Instructions Ketonal solution for injection 100 mg/2 ml ampoule 2 ml No. 10
Composition
active ingredient: ketoprofen;
2 ml of solution contain 100 mg of ketoprofen;
Excipients: propylene glycol, ethanol 96%, benzyl alcohol, sodium hydroxide, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: colorless or slightly yellowish transparent solution with practically no visible particles.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Ketoprofen. ATX code M01A E03.
Pharmacological properties
Pharmacodynamics.
Ketoprofen is a nonsteroidal anti-inflammatory drug that has analgesic, anti-inflammatory, and antipyretic effects.
During inflammation, ketoprofen inhibits the synthesis of prostaglandins and leukotrienes, inhibiting the activity of cyclooxygenase and partially lipoxygenase. It also inhibits the synthesis of bradykinin and stabilizes lysosomal membranes.
It has a central and peripheral analgesic effect and eliminates the symptoms of inflammatory and degenerative diseases of the musculoskeletal system.
In women, ketoprofen reduces the symptoms of primary dysmenorrhea due to inhibition of prostaglandin synthesis.
Pharmacokinetics.
Absorption: The average concentration of ketoprofen in blood plasma is 26.4 ± 5.4 μg/ml 4–5 minutes after intravenous infusion or intramuscular injection. The bioavailability of ketoprofen is 90%.
In most patients, after intramuscular administration, ketoprofen is detected in the blood within 15 minutes, and the maximum concentration in the blood plasma is reached after 2 hours. The bioavailability of ketoprofen in the form of a solution for injection is linearly dependent on the dose of the drug.
Distribution. Protein binding is 99%. Volume of distribution is 0.1–0.2 l/kg. Ketoprofen penetrates into the synovial fluid. 3 hours after administration of 100 mg of ketoprofen, its concentration in blood plasma is approximately 3 μg/ml, and the concentration in synovial fluid is 1.5 μg/ml. Although the concentration of ketoprofen in synovial fluid is somewhat lower than in blood plasma, it is more stable (after 9 hours, the concentration of ketoprofen in blood plasma is 0.3 μg/ml, and in synovial fluid - 0.8 μg/ml), so pain syndrome and joint stiffness are reduced for a long time. Stable concentration of ketoprofen in blood plasma is achieved within 24 hours after administration. In elderly patients, a stable concentration of ketoprofen in blood plasma is achieved after 8.7 hours and is 6.3 μg/ml. Cumulation of ketoprofen in tissues is not observed.
After intramuscular administration of ketoprofen at a dose of 100 mg, its concentration in serum and cerebrospinal fluid was detected after 15 minutes. The peak concentration of ketoprofen in blood plasma was reached within 2 hours (1.3 μg/ml).
Metabolism and excretion. Ketoprofen is extensively metabolized in the liver by microsomal enzymes. It is excreted from the body as a conjugate with glucuronic acid. The half-life is 2 hours. Up to 80% of the administered dose of ketoprofen is excreted in the urine, usually (over 90%) in the form of glucuronide, approximately 10% in the feces.
In patients with impaired renal function, the elimination of ketoprofen is slowed down, the half-life is increased by 1 hour. In patients with impaired liver function, ketoprofen may accumulate in the tissues. In elderly patients, the metabolism and elimination of ketoprofen are slowed down, but this is of clinical significance only in cases of impaired renal function.
Indication
Joint diseases: rheumatoid arthritis; seronegative spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, reactive arthritis); gout, pseudogout; osteoarthritis; extra-articular rheumatism (tendinitis, bursitis, capsulitis of the shoulder joint).
Pain syndrome: lumbago, post-traumatic pain in joints, muscles; postoperative pain; pain with tumor metastases to the bones; algodysmenorrhea.
Contraindication
Hypersensitivity reactions to ketoprofen or to excipients. Contraindicated in patients in whom the use of ketoprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) provokes bronchospasm, asthma attacks, urticaria, angioedema, acute rhinitis or other allergic reactions. Severe heart failure. Treatment of perioperative pain during coronary artery bypass grafting. Chronic dyspepsia in history; gastric or duodenal ulcer in the acute stage or gastrointestinal bleeding, ulcerative diseases or perforation in history. Cerebrovascular or other bleeding. Patient's tendency to hemorrhage; hemorrhagic diathesis. Severe liver or kidney dysfunction. Bronchial asthma and rhinitis in history. Ketoprofen is contraindicated in patients with hemostatic disorders or those receiving anticoagulant therapy.
