Ketesse

FC tab: Dexketoprofen trometamol 36.9 mg corresponding to dexketoprofen 25 mg.
Granules for oral soln: Each sachet of granules for oral solution contains 25 mg, as dexketoprofen trometamol.
Soln for inj: Each ampoule of 2 ml contains dexketoprofen 50 mg (as dexketoprofen trometamol). Each ml of solution for injection contains dexketoprofen 25 mg (as dexketoprofen trometamol).
Excipients/Inactive Ingredients: Granules for oral soln: Excipients with known effect: Sucrose with colloidal silica 2.40-2.44 g respectively.
Ammonium glycyrrhizinate, Neohesperidin-dihydrochalcone, Quinoline yellow (E-104), Lemon aroma, Sucrose, Silica, colloidal hydrated.
Soln for inj: Excipients with known effects: 100 mg ethanol (96 per cent) and 4.0 mg sodium chloride.
Ethanol (96 per cent), Sodium chloride, Sodium hydroxide (for pH adjustment), Water for injections.

Pharmacology: Pharmacodynamics: 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). 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 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).

FC tab/granules for oral soln: Symptomatic treatment of pain of mild to moderate intensity, such as musculo-skeletal pain, dysmenorrhoea, dental pain.
Soln for inj: Symptomatic treatment of acute pain of moderate to severe intensity, when oral administration is not appropriate such as post-operative pain, renal colic and low back pain.

FC tab: General population: 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. KETESSE 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 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. KETESSE 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. KETESSE tablets should not be used in patients with moderate to severe renal dysfunction.
Children: KETESSE tablets has not been studied in children. Therefore, safety and efficacy have not been established and the product should not be used in children.
Mode of Administration: Oral
Granules for oral soln: Posology: Adults: 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.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Precautions).
KETESSE is only intended for short term use and the treatment must be limited to the symptomatic period.
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 Precautions), 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. KETESSE 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 60–89 ml/min) (see Precautions). KETESSE should not be used in patients with moderate to severe renal dysfunction (creatinine clearance ≤59 ml/min) (see Contraindications).
Paediatric population: KETESSE 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.
Method of administration: Dissolve the whole contents of each sachet in a glass of water; shake/ stir well to help to dissolve.
The obtained solution should be immediately ingested after reconstitution.
Concomitant administration with food delays the absorption rate of the drug (see Pharmacology: Pharmacokinetics under Actions), thus in case of acute pain it is recommended that administration is at least 15 minutes before meals.
Soln for inj: Posology: Adults: The recommended dose is 50 mg every 8-12 hours. If necessary, the administration can be repeated 6 hours apart.
The total daily dose should not exceed 150 mg.
KETESSE Solution for injection or concentrate for solution for infusion is intended for short term use and the treatment must be limited to the acute symptomatic period (no more than two days). Patients should be switched to an oral analgesic treatment when possible.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Precautions).
In case of moderate to severe postoperative pain, KETESSE Solution for injection or concentrate for solution for infusion can be used in combination with opioid analgesics, if indicated, at the same recommended doses in adults (see Pharmacology: Pharmacodynamics under Actions).
Pediatric population: KETESSE has not been studied in children and adolescent. Therefore the safety and efficacy in children and adolescents have not been established and the product should not be used in children and adolescent.
Older people: No dosage adjustment is generally necessary in older patients. However because of the physiological decline in renal function in elderly patients a lower dose is recommended in case of mild renal function impairment: 50 mg total daily dose (see Precautions).
Hepatic dysfunction: The dosage should be reduced to 50 mg total daily dose in patients with mild to moderate (Child-Pugh score 5-9) hepatic impairment and hepatic function should be closely monitored (see Precautions). KETESSE Solution for injection or concentrate for solution for infusion should not be used in patients with severe hepatic dysfunction (Child-Pugh score 10-15) (see Contraindications).
Renal dysfunction: The dosage should be reduced to 50 mg total daily dose in patients with mildly impaired renal function (creatinine clearance 60–89 ml/min) (see Precautions). KETESSE Solution for injection or concentrate for solution for infusion should not be used in patients with moderate to severe renal dysfunction (creatinine clearance ≤59 ml/min) (see Contraindications).
Method of administration: KETESSE Solution for injection or concentrate for solution for infusion can be administered either by intramuscular or by intravenous route: Intramuscular use: the content of one ampoule (2 ml) of KETESSE Solution for injection or concentrate for solution for infusion should be administered by slow injection deep into the muscle.
Intravenous use: Intravenous infusion: the diluted solution, prepared as described in Instructions for use and handling under Cautions for Usage, should be administered as a slow intravenous infusion, lasting 10 to 30 min. The solution must be always protected from natural daylight.
Intravenous bolus: if necessary, the content of one ampoule (2 ml) of KETESSE Solution for injection or concentrate for solution for infusion can be administered in a slow intravenous bolus over no less than 15 seconds.
Instructions on handling the product: When KETESSE is administered intramuscularly or as intravenous bolus, the solution should be injected immediately after its removal from the coloured ampoule (see Instructions for use and handling and Incompatibilities under Cautions for Usage).
For administration as intravenous infusion, the solution should be diluted aseptically and protected from natural daylight (see Instructions for use and handling under Cautions for Usage and Shelf-Life under Storage). For instructions on dilution of the medicinal product before administration, see Instructions for use and handling under Cautions for Usage.

