INSTRUCTION

for medical use of the medicinal product

DEXIL

 

Composition:

active substance: dexketoprofen;

1 ml of solution for injection contains dexketoprofen trometamol 36.909 mg equivalent to dexketoprofen 25 mg;

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

Pharmaceutical form. Solution for injection.

Basic physical and chemical properties: a clear, colourless solution.

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

Pharmacological properties

Pharmacodynamics

Dexketoprofen trometamol is a propionic acid salt 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 reducing the synthesis of prostaglandins by the inhibition of cyclooxygenase pathway. Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, 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 action which would be additional to the direct action. The inhibitory effect of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 has been found. It has been established that dexketoprofen trometamol has a pronounced analgesic effect with a rapid onset and reaching the maximum effect within the first 45 minutes in various types of pain, including postoperative pain (orthopedic and gynecological operations, abdominal operations), musculoskeletal pain (acute lower back pain) and renal colic. The duration of the analgesic effect after the use of 50 mg of dexketoprofen trometamol, as a rule, is 8 hours. It is known that the use of dexketoprofen allows to significantly reduce the dose of opiates when they are used concomitantly to relieve postoperative pain. Patients who received morphine with a patient-controlled analgesia device and dexketoprofen trometamol for postoperative pain required significantly less morphine (by 30-45%) than patients who received placebo.

Pharmacokinetics

After intramuscular administration of dexketoprofen trometamol, the maximum concentration is reached after about 20 minutes (10-45 minutes). It has been proven that with a single intramuscular or intravenous injection of 25-50 mg of the drug, the AUC ("concentration - time") is proportional to the dose. Pharmacokinetic studies of repeated use of the drug have proven that the AUC and Cmax (average maximum value) after the last intramuscular and intravenous administration do not differ from those after a single use, which indicates the absence of drug accumulation. Similar to other drugs with a high degree of binding to blood plasma proteins (99%), the volume of distribution of dexketoprofen is on average 0.25 l/kg. The half-life is approximately 0.35 hours, and the elimination half-life is 1 to 2.7 hours. Metabolism of dexketoprofen mainly occurs by conjugation with glucuronic acid and subsequent excretion by the kidneys. After the administration of dexketoprofen trometamol, only the optical isomer S-(+) is detected in the urine. This indicates the absence of transformation of the drug into the optical isomer R-(-). After the administration of single and multiple doses, the degree of drug exposure to healthy elderly volunteers (from 65 years) is significantly higher (up to 55%) than to young volunteers. However, there was no statistically significant difference in the maximum concentration and the time of its achievement. The average elimination half-life increased (up to 48%), and the determined total clearance decreased.

 

Clinical particulars.

Indications.

Symptomatic treatment of acute pain of moderate and high intensity when oral administration of the drug is inappropriate (e.g., postoperative pain, renal colic and pain in the lower back (back pain)).

Contraindications.

- patients hypersensitive to dexketoprofen, 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 or gastrointestinal haemorrhage, suspicion of them or with recurrent peptic ulcer disease or any history of gastrointestinal bleeding (at least two confirmed cases of ulcer or bleeding) or chronic dyspepsia;

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

- 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 impairment (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 the neuraxial, intrathecal or epidural administration (due to the ethanol content).

Interaction with other medicinal products and other types of interactions.

It is not recommended to use the following products with NSAIDs:

- 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 and 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 (at least 15 mg/week). Due to the decrease in the renal clearance of methotrexate against the background of the use of NSAIDs, its negative effect on the blood system is generally increased;

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

The co-administration of the following agents with NSAIDs requires caution:

- 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 co-administration 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;

- 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. In the first weeks of concomitant use, it is necessary to conduct a blood test every week. Increased surveillance in the presence of even mildly impaired renal function, as well as in the elderly should be carried out;

- 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.

Possible interactions should be taken into account when using the following agents:

- 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;

- 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 mifepristone therapy;

- Quinolone: the results of animal studies have shown that when quinolone derivatives are used in high doses in combination with NSAIDs, the risk of convulsions increases.

