INSTRUCTION

for medical use of the medicinal product

KEDOL

 

Composition:

active substance: dexketoprofen;

1 ml of solution contains dexketoprofen 25 mg (as trometamol);

excipients: ethanol 96%, sodium chloride, sodium hydroxide, water for injection.

Pharmaceutical form. Solution for injection 50 mg/2 ml.

Basic physical and chemical properties: colourless transparent liquid.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATC code M01A E17.

Pharmacological properties.

Pharmacodynamics.

Dexketoprofen trometamol is the salt of propionic acid that has analgesic, anti-inflammatory and antipyretic effects and belongs to the non-steroidal anti-inflammatory group of drugs (NSAIDs). The mechanism of action is based on the reduction of prostaglandin synthesis due to the inhibition of cyclooxygenase. Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, PGF2α 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 effect on the main action of the drug. There have been revealed the inhibitory effect of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2. Clinical studies performed on several pain models demonstrated effective analgesic activity of dexketoprofen. The analgesic effect of dexketoprofen trometamol when administered intramuscularly and intravenously to patients with moderate to severe pain has been studied in various types of pain in surgery (orthopaedic and gynaecologic surgery, abdominal surgery), and pain in the musculoskeletal system (acute low back pain) and renal colic as well. Within the studies, the analgesic effect of the drug onset rapidly and reached a maximum within the first 45 minutes. The duration of analgesic effect after the use of dexketoprofen trometamol 50 mg is usually 8 hours. Clinical studies have shown that the use of KEDOL can significantly reduce the dose of opiates when the drug is used concomitantly to relieve postoperative pain. If morphine with a patient-controlled analgesic device and dexketoprofen trometamol were co-administrated to patients for postoperative pain relief, such patients required significantly less morphine (30-45%) than those receiving placebo.

Pharmacokinetics.

After intramuscular administration of dexketoprofen trometamol, the Cmax is reached at 20 minutes (10-45 minutes) approximately. There has been shown that the AUC ("concentration-time") is dose proportional in a single intramuscular or intravenous administration of 25-50 mg of the drug. In multiple-dose pharmacokinetic studies, it was observed that AUC and Cmax (average maximum value) after the last intramuscular and intravenous administration do not differ from those obtained following a single administration, indicating that no drug accumulation occurs. 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 distribution half-life and elimination half-life values of dexketoprofen are 0.35 and 1-2.7 hours, respectively. Biotransformation of dexketoprofen occurs mainly through conjugation with glucuronic acid and subsequent excretion by the kidneys. After administration of dexketoprofen trometamol only the S-(+) enantiomer is obtained in urine, demonstrating that no conversion to the R-(-) enantiomer occurs. After single and multiple doses, the drug effect was significantly higher (up to 55%) in healthy elderly volunteers (65 years) who participated in the study compared to young volunteers, but a statistically significant difference in the maximum concentration and time of its achievement was not observed. The average half-life was increased (up to 48%), but the determined total clearance was decreased.

Clinical particulars.

Indications.

Symptomatic treatment of acute pain of moderate and high intensity if oral administration of the drug is impractical, e.g. postoperative pain, renal colic and low back pain (back pain).

 

Contraindications.

-   patients hypersensitive to the active substance, to any other NSAID, or to any of the excipients;

-   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 peptic ulcer bleeding or suspected or recurrent peptic ulcer disease or any history of gastrointestinal bleeding (at least two confirmed facts of ulcer or bleeding) or chronic dyspepsia;

-   patients with gastrointestinal bleeding, other active bleedings or increased bleeding;

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

-  patients with Crohn's disease or ulcerative colitis;

-  patients with 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;

- use for neuroaxial, intrathecal or epidural administration due to ethanol content.

 

Interaction with other medicinal products and other forms of interaction.

Co-administration of such drugs with NSAIDs is not recommended:

- 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, 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;

- 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 (not less than 15 mg/week). Due to the decreased renal clearance of methotrexate on the background of NSAIDs, its negative effect on the blood system increases;

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

Co-administration of such drugs with NSAIDs requires 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) the co-administration of agents that inhibit cyclooxygenase 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;

- Methotrexate, used at low doses (less than 15 mg/week): due to the decreased renal clearance of methotrexate on the background of NSAIDs, its negative effect on the blood system increases.