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.

FC tab: KETESSE tablets must not be administered in the following cases: patients previously sensitive 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. 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 haemorrhagic diathesis and other coagulation disorders, or patients receiving anticoagulant therapy.
during pregnancy and lactation period.
Soln for inj: KETESSE Solution for injection or concentrate for solution for infusion is contraindicated for neuraxial (intrathecal or epidural) administration due to its ethanol content.

The safe use in children has not been established. Administer 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.
Risk of GI Ulceration, Bleeding and Perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at anytime, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious adverse events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events. 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. KETESSE 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. 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. 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.

KETESSE tablets should not be administered during pregnancy and lactation. Insufficient information is available to assess the safety of the use of KETESSE tablets during pregnancy. In animal studies foetal effects were found at high doses, probably resulting from the inhibitory effects of dexketoprofen on prostaglandin synthesis. It is not known whether dexketoprofen is excreted in human milk.

FC tab: The adverse reactions reported as at least possibly related with dexketoprofen trometamol in clinical trials, as well as the adverse reactions reported after the marketing of KETESSE tablets are tabulated as follows, classified by system organ class and ordered by frequency: (See Table 1.)

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Granules for oral soln/soln for inj: The adverse events reported as at least possibly related with dexketoprofen trometamol in clinical trials, as well as the adverse reaction reported after the marketing of Ketesse granules and KETESSE 50 mg/2 ml solution for injection or concentrate for solution for infusion are tabulated in Table 2, classified by system organ class and ordered by frequency: (See Table 2.)

Click on icon to see table/diagram/image

Granules for oral soln: 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 Precautions). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see Precautions) have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension and cardiac failure have been reported in association with NSAIDs treatment.
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 Precautions).
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).
Soln for inj: 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 Precautions). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see Precautions) have been reported following administration. Less frequently, gastritis has been observed.
Oedema, hypertension, and cardiac failure, have been reported in association with NSAID 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, rarely agranulocytosis and medullar hypoplasia).
Bullous reactions including 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) (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

FC tab: The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general: 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 antiinflammatory agents in general.
Hydantoines and sulphonamides: the toxic effects of these substances may be increased.
Granules for oral soln/soln for inj: The following interactions apply to non-steroidal antinflammatory 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 Precautions), 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 Precautions).
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 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 other 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 Precautions).
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 even mildly impaired renal function, as well as in the elderly.
Pentoxyfylline: increased risk of bleeding. Intensify 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 Precautions).
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.
Granules for oral soln: Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin 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.

Instructions for use and handling: Granules for oral soln: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Soln for inj: KETESSE Solution for injection or concentrate for solution for infusion has shown to be compatible when mixed in small volumes (e.g. in a syringe) with injectable solutions of heparin, lidocaine, morphine and theophylline.
For administration as intravenous infusion the content of one ampoule (2 ml) of KETESSE Solution for injection or concentrate for solution for infusion should be diluted in a volume of 30 to 100 ml of normal saline, glucose or Ringer lactate solution. The solution should be diluted aseptically and protected from natural daylight (see Shelf-Life under Storage). The diluted solution is a clear solution.
KETESSE Solution for injection or concentrate for solution for infusion, diluted in a volume of 100 ml of normal saline or glucose solution has shown to be compatible with the following medicinal products: dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine and theophylline.
No sorption of the active ingredient has been found when diluted solutions of KETESSE Solution for injection or concentrate for solution for infusion have been stored in plastic bags or administration devices made of Ethyl Vinyl Acetate (EVA), Cellulose Propionate (CP), Low Density PolyEthylene (LDPE) and PolyVinyl Chloride (PVC).
KETESSE Solution for injection or concentrate for infusion is for single use only and any unused solution should be discarded. Prior to administration, the solution should be inspected visually to make sure it is clear and colourless: it should not be used if particulate matter is observed.
Incompatibilities: Granules for oral soln: Not applicable.
Soln for inj: KETESSE Solution for injection or concentrate for solution for infusion must not be mixed in a small volume (e.g. in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine or hydroxyzine, as this will result in a precipitation of the solution.
The diluted solutions for infusion obtained as stated previously in Instructions for use and handling must not be mixed with promethazine or pentazocine.
This medicinal product must not be mixed with other medicinal products except those mentioned previously in Instructions for use and handling.

Granules for oral soln: Store below 30°C.
Soln for inj or concentrate for soln for infusion: Keep the ampoules in the outer carton in order to protect it from the light.
Shelf-Life: FC tab: 36 months from the date of manufacturing.
Granules for oral soln: 3 years.
Soln for inj: 5 years. After dilution according to directions given in Section Instructions for use and handling under Cautions for Usage, the diluted solution, provided it is adequately protected from natural daylight, has been shown to be chemically stable for 24 hours, when stored at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

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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