Precautions for use.

Caution should be exercised in patients with a history of allergic conditions. The use of dexketoprofen 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 anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding occurs in patients receiving the drug, 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 relapses of nonspecific ulcerative colitis, as well as Crohn's disease in patients with remission. Before starting the use of dexketoprofen trometamol in patients with a history of esophagitis, gastritis and/or peptic ulcer disease, it should be certain that these diseases are in remission. In patients with existing symptoms of the pathology of the digestive tract and a history of digestive disorders during the use of the drug, the state of the digestive tract should be monitored for the occurrence of possible disorders, especially gastrointestinal bleeding.

For such patients and patients using low-dose acetylsalicylic acid or other agents that increase the risk of adverse gastrointestinal reactions, combination therapy with protective agents such as misoprostol or proton pump inhibitors should be considered.

Patients, especially the elderly, who have a history of the digestive tract adverse reactions, should inform the doctor on any unusual symptoms related to the digestive system, in particular, gastrointestinal bleeding, especially 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.

Non-selective NSAIDs are able to reduce platelet aggregation and increase bleeding time due to inhibition of prostaglandin synthesis. It is known that the concomitant use of dexketoprofen trometamol and low molecular weight heparin in prophylactic doses in the postoperative period does not affect coagulation parameters. However, patients who use dexketoprofen trometamol concomitantly with drugs that affect hemostasis (e.g., warfarin, other coumarin drugs or heparins), must be under the close supervision of a doctor.

Patients with arterial hypertension and/or congestive heart failure of mild or moderate severity should be under the close supervision of a doctor due to the possible fluid retention and peripheral oedema.

The use of some NSAIDs, especially in high doses and for a long time, may be accompanied by some increase in the risk of conditions caused by arterial thrombosis, such as myocardial infarction or stroke. There are insufficient data to exclude such a risk for dexketoprofen.

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. Dexil 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 SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued.

Caution should be exercised in patients with impaired liver and/or kidney function, as well as patients with arterial hypertension and/or congestive heart failure, since they may experience deterioration of kidney function, fluid retention, and peripheral edema while taking NSAIDs. 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 renal impairment, cardiovascular and liver disorders

Dexketoprofen should be administered with caution to patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

As with other NSAIDs, dexketoprofen trometamol can mask symptoms of infection during its use. In isolated cases, during the use of NSAIDs, there were reports of activation of infectious processes localized in soft tissues. Therefore, if symptoms of a bacterial infection appear or worsen during use, patients are advised to seek medical attention immediately.

As with other NSAIDs, dexketoprofen trometamol can reduce female fertility, so it is not recommended for women attempting to conceive. Women, having problems conceiving or being tested for infertility, should consider discontinuing the drug. The prescription of dexketoprofen in the I and II trimesters of pregnancy is possible in cases of extreme necessity.

Each ampoule of Dexil contains 200 mg of ethanol, which is equal to 5 ml of beer or 2.08 of wine per dose. The drug can have a negative effect on people suffering from alcoholism. Ethanol should be taken into account for patients from the risk groups (e.g., liver diseases, epilepsy), and when using the drug in the I and II trimesters of pregnancy. The drug contains less than 1 mmol of sodium (23 mg) per dose, so it practically does not contain free sodium.

Pregnancy and lactation.

Dexil 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. 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 foetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- renal impairment, 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.

Dexil may cause dizziness, drowsiness and increased fatigue, so mild or moderate effect on the ability to drive vehicles or operate other mechanisms 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 with an interval of 8-12 hours. If necessary, a second dose should be administered 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 in case of acute pain only (no longer than 2 days). Patients should be switched to oral analgesics if possible. Adverse reactions can be reduced by using the lowest effective dose for the shortest possible time needed to improve the condition. For postoperative pain of moderate or severe severity, the drug can be used according to indications in the same recommended doses in combination with opioid analgesics.