Interaction with other medicinal products and other types of interactions
Concomitant use of ketoprofen with other NSAIDs and salicylates, including selective cyclooxygenase-2 inhibitors, anticoagulants (heparin and warfarin), platelet aggregation inhibitors (ticlopidine, clopidogrel), thrombin inhibitors (dabigatran), direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), lithium preparations, methotrexate in doses above 15 mg/week should be avoided. The risk of gastrointestinal bleeding/ulceration increases.
Ketoprofen is protein bound; when used concomitantly with other protein bound drugs, such as anticoagulants, sulfonamides, hydantoins, dose adjustment may be necessary to prevent increased levels of these drugs due to competition for binding to plasma proteins.
Concomitant use with corticosteroids increases the risk of gastrointestinal ulceration or bleeding.
NSAIDs may enhance the effects of anticoagulants such as warfarin and heparin.
The use of ketoprofen together with antithrombotic agents and selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.
If concomitant use of anticoagulants (heparin and warfarin) and antiplatelet agents (e.g. ticlopidine, clopidogrel) cannot be avoided, patients should be closely monitored. The simultaneous use of multiple antiplatelet agents increases the risk of bleeding.
With simultaneous use with lithium preparations, lithium excretion is reduced. Risk of increased plasma lithium levels, sometimes reaching toxic levels due to reduced renal lithium excretion. If necessary, careful monitoring of plasma lithium levels should be established and the lithium dose adjusted during and after NSAID therapy.
Severe, sometimes fatal, toxicity has occurred after the use of ketoprofen with methotrexate (doses greater than 15 mg/week). The toxicity is due to an increase and prolongation of the concentration of methotrexate in the blood. A 12-hour interval should be allowed between the administration of ketoprofen and methotrexate.
Concomitant use with ketoprofen requires safety precautions.
Ketoprofen may reduce the effects of antihypertensive agents and diuretics.
Diuretics may increase the risk of nephrotoxicity of NSAIDs. Patients, especially those dehydrated by diuretics, are at greater risk of developing renal failure due to decreased renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated and their renal function checked before initiating treatment.
When ketoprofen is used concomitantly with methotrexate (doses below 15 mg/week), blood cell counts should be monitored weekly.
The risk of renal impairment is increased in patients taking diuretics or angiotensin-converting enzyme inhibitors concomitantly with NSAIDs. In some patients with compromised renal function (dehydrated patients or elderly patients), the concomitant use of ACE inhibitors or angiotensin II receptor antagonists and cyclooxygenase inhibitors may result in further deterioration of renal function, including acute renal failure.
The risk of bleeding increases with the simultaneous use of ketoprofen and pentoxifylline. It is necessary to monitor the state of the blood coagulation system.
Concomitant use with ketoprofen requires caution.
Ketoprofen may reduce the effects of antihypertensive agents (beta-blockers, ACE inhibitors) and diuretics due to inhibition of prostaglandin synthesis.
The use of ketoprofen together with thrombolytics and selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.
Concomitant use of probenecid may lead to a significant decrease in the clearance of ketoprofen from blood plasma.
Potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus and trimethoprim may cause hyperkalemia.
Concomitant use with tenofovir increases the risk of renal failure.
Concomitant use with nicorandil increases the risk of serious complications such as gastrointestinal ulcers, perforation and bleeding.
Ketoprofen enhances the effects of oral antidiabetic and antiepileptic drugs (phenytoin).
Concomitant use of NSAIDs and cardiac glycosides may cause exacerbation of heart failure, reduce glomerular filtration rate, and increase plasma glycoside levels.
Concomitant use with cyclosporine and tacrolimus increases the risk of nephrotoxicity, especially in elderly patients.
When used simultaneously with NSAIDs, the effect of mifepristone may be reduced. Nonsteroidal anti-inflammatory drugs should be taken 8–12 days after mifepristone administration.
Application features
Ketoprofen should be administered with caution to patients with a history of gastrointestinal disease. Bleeding and perforation may develop suddenly without prior symptoms.
The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses of NSAIDs, in patients with a history of ulcer, especially if complicated by haemorrhage or perforation, and in the elderly. These patients should be started on the lowest dose.
