INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETONALâ (KETONALâ)

Composition:

*active substance: ketoprofen;

2 ml of solution contain ketoprofen 100 mg;

excipients: propylene glycol, 96% ethanol, benzyl alcohol, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: colorless or slightly yellowish clear solution, practically free of visible particles.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ketoprofen. ATC code M01A E03.

Pharmacological Properties.

Pharmacodynamics.

Ketoprofen is a non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory, and antipyretic effects.

In inflammation, ketoprofen inhibits the synthesis of prostaglandins and leukotrienes by suppressing cyclooxygenase activity and partially lipoxygenase activity. It also inhibits bradykinin synthesis and stabilizes lysosomal membranes.

It exerts central and peripheral analgesic effects and alleviates symptoms of inflammatory-degenerative disorders of the musculoskeletal system.

In women, ketoprofen reduces symptoms of primary dysmenorrhea due to inhibition of prostaglandin synthesis.

Pharmacokinetics.

Absorption. The mean plasma concentration of ketoprofen is 26.4 + 5.4 µg/mL within 4–5 minutes after intravenous infusion or intramuscular administration. The bioavailability of ketoprofen is 90%.

In most patients, ketoprofen is detectable in blood 15 minutes after intramuscular administration, and maximum plasma concentration is reached within 2 hours. The bioavailability of ketoprofen in the form of an injectable solution is linearly dependent on the administered dose.

Distribution. Protein binding is 99%. The volume of distribution is 0.1–0.2 L/kg. Ketoprofen penetrates into synovial fluid. Three hours after administration of 100 mg ketoprofen, its plasma concentration is approximately 3 µg/mL, while its concentration in synovial fluid is 1.5 µg/mL. Although the concentration of ketoprofen in synovial fluid is somewhat lower than in plasma, it is more stable (after 9 hours, the plasma concentration of ketoprofen is 0.3 µg/mL, while in synovial fluid it is 0.8 µg/mL), resulting in prolonged reduction of pain and joint stiffness. A steady-state plasma concentration of ketoprofen is achieved within 24 hours after administration. In elderly patients, steady-state plasma concentration is reached within 8.7 hours and amounts to 6.3 µg/mL. Tissue accumulation of ketoprofen does not occur.

Fifteen minutes after intramuscular administration of 100 mg ketoprofen, its concentration was detected in blood serum and cerebrospinal fluid. Peak plasma concentration of ketoprofen was achieved within 2 hours (1.3 µg/mL).

Metabolism and Elimination. Ketoprofen is extensively metabolized in the liver by microsomal enzymes. It is excreted from the body as a glucuronic acid conjugate. The elimination half-life is 2 hours. Up to 80% of the administered dose of ketoprofen is excreted in urine, predominantly (over 90%) as glucuronide, and approximately 10% in feces.

In patients with impaired renal function, ketoprofen elimination is delayed, and the elimination half-life is prolonged by 1 hour. In patients with impaired hepatic function, ketoprofen may accumulate in tissues. In elderly patients, metabolism and elimination of ketoprofen are slowed, although this is clinically significant only in the presence of impaired renal function.

Clinical Characteristics.

Indications.

Joint diseases: rheumatoid arthritis; seronegative spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, reactive arthritis); gout, pseudogout; osteoarthritis; extra-articular rheumatism (tendinitis, bursitis, shoulder capsulitis).

Pain syndromes: lumbar pain (lumbago), post-traumatic joint and muscle pain; postoperative pain; bone metastasis-related pain; algomenorrhea.

Contraindications.

Hypersensitivity reactions to ketoprofen or excipients. Contraindicated in patients in whom administration of ketoprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs (NSAIDs) triggers bronchospasm, asthmatic attacks, urticaria, angioneurotic edema, acute rhinitis, or other allergic reactions. Severe heart failure. Treatment of perioperative pain associated with coronary artery bypass graft (CABG) surgery. Chronic dyspepsia in medical history; active gastric or duodenal ulcer, gastrointestinal bleeding, or history of peptic ulcer disease or perforation. Cerebrovascular or other hemorrhages. Patient predisposition to hemorrhage; hemorrhagic diathesis. Severe hepatic or renal dysfunction. History of bronchial asthma and rhinitis. Ketoprofen is contraindicated in patients with coagulation disorders or those receiving anticoagulant therapy.