Elderly. No dose adjustment is necessary. However, due to the physiological decrease in kidney 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 or moderate liver disease (Child-Pugh score of 5 to 9), the maximum daily dose should be reduced to 50 mg and liver function should be closely monitored. The drug is contraindicated in severe liver diseases (Child-Pugh score of 10 to 15).

Renal impairment. For patients with mild renal impairment (creatinine clearance 50-80 ml/min), the maximum daily dose should be reduced to 50 mg. The drug is contraindicated in moderate or severe renal impairment (creatinine clearance < 50 ml/min).

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

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

Intravenous infusion.

For intravenous infusion, dilute the contents of 2 ml ampoule in 30-100 ml of 0.9% sodium chloride solution, glucose solution or Ringer's lactate solution. The solution for infusions should be prepared in aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear. Infusion should be carried out within 10-30 minutes. Do not allow natural daylight to affect the prepared solution.

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

Dexketoprofen should not be mixed in the infusion solution with promethazine and pentazocine.

Intravenous injection (bolus administration).

If necessary, the contents of 1 ampoule (2 ml of solution for injection) should be administered intravenously within at least 15 seconds.

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

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

The drug can be mixed only with the medicinal products indicated above.

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

When storing diluted solutions of the drug in polyethylene bags or in products from ethyl vinyl acetate, cellulose propionate, low-density polyethylene and polyvinyl chloride prepared for administration, changes in the content of the active substance due to sorption were not observed.

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

Children.

The drug should not be used for children and adolescents due to the 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 overdose, immediate symptomatic therapy should be initiated according to the patient's clinical condition. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below shows adverse reactions classified by system organ class and ordered by frequency.

System organ class	Common   (≥1/100 to <1/10)	Uncommon   (≥1/1,000 to <1/100)	Rare   (≥1/10,000 to <1/1,000)	Very rare (<1/10,000)
Blood and lymphatic system disorders	_	Anaemia	_	Neutropenia, thrombocytopenia
Immune system disorders	_	_	Laryngeal oedema	Anaphylactic reaction, including anaphylactic shock
Metabolism and nutrition disorders	_	_	Hyperglycaemia, hypoglycaemia, hypertriglyceridemia, 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	_	Arterial hypotension, flushing	Arterial hypertension, superficial thrombophlebitis	_
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 hemorrhage or peptic ulcer perforation	Pancreatitis
Hepatobiliary disorders	_	_	Hepatitis, jaundice	Hepatocellular injury
Skin and subcutaneous tissue disorders	_	Dermatitis, itching, rash, sweating increased	Urticaria, acne	Stevens Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial oedema, photosensitivity reaction
Musculoskeletal and connective tissue disorders	_	_	Muscle stiffness, joint stiffness, muscle cramps, back pain	_
Renal and urinary disorders	_	_	Acute renal failure, polyuria, kidney pain, ketonuria, proteinuria	Nephritis or nephrotic syndrome
Reproductive system and breast disorders	_	_	Menstrual disorder, prostatic disorder	_
General disorders and administration site conditions	Pain at the injection site, reactions at the injection site, including inflammation, hematoma, bleeding	Fever, increased fatigue, pain, chills, asthenia, malaise	Tremor, 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) are possible.

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.

Storage conditions.

Store in the original packaging (avoid from daylight) at a temperature not exceeding 25°C. After dilution, store the solution for 24 hours at a temperature of 2 to 8°C. Keep out of reach of children.

Incompatibility.

Dexketoprofen should not be mixed in small volumes (e.g. in a syringe) with solutions of dopamine, promethazine pentazocine, pethidine and hydrocortisone because a white precipitate is formed.

Diluted solution for infusion obtained as indicated in the section "Intravenous infusion" should not be mixed with promethazine or pentazocine.

Packaging.

2 ml in an ampoule, 5 ampoules in a contoured blister pack, in a cardboard pack.

Terms of dispensing. On prescription.

Manufacturer.

Steril-Gene Life Sciences (P) Ltd.

Manufacturer’s registered address.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India.

Applicant. SCAN BIOTECH LTD, India.

Applicant’s registered address. E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.

Date of last update: 30.07.2021