Such patients should be treated with combination therapy with protective drugs (e.g., misoprostol or proton pump inhibitors).
Patients with a history of gastrointestinal adverse reactions, especially elderly patients, should report any unusual abdominal symptoms (including gastrointestinal bleeding), especially at the beginning of treatment.
The drug should be used with caution in patients taking concomitant medications that may increase the risk of bleeding or ulceration, such as oral corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors, and antithrombotic drugs (acetylsalicylic acid, nicorandil).
There is a relative increased risk of gastrointestinal bleeding in patients with low body weight. If bleeding or ulceration occurs in patients treated with ketoprofen, therapy should be discontinued.
The drug should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as their condition may worsen.
An increased risk of arterial thrombotic events has been reported in patients receiving non-aspirin NSAIDs for perioperative pain management during coronary artery bypass grafting.
Close monitoring is necessary in patients with a history of hypertension and/or mild to moderate chronic heart failure, as fluid retention and edema have been reported with NSAID therapy.
Patients with uncontrolled arterial hypertension, chronic heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should take ketoprofen only after careful monitoring. Patients with risk factors such as hyperlipidemia, diabetes mellitus, or smoking should also be carefully examined before starting long-term treatment.
Patients with bronchial asthma accompanied by chronic rhinitis, sinusitis and/or nasal polyposis most often experience allergic reactions after taking acetylsalicylic acid and/or NSAIDs. The use of such drugs can cause bronchial asthma.
The drug should be used with caution in patients with hemostasis disorders, hemophilia, von Willebrand disease, severe thrombocytopenia, renal or hepatic insufficiency, as well as in individuals taking anticoagulants (coumarin and heparin derivatives, mainly low molecular weight heparins).
Careful monitoring of diuresis and renal function is necessary in patients with hepatic impairment, in patients receiving diuretics, in hypovolemia due to major surgery, especially in elderly patients.
Ketoprofen should be used with caution in individuals suffering from alcoholism.
In isolated cases, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with NSAIDs. The highest risk of such reactions is at the beginning of therapy. Ketonal® should be discontinued at the first appearance of skin rashes, mucosal lesions or other signs of hypersensitivity.
During long-term treatment with ketoprofen, especially in elderly patients, it is necessary to monitor the blood count, as well as liver and kidney function. If creatinine clearance is below 0.33 ml/s (20 ml/min), the dose of ketoprofen should be adjusted.
Ketoprofen may mask the signs and symptoms of infectious diseases, such as fever.
The use of the drug must be discontinued before major surgical interventions.
The use of ketoprofen may impair female fertility and is not recommended for women attempting to become pregnant. Women who are unable to become pregnant or who are undergoing treatment for infertility should not be treated with ketoprofen.
At the beginning of treatment, careful monitoring of renal function should be carried out in patients with heart failure, cirrhosis and nephrosis, chronic renal failure, especially in elderly patients, as well as in patients receiving diuretic therapy. In these patients, the use of ketoprofen may cause a decrease in renal blood flow caused by prostaglandin inhibition and lead to decompensation of renal function.
In patients with impaired liver function or a history of liver disease, transaminase levels should be measured periodically, especially during long-term treatment.
For severe pain, ketoprofen can be used in combination with morphine intravenously.
Masking of symptoms of underlying infections: Ketonal may mask the symptoms of an infectious disease, which may delay the initiation of appropriate treatment and thereby complicate the course of the disease. This has been observed in bacterial community-acquired pneumonia and bacterial complications of chickenpox. When Ketonal is used for fever or to relieve pain in an infection, monitoring for the infectious disease is recommended. In outpatient settings, the patient should consult a doctor if symptoms persist or worsen.
Use during pregnancy or breastfeeding
Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or the development of the fetus/embryo. Epidemiological studies have shown an increased risk of miscarriage, heart defects and gastroschisis when prostaglandin synthesis inhibitors are used in early pregnancy. The absolute risk of cardiovascular anomalies increases from 1% to approximately 1.5%. It is believed that the risk of such events increases with increasing dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors increased the rate of pre- and post-implantation fetal death and embryo-fetal lethality. In addition, in animals treated with prostaglandin synthesis inhibitors during the period of organogenesis, the incidence of various malformations, including cardiovascular, increased. The use of Ketonal from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible after discontinuation of the drug. In addition, cases of narrowing of the ductus arteriosus have been reported after treatment in the second trimester of pregnancy, most of which resolved after discontinuation of the drug. Therefore, ketoprofen should not be used during the first and second trimesters of pregnancy unless clearly necessary. If ketoprofen is used in women planning to become pregnant or during the first and second trimesters of pregnancy, the dose should be kept as low and the duration of treatment as short as possible.