Interaction with other medicinal products and other forms of interactions.

Concomitant use with ketoprofen is not recommended.

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, and methotrexate at doses exceeding 15 mg/week should be avoided. The risk of gastrointestinal bleeding/ulceration is increased.

Ketoprofen is protein-bound; when used concomitantly with other protein-binding drugs such as anticoagulants, sulfonamides, and hydantoins, dose adjustments may be required to prevent elevated levels of these drugs due to competition for plasma protein binding.

Concomitant use with corticosteroids increases the risk of gastrointestinal ulceration or bleeding.

NSAIDs may potentiate the effects of anticoagulants such as warfarin and heparin.

Concomitant use of ketoprofen with antithrombotic agents and selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.

If concomitant use of anticoagulants (heparin and warfarin) and antithrombotic agents (e.g., ticlopidine, clopidogrel) cannot be avoided, patients must be under close medical supervision. Simultaneous use of multiple antithrombotic agents increases the risk of bleeding.

Concomitant use with lithium decreases lithium excretion. This increases the risk of elevated plasma lithium levels, sometimes reaching toxic levels, due to reduced renal clearance of lithium. If necessary, close monitoring of plasma lithium levels and dose adjustment of lithium during and after NSAID therapy are required.

Severe, sometimes fatal, toxicity has occurred after concomitant use of ketoprofen with methotrexate (doses exceeding 15 mg/week). Toxicity is due to increased and prolonged methotrexate plasma concentration. A 12-hour interval should be maintained between administration of ketoprofen and methotrexate.

Concomitant use with ketoprofen requires safety measures.

Ketoprofen may reduce the efficacy of antihypertensive agents and diuretics.

Diuretics may increase the risk of NSAID nephrotoxicity. Patients, especially those dehydrated due to diuretic use, are at higher risk of renal failure due to reduced renal blood flow caused by prostaglandin inhibition. Before initiating treatment in such patients, fluid balance should be restored and renal function assessed.

When ketoprofen is used concomitantly with methotrexate (doses below 15 mg/week), weekly monitoring of blood cell counts is recommended.

The risk of renal impairment increases in patients taking diuretics or angiotensin-converting enzyme (ACE) inhibitors concurrently with nonsteroidal anti-rheumatic agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients), concomitant use of ACE inhibitors or angiotensin II receptor antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including acute renal failure.

Concomitant use of ketoprofen with pentoxifylline increases the risk of bleeding. Monitoring of the blood coagulation system is required.

Concomitant use with ketoprofen requires caution.

Ketoprofen may reduce the efficacy of antihypertensive agents (beta-blockers, ACE inhibitors) and diuretics due to inhibition of prostaglandin synthesis.

Concomitant use of ketoprofen with thrombolytics and selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.

Concomitant use of probenecid may lead to a significant reduction in ketoprofen plasma clearance.

Potassium salts, potassium-sparing diuretics, ACE 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 agents (phenytoin).

Concomitant use of NSAIDs and cardiac glycosides may exacerbate 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.

Concomitant use with NSAIDs may reduce the effect of mifepristone. Nonsteroidal anti-rheumatic agents should be administered 8–12 days after mifepristone use.

Special precautions for use.

Adverse effects (especially those affecting the gastrointestinal tract and cardiovascular system) can be avoided by taking the lowest effective dose for the shortest duration necessary.

Ketoprofen should be prescribed with caution to patients with a history of gastrointestinal disorders. Bleeding and perforation may occur suddenly without preceding symptoms.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly complicated by hemorrhage or perforation, and in elderly patients. These patients should initiate treatment with the lowest possible dose.

Such patients should receive concomitant therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

Patients who have previously experienced gastrointestinal adverse effects, especially elderly patients, should report any unusual abdominal symptoms (including gastrointestinal bleeding), particularly 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 antiplatelet agents (acetylsalicylic acid, nicorandil).

A relatively increased risk of gastrointestinal bleeding has been observed in patients with low body weight. If bleeding or ulceration occurs in patients receiving ketoprofen, therapy should be discontinued.

The medicinal product should be used with caution in patients with a history of gastrointestinal disorders (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 the management of perioperative pain following coronary artery bypass graft (CABG) surgery.