Weekly monitoring of blood count should be performed during the first weeks of the concomitant use. Increased surveillance should be carried out in the presence of even mildly impaired renal function, as well as in the elderly;

- Pentoxyfilline: increased risk of bleeding. Clinical monitoring should be increased and bleeding time should be checked 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. Complete blood count and reticulocyte count should be checked 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 NSAIDs 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;

-   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: Due to the theoretical probability of reducing the effectiveness of mifepristone under the influence of prostaglandin synthetase inhibitors, NSAIDs should be prescribed only 8-12 days after treatment with mifepristone;

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

 

Special precautions.

Administer with caution in patients with a history of allergic conditions. The use of KEDOL 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.

Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding occurs, 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 and in the elderly. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. These patients should commence treatment on the lowest dose available. NSAIDs should be given with care to patients with a history of gastrointestinal disease as their condition may be exacerbated. The use of NSAIDs can lead to recurrence of nonspecific ulcerative colitis, as well as Crohn's disease in patients in remission. Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with dexketoprofen. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding.

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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk.

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 acetylsalicylic acid.

All non-selective NSAIDs can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Concomitant use of dexketoprofen trometamol and low molecular weight heparin in prophylactic doses in the postoperative period was studied in clinical trials and no effect on coagulation parameters was determined. However, the patients using  dexketoprofen trometamol concomitantly with drugs affecting hemostasis, such as warfarin, other coumarins or heparins, should be under close medical supervision.

Patients with hypertension and/or mild or moderate congestive heart failure should be closely monitored by a physician due to possible fluid retention and peripheral edema.

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 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 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).

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. KEDOL should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. 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 AST and ALT. In case of a relevant increase in such parameters, therapy must be discontinued.

Caution should be exercised in patients with hepatic and/or renal impairment, and patients with hypertension and/or congestive heart failure, as NSAIDs may impair renal function, fluid retention and peripheral edema. 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, hepatic and cardiovascular systems.

KEDOL 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 during its use. In isolated cases, during the use of NSAIDs there were reports on activation of infectious processes localized in soft tissues. Therefore, if symptoms of a bacterial infection appear or worsen when using the drug, patients are advised to seek immediate medical attention.

As with other NSAIDs, 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 should be considered. During the first and second trimester of pregnancy, KEDOL should not be given unless clearly necessary..

Each ampoule of KEDOL contains 200 mg of ethanol, equal to 5 ml of beer or 2.08 wine per dose. The drug can adversely effect on people suffering from alcoholism. The ethanol content should be considered when using the drug in the first and second trimesters of pregnancy, in children and in patients at risk, such as liver disease, and patients with epilepsy as well.

The medicinal product contains less than 1 mmol of sodium (23 mg) per dose, so it contains virtually no free sodium.

 

Pregnancy and lactation.

KEDOL is contraindicated during third trimester of pregnancy and lactation.

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 haven't shown reproductive toxicity. During the first and second trimester of pregnancy, dexketoprofen should not be given unless clearly necessary. If dexketoprofen 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.

 

Effects on ability to drive and use machines.

KEDOL may cause dizziness, drowsiness and increased fatigue, so a weak or moderate effect on the ability to drive or operate other machinery is not excluded. Patients should take this into account and objectively assess their ability to perform such work.

 

Method of administration and dosage.

Adults. The recommended dose is 50 mg every 8-12 hours. If necessary, repeat the dose after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use, so it should be used only during acute pain (not longer than 2 days). Patients should be switched to oral analgesics if possible. Adverse reactions may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. In postoperative pain of moderate or severe severity, the drug may be used according to the indications in the same recommended doses in combination with opioid analgesics.

Elderly. No dose adjustment is usually required. However, due to the physiological decrease in renal function, a lower dose of the drug is recommended, namely, the maximum daily dose is 50 mg in case of mild renal impairment..

Hepatic impairment. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the maximum daily dose should be reduced to 50 mg and liver function monitored closely as well. The drug is contraindicated in severe liver disease (Child-Pugh score 10-15).

Renal impairment. 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). The drug should not be used in patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min).

Children and adolescents. The drug should not be used in children and adolescents due to lack of data on its effectiveness and safety.

Intramuscular administration. The solution for injection should be slowly injected deep into the muscle. 

Intravenous infusion.

For intravenous infusion, the contents of an ampoule of 2 ml must be diluted in 30-100 ml of 0.9% sodium chloride solution, glucose solution or lactated Ringer's solution. The solution for infusion should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear. The infusion should be administrated for 10-30 minutes. Avoid exposure to natural daylight on the prepared solution.

KEDOL diluted in 100 ml of 0.9% sodium chloride solution or in glucose solution may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine and theophylline.

KEDOL should not be mixed with solution for infusion of promethazine and pentazocine.