Antenatal monitoring for oligohydramnios and narrowing of the ductus arteriosus should be considered after exposure to Ketonal for several days, starting from the 20th week of gestation. Ketonal should be discontinued if oligohydramnios or narrowing of the ductus arteriosus is detected.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks:
for the fetus:
cardiopulmonary toxicity (premature narrowing/closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction (see above);
for a woman at the end of pregnancy and for a newborn:
possible prolongation of bleeding time, anti-aggregation effect, which can occur even at very low doses;
suppression of uterine contractions, leading to delayed or prolonged labor.
Breastfeeding. There are no data on the excretion of ketoprofen into breast milk. Ketoprofen is not recommended for use during breastfeeding, as the safety of ketoprofen during lactation has not been proven.
Ability to influence reaction speed when driving vehicles or other mechanisms
Until the individual reaction to the drug is determined (dizziness, drowsiness, seizures, and visual disturbances may occur), it is recommended to refrain from driving or operating complex mechanisms.
Method of administration and doses
Doses should be selected individually, depending on the patient's condition and response to treatment.
For parenteral use.
Recommended doses for adults.
Intramuscular administration: use 1 ampoule (100 mg) of ketoprofen 1–2 times a day.
If necessary, intramuscular administration can be supplemented with oral or rectal forms of Ketonal®. The maximum daily dose should not exceed 200 mg.
Intravenous infusion: Ketoprofen infusions should be performed only in a hospital setting. The infusion should be performed over 0.5–1 hour, the course of treatment with intravenous administration should not exceed 48 hours. The maximum daily dose is 200 mg.
Intermittent intravenous infusion: 100–200 mg of ketoprofen should be dissolved in 100 ml of 0.9% sodium chloride solution and administered over 0.5–1 hour. The maximum daily dose is 200 mg.
Continuous intravenous infusion: 100–200 mg of ketoprofen dissolved in 500 ml of infusion solution (0.9% sodium chloride solution, lactated Ringer's solution, glucose) and administered over 8 hours. Maximum daily dose – 200 mg.
Ketoprofen can be used together with centrally acting analgesics; it can be mixed with morphine in one vial: 10–20 mg of morphine and 100–200 mg of ketoprofen are dissolved in 500 ml of infusion solution (0.9% sodium chloride solution or lactated Ringer's solution). The maximum daily dose is 200 mg.
To prevent the negative effects of ketoprofen on the mucous membranes of the gastrointestinal tract, antacids can be taken simultaneously.
Caution: vials with infusion solution should be wrapped in dark paper or aluminum foil, as ketoprofen is sensitive to light.
Tramadol and ketoprofen should be administered separately, as a precipitate may form when mixed.
Elderly patients. Elderly patients are at increased risk of adverse reactions. After 4 weeks of treatment, monitoring for gastrointestinal bleeding should be performed. It is recommended to start ketoprofen therapy at the lowest dose in order to keep patients on the lowest effective dose.
Renal impairment: In patients with moderate renal impairment with creatinine clearance less than 0.33 ml/s (20 ml/min), the dose of ketoprofen should be reduced.
The use of ketoprofen is contraindicated in patients with severe renal impairment.
Liver dysfunction: Patients with chronic liver disease and reduced serum albumin levels should have their ketoprofen dose reduced.
The use of ketoprofen is contraindicated in patients with severe hepatic impairment.
Children
Do not use the drug in children.
Overdose
Symptoms: headache, drowsiness, nausea, vomiting, epigastric pain, bloody vomiting, diarrhea, black stools, impaired consciousness, respiratory depression, shortness of breath, convulsions, dizziness, arterial hypotension, decreased renal function and renal failure, gastrointestinal bleeding.
Treatment: symptomatic therapy should be applied immediately in a hospital setting: gastric lavage and administration of activated charcoal. Treatment is symptomatic. H2 receptor antagonists, proton pump inhibitors and prostaglandins alleviate the dangerous effects of ketoprofen on the digestive tract. There is no specific antidote.