Careful monitoring is required in patients with arterial hypertension and/or a history of mild to moderate chronic heart failure, as fluid retention and edema have been reported during 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 under close monitoring. Prior to initiating long-term treatment in patients with risk factors such as hyperlipidemia, diabetes, or smoking, thorough evaluation is also necessary.

Allergic reactions after taking acetylsalicylic acid and/or NSAIDs most commonly occur in patients with bronchial asthma associated with chronic rhinitis, sinusitis, and/or nasal polyps. The use of such medicinal products may trigger bronchial asthma.

The drug should be used with caution in patients with coagulation disorders, hemophilia, von Willebrand disease, severe thrombocytopenia, renal or hepatic impairment, and in individuals taking anticoagulants (coumarin derivatives and heparins, particularly low-molecular-weight heparins).

Careful monitoring of diuresis and renal function is required in patients with hepatic impairment, in patients receiving diuretics, and in those with hypovolemia following major surgery, especially in elderly patients.

Ketoprofen should be used cautiously in individuals with alcoholism.

In isolated cases, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been observed with the use of NSAIDs. The risk of such reactions is highest at the beginning of therapy. Ketalon® should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

During prolonged treatment with ketoprofen, especially in elderly patients, blood counts as well as liver and kidney function should be monitored. If creatinine clearance is below 0.33 ml/s (20 ml/min), the dose of ketoprofen should be adjusted.

Ketoprofen may mask signs and symptoms of infectious diseases, such as fever.

The use of the drug should be discontinued prior to major surgical procedures.

Ketoprofen may impair female fertility and is not recommended for women who are trying to conceive. Women who are infertile or undergoing infertility treatment should not be treated with ketoprofen.

At the beginning of treatment, careful monitoring of renal function is recommended in patients with heart failure, cirrhosis, nephrotic syndrome, chronic renal failure, particularly in elderly patients, and in patients receiving diuretic therapy. In these patients, ketoprofen use may reduce renal blood flow due to inhibition of prostaglandin synthesis, potentially leading to renal decompensation.

In patients with impaired liver function or a history of liver disease, transaminase levels should be periodically measured, especially during long-term treatment.

In cases of severe pain, ketoprofen may be used in combination with morphine via intravenous administration.

Hyperkalemia may occur during treatment with ketoprofen, particularly in patients with diabetes, renal impairment, and/or concomitant therapy with drugs that predispose to hyperkalemia.

Masking symptoms of underlying infections: Ketalon may mask symptoms of infectious disease, potentially delaying the initiation of appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Ketalon is used for fever reduction or pain relief during infection, monitoring of the infectious condition is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following exposure to prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increases from 1% to approximately 1.5%. The risk is believed to increase with higher drug doses and longer duration of therapy. In animal studies, administration of prostaglandin synthesis inhibitors increased pre- and post-implantation embryo-fetal loss and embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular malformations, was observed. Use of Ketalon from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, cases of fetal ductus arteriosus constriction after second-trimester treatment have been reported, most of which resolved after stopping the drug. Therefore, ketoprofen should not be used during the first and second trimesters of pregnancy unless clearly indicated. If ketoprofen is used in women planning pregnancy or during the first and second trimesters, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to Ketalon for several days starting from the 20th gestational week. Use of Ketalon should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks:

to the fetus:

cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction (see above);

to the mother at the end of pregnancy and to the newborn:

possible prolongation of bleeding time, antiplatelet effect, which may occur even at very low doses;
inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding. Data on the excretion of ketoprofen into breast milk are lacking. Ketoprofen is not recommended during breastfeeding, as the safety of ketoprofen during lactation has not been established.

Ability to affect reaction speed when driving or operating machinery.

Until individual response to the medicinal product is known (dizziness, drowsiness, seizures, and visual disturbances may occur), it is recommended to refrain from driving or operating complex machinery.

Method of Administration and Dosage

Dosages should be individually adjusted depending on the patient's condition and response to treatment.

For parenteral use.

Recommended doses for adults.

Intramuscular administration: administer 1 ampoule (100 mg) of ketoprofen 1–2 times daily.

If necessary, intramuscular administration may be supplemented with oral or rectal formulations of Ketonal®. The maximum daily dose should not exceed 200 mg.

Intravenous infusion: ketoprofen infusions should only be administered under hospital conditions. Infusion should be given over 0.5–1 hour. The treatment course 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 should be dissolved in 500 ml of infusion solution (0.9% sodium chloride solution, Ringer's lactate solution, glucose) and administered over 8 hours. The maximum daily dose is 200 mg.

Ketoprofen may be used concomitantly with centrally-acting analgesics; it may be mixed with morphine in the same bottle: 10–20 mg of morphine and 100–200 mg of ketoprofen dissolved in 500 ml of infusion solution (0.9% sodium chloride solution or Ringer's lactate solution). The maximum daily dose is 200 mg.

The duration of treatment depends on the severity and course of the disease; however, adverse effects can be minimized by using the lowest effective dose for the shortest possible duration.

To prevent the negative effects of ketoprofen on gastrointestinal mucosa, antacid agents may be administered concomitantly.

Warning: bottles containing 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 their mixture may result in precipitate formation.

Elderly patients. In elderly patients, the risk of adverse reactions increases. After 4 weeks of treatment initiation, monitoring for gastrointestinal bleeding manifestations is recommended. Therapy with ketoprofen should be initiated at the lowest dose to maintain patients on the lowest effective dose.

Renal impairment. In patients with moderate renal impairment and creatinine clearance less than 0.33 ml/s (20 ml/min), the dose of ketoprofen should be reduced.

Ketoprofen is contraindicated in patients with severe renal impairment.

Hepatic impairment. In patients with chronic liver disease and reduced serum albumin levels, the dose of ketoprofen should be reduced.

Ketoprofen is contraindicated in patients with severe hepatic impairment.

Children.

The drug should not be administered to children.

Overdose.

Symptoms: headache, drowsiness, nausea, vomiting, epigastric pain, hematemesis, diarrhea, black stools, impaired consciousness, respiratory depression, apnea, convulsions, dizziness, arterial hypotension, reduced renal function and renal failure, gastrointestinal bleeding.

Treatment: symptomatic therapy should be immediately initiated under hospital conditions: gastric lavage and administration of activated charcoal. Treatment is symptomatic. H2-receptor antagonists, proton pump inhibitors, and prostaglandins may alleviate the dangerous gastrointestinal effects of ketoprofen. There is no specific antidote.

Side effects

Classification of adverse effects by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10 000, < 1/1000), very rare (< 1/10 000), frequency not known (cannot be estimated based on available data).

Adverse effects are usually transient. Gastrointestinal disorders are the most commonly observed.

Blood system:
Uncommon – haemorrhagic anaemia, haemolysis, purpura, thrombocytopenia, agranulocytosis, leucopenia; frequency not known – haemolytic anaemia.

High doses of ketoprofen may inhibit platelet aggregation, thereby prolonging bleeding time, and may cause epistaxis and bruising.

Immune system:
Rare – exacerbation of bronchial asthma; frequency not known – bronchospasm or dyspnoea (particularly in patients with hypersensitivity to acetylsalicylic acid or other NSAIDs), angioneurotic oedema and anaphylaxis, anaphylactic reactions including shock.

Psychiatric disorders:
Common – depression, nervousness, nightmares, drowsiness; rare – delirium with visual and auditory hallucinations, disorientation, speech disturbances, mood changes.

Nervous system:
Uncommon – headache, asthenia, discomfort, increased fatigue, weakness, drowsiness; rare – paraesthesia; frequency not known – aseptic meningitis, convulsions, dizziness; isolated cases of pseudotumour cerebri have been reported.

Eye disorders:
Common – visual disturbances; rare – blurred vision, conjunctivitis.

Ear and labyrinth disorders:
Common – tinnitus.

Cardiovascular system:
Common – oedema; uncommon – heart failure, arterial hypertension; frequency not known – vasculitis (including leukocytoclastic vasculitis).

Clinical studies and epidemiological data confirm that use of certain NSAIDs (particularly at high doses and with long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction and stroke). Data on ketoprofen are insufficient to exclude such a risk.

Respiratory system:
Uncommon – haemoptysis, dyspnoea, pharyngitis, rhinitis, bronchospasm (particularly in patients with hypersensitivity to acetylsalicylic acid or other NSAIDs), laryngeal oedema (signs of anaphylactic reaction); rare – attacks of bronchial asthma.

Gastrointestinal system:
Very common – dyspepsia; common – nausea, abdominal pain, diarrhoea, constipation, flatulence, anorexia, vomiting, stomatitis, gastritis; frequency not known – colitis, intestinal perforation (as