Intravenous injection (bolus injection).

If necessary, the contents of 1 mg (solution for injection 2 ml) is administered intravenously for at least 15 seconds..

The drug may be mixed with solutions for injection of heparin, lidocaine, morphine and theophylline in small volumes (e.g. syringe).

KEDOL should not be mixed with solutions of dopamine, promethazine, pentazocine, pethidine and hydrocortisone in small volumes (e.g. syringe) due to white precipitate formation.

The drug can be mixed only with the drugs listed above.

For intramuscular or intravenous injections, the drug should be immediately administered after it has been collected from the ampoule. The solution for intravenous infusion should be used immediately after preparation.

No changes in the active substance content due to sorption were observed during storage of diluted solutions of the drug in plastic bags or in products made of ethyl vinyl acetate, cellulose propionate, low density polyethylene and polyvinyl chloride.

KEDOL is intended for a single use, so the remnants of the finished solution should be poured. Before administering the drug, make sure that the solution is clear and colourless. The solution containing solid particles must not be used.

 

Children.

The drug is contraindicated for children and adolescents due to lack of data on its effectiveness and safety.

 

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. Dexketoprofen trometamol may be removed by dialysis.

 

Adverse reactions.

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

 

System Organ Class	Common (1/100 to 1/10)	Uncommon (1/1000 to 1/100)	Rare  (1/10000 to 1/1000)	Very rare (less than 1/10000)
Blood and lymphatic system disorders	_	Anaemia	_	Neutropenia, thrombocytopenia
Immune system disorders	_	_	Laryngeal oedema	Anaphylactic reaction, including anaphylactic shock
Metabolism and nutrition disorders	_	_	Hyperglycemia, hypoglycemia, ypertriglyceridemia, anorexia, lack of appetite
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	Extrasystole, Tachycardia	_
Vascular disorders	_	Hypotension,  Flushing	Hypertension, Thrombophlebitis of superficial veins	_
Respiratory, thoracic and mediastinal disorders	_	_	Bradypnoea	Bronchospasm, dyspnoea
Gastrointestinal disorders	Nausea, vomiting	Abdominal pain, dyspepsia, diarrhoea, constipation, vomiting blood, dry mouth	Peptic ulcer, peptic ulcer haemorrhage or peptic ulcer perforation	Pancreatitis
Hepatobiliary disorders	_	_	Hepatitis, jaundice	Hepatocellular injury
Skin and subcutaneous tissue disorders	_	Dermatitis, pruritus, rash, sweating increased	Urticaria, acne	Stevens Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial oedema, photosensitivity reaction, pruritus
Musculoskeletal and connective tissue disorders	_	_	Muscle stiffness, joint stiffness, muscle cramps, back pain	_
Renal and urinary disorders	_	_	Acute renal failure, polyuria, renal pain, ketonuria, proteinuria	Nephritis, nephrotic syndrome
Reproductive system disorders	_	_	Menstrual disorder, prostatic disorder	_
General disorders and administration site conditions	Injection site pain, injection site reactions, including inflammation, hematoma, bleeding	Propagation, increased fatigue, pain, chills, asthenia, malaise	Trembling, 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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease 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). 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).

Shelf-life.

2 years.

From a microbiological point of view, the reconstituted drug should be used immediately. If the drug is not used immediately, in-use stability time and storage conditions are the responsibility of the user. However, the physical and chemical stability of the reconstituted drug is maintained for 24 hours at 2-8 ºC.

Storage conditions.

Store in the original package to protect from light. This medicinal product does not require any special temperature storage conditions. Keep out of reach of children.

Incompatibility.

KEDOL should not be mixed in small volumes (e.g. syringe) with solutions of dopamine, promethazine, pentazocine, pethidine and hydrocortisone due to white precipitate formation. The reconstituted solutions for infusion obtained as described in the section "Intravenous infusions" should not be mixed with promethazine or pentazocine.

Packaging.

2 ml ampoule; 50 ampoules in a box;

5 ampoules in a blister, 1 or 2 blisters in a box.

Terms of dispensing. On prescription.

Manufacturer.

Private Joint-Stock Company "Lekhim Kharkiv".

Manufacturer’s registered address.

36, Severina Potockogo str., Kharkiv, Kharkiv oblast, 61115, Ukraine.

Applicant.

Limited Liability Company "BERKANA+".

 

Applicant’s registered address.

20/1, Pushkina str., Bohodukhiv, Bohodukhiv district, Kharkiv oblast, 62103, Ukraine.