Side effects
Classification of side effects by frequency of occurrence: very common (≥ 1/10), common ≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), isolated (≥ 1/10,000, < 1/1000), rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
Side effects are usually transient. The most common side effects are gastrointestinal disorders.
From the blood system: infrequently - hemorrhagic anemia, hemolysis, purpura, thrombocytopenia, agranulocytosis, leukopenia; frequency unknown - hemolytic anemia.
High doses of ketoprofen may inhibit platelet aggregation, thereby prolonging bleeding time, and cause nosebleeds and hematoma formation.
On the part of the immune system: rare - exacerbation of bronchial asthma; frequency unknown - bronchospasm or shortness of breath (especially in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs), angioedema and anaphylaxis, anaphylactic reactions, including shock.
Mental disorders: common - depression, nervousness, nightmares, drowsiness; rare - delirium with visual and auditory hallucinations, disorientation, speech disorders, mood changes.
Nervous system: infrequent - headache, asthenia, discomfort, fatigue, weakness, drowsiness; rare - paresthesia; frequency unknown - aseptic meningitis, convulsions, dizziness; there have been isolated reports of cases of pseudotumor cerebri.
On the part of the organs of vision: frequent - visual impairment; rare - blurred vision, conjunctivitis.
On the part of the organs of hearing: frequent - tinnitus.
Cardiovascular system: frequent - edema; infrequent - heart failure, arterial hypertension; frequency unknown - vasculitis (including leukocytic vasculitis).
Clinical trials and epidemiological data suggest that the use of some NSAIDs (especially at high doses and in long-term use) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction and stroke). There are insufficient data to exclude such a risk with ketoprofen.
On the part of the respiratory system: infrequent - hemoptysis, shortness of breath, pharyngitis, rhinitis, bronchospasm (especially in patients with hypersensitivity to acetylsalicylic acid or other NSAIDs), laryngeal edema (signs of an anaphylactic reaction); rare - attacks of bronchial asthma.
From the digestive tract: very common - dyspepsia; common - nausea, abdominal pain, diarrhea, constipation, flatulence, anorexia, vomiting, stomatitis, gastritis; frequency unknown - colitis, intestinal perforation (as a complication of diverticulitis), melena, hematemesis, stomatitis, gastric or duodenal ulcer, exacerbation of ulcerative colitis or Crohn's disease, enteropathy with perforation, stenosis, pancreatitis. Peptic ulcers, perforation or gastrointestinal bleeding may occur. Enteropathy may be accompanied by mild bleeding with protein loss. Gastrointestinal discomfort, stomach pain, and in rare cases, colitis have been observed.
There have been reports of a case of rectal perforation in an elderly woman.
Ulceration, hemorrhage, or perforation may develop in 1% of patients after 3–6 months of treatment or in 2–4% of patients after 1 year of treatment with NSAIDs.
Skin: common - skin rash, itching; uncommon - alopecia, eczema, purpura-like rashes, increased sweating, urticaria, exacerbation of chronic urticaria, exfoliative dermatitis; rare - photosensitivity, photodermatitis; frequency unknown - bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis.
On the part of the urinary system: frequency unknown - acute renal failure, interstitial nephritis, nephrotic syndrome, acute pyelonephritis, organic kidney damage, acute tubular necrosis, acute papillary necrosis; fluid/sodium retention, hyperkalemia.
Reproductive system: infrequent - menometrorrhagia.
Metabolic disorders: frequency unknown - hyponatremia, hyperkalemia.
Laboratory indicators: very common – deviations from the norm of liver transaminase levels (ALT, AST), increased bilirubin levels in blood serum.
Injection site reactions: uncommon - burning sensation and/or pain at the injection site, swelling; frequency unknown - injection site reaction known as Nicolau syndrome.
Ketoprofen reduces platelet aggregation, thereby prolonging bleeding time.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
Incompatibility
Do not mix tramadol and ketoprofen in the same bottle due to the formation of sediment.
Packaging
2 ml of solution in an ampoule; 5 ampoules in a blister; 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Lek Pharmaceutical Company Ltd.
Location of the manufacturer and address of its place of business.
Verovškova 57, Ljubljana 1526, Slovenia.
