disorders Insomnia, anxiety

Nervous system

disorders Headache,

dizziness,

somnolence Paraesthesia,

syncope

Eye disorders Blurred vision

Ear and

labyrinth

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Gastrointestinal: 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 Special warnings and precautions for use) 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; haematological reactions

(purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia).

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 Hepatitis Hepatocellular

injury

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 Acute renal

failure, Polyuria Nephritis or

nephrotic

syndrome

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

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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) (see section 4.4).

4.9 Overdose

The symptomatology following overdose is not known. Similar medicinal products have produced gastrointestinal

(vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo, disorientation, headache) disorders.

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, PGG and PGH , which produce prostaglandins PGE , PGE , PGF and PGD and

also prostacyclin PGI and thromboxanes (TxA and TxB ). 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

After oral administration of dexketoprofen trometamol to humans, the Cmax is reached at 30 min (range 15 to 60 min).

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).

5.3 Preclinical safety data

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

2 2 1 2 2 2

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observed at high doses was gastrointestinal erosions and ulcers that developed dose-dependently.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Microcrystalline cellulose

Sodium starch glycollate

Glycerol distearate

Hypromellose

Titanium dioxide

Propylene glycol

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 30ºC; keep the blister packs in the outer carton in order to protect from light.

6.5 Nature and contents of container

Tablets are provided in blister packs (PVC-aluminium blister)

4, 10, 20, 30, 50, or 500 film-coated tablets/pack

(Not all pack sizes may be marketed).

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Laboratorios Menarini, S.A.

C/ Alfonso XII, 587

08918-Badalona (Barcelona)

Spain.

8 MARKETING AUTHORISATION NUMBER

PA0901/001/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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Date of last renewal: 25 April 2006

10 DATE OF REVISION OF THE TEXT

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There are no safety alerts related to this product.

There are no news related to this product.

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