Infen-25

Dexketoprofen, an arylpropionic acid derivative, is the S(+)-enantiomer of ketoprofen. 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. The empirical formula is C₁₆H₁₄O₃·C₄H₁₁NO₃ with a molecular weight of 375.42.
Each film coated tablet contains: Dexketoprofen Trometamol equivalent to Dexketoprofen 25 mg, Excipients q.s.

Non-steroidal anti-inflammatory.
Pharmacology: Mechanism of Action: The mechanism of action of non-steroidal anti-inflammatory drugs is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Dexketoprofen has been demonstrated to be an inhibitor of COX-1 and COX-2 activities in experimental animals and humans. Specifically, there is an inhibition of the transformation of arachidonic into cyclic endoperoxides, PGG₂ and PGH₂, which produce prostaglandins PGE₁, PGE₂, PGF_2α and PGD₂ and also prostacyclin PGI₂ and thromboxanes (TxA₂ and TxB₂). Inhibition of the synthesis of prostaglandins may also affect other inflammatory mediators like kinins which is an indirect action. 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.
Pharmacokinetics: After oral administration of dexketoprofen trometamol to humans, the C_max is reached at 30 min (range 15 to 60 min). When administered concomitantly with food, the AUC does not change, however the C_max of dexketoprofen trometamol decreases and its absorption rate is delayed (increased t_max). 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. There is no conversion of dexketoprofen to the R-(-) enantiomer in humans. Dexketoprofen does not accumulate after multiple-doses in humans.

Treatment of pain of mild to moderate intensity such as musculo-skeletal pain, dysmenorrhoea, dental pain.

According to the nature and severity of pain, the recommended dosage is 25 mg every 8 hours. The total daily dose should not exceed 75 mg. Dexketoprofen 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, thus in case of acute pain is recommended that administration is at least 30 minutes before meals.

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.

Dexketoprofen tablets must not be administered in the following cases: Patients previously sensitive to dexketoprofen, to any other NSAID, or to any of the ingredients of the product.
Patients in whom substances with a similar action (e.g. Aspirin, or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema.
Patients with active or suspected gastrointestinal ulcer or history of gastrointestinal ulcer or chronic dyspepsia.
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.
Patients with severely impaired hepatic function.
Patients with hemorrhagic diathesis and other coagulation disorders.
During third trimester of pregnancy and lactation period.

The safe use of dexketoprofen in children and adolescents has not been established.
Dexketoprofen should be administered with caution in patients with a history of allergic conditions.
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. In the rare instances where gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen trometamol, treatment should be immediately discontinued.
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.
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.
Dexketoprofen 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, renal or cardiac function as well as in patients with other conditions predisposing to fluid retention. 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.
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.
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. Dexketoprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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 NSAID 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).
Hepatic dysfunction: Patients with mild to moderate hepatic dysfunction should start therapy at reduced dose (50 mg total daily dose) and be closely monitored. Dexketoprofen tablets should not be used in patients with severe hepatic dysfunction.
Renal dysfunction: In these patients, the use of NSAIDs may result in deterioration of renal function and fluid retention. Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity. The initial dosage should be reduced to 50 mg total daily dose in patients with mildly impaired renal function. Dexketoprofen tablets should not be used in patients with moderate to severe renal dysfunction.
Use in Children: Children and adolescents: Safety and efficacy has not been established.
Use in the Elderly: Caution should be exercised in the treatment of elderly patients who are generally more prone to adverse reactions. The consequences, e.g. gastrointestinal bleeding and/or perforation are dose-dependent, often more serious and may occur without warning symptoms or previous history, at any time during treatment. Elderly patients are more likely to be suffering from impaired renal cardiovascular or hepatic function. 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.

Dexketoprofen tablets are contraindicated during third trimester of pregnancy and lactation. 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 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 the risk of premature closure of the ductus arteriosus, pulmonary hypertension, renal dysfunction, prolongation of bleeding time, an anti-aggregating, delayed or prolonged labour. It is not known whether dexketoprofen is excreted in human milk.

Following are the adverse reactions reported as at least possibly related with dexketoprofen trometamol.
Common: Nausea and/or vomiting, abdominal pain, diarrhoea, dyspepsia.
Uncommon: Sleep disorder, anxiety, headache, dizziness, vertigo, palpitations, flushing, gastritis, constipation, dry mouth, flatulence, rash, fatigue, pain, asthenia, malaise, rigors.
Rare: Paraesthesia, syncope, hypertension, bradypnoea, peptic ulcer, peptic ulcer haemorrhage or peptic ulcer perforation, urticaria, acne, increased sweating, back pain, polyuria, menstrual disorder, prostatic disorder, peripheral oedema, liver function test abnormality.
Very rare: Neutropenia, thrombocytopenia, anaphylactic reaction, including anaphylactic shock, blurred vision, tinnitus, tachycardia, hypotension, bronchospasm, dyspnoea, pancreatitis, hepatocellular damage, Stevens Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioneurotic oedema, facial oedema, photosensitivity reactions, pruritus, nephritis or nephrotic syndrome.
The following undesirable effects may appear because they have been observed with other non-steroidal anti-inflammatory drugs and may be associated with prostaglandin synthesis inhibitors: 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), bullous reactions in Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). 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).

The following interactions apply to non-steroidal anti-inflammatory 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.
Oral anticoagulants: increased risk of haemorrhagic effect of the oral anticoagulant (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.
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 anti-inflammatory agents in general.
Hydantoins and sulphonamides: the toxic effects of these substances may be increased.
Combinations requiring precautions: Diuretics, ACE inhibitors 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 cyclo-oxygenase and ACE inhibitors or angiotensin II receptor antagonists 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.
Methotrexate, used at low doses, less than 15 mg/week: increased haematological toxicity of methotrexate via a decrease in its renal clearance by anti-inflammatory agents in general. Weekly monitoring of blood count during the first weeks of the combination. Increased surveillance in the presence of event mildly impaired renal function, as well as in the elderly.
Pentoxifylline: 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 starting treatment with the NSAID.
Sulfonylureas: NSAIDs can increase the hypoglycemic effect of sulfonylureas by displacement from plasma protein binding sites.
Associations needing to be taken into account: Beta-blockers: treatment with an 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.
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.

Store at temperature not exceeding 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AE17 - dexketoprofen ; Belongs to the class of propionic acid derivatives of non-steroidal antiinflammatory and antirheumatic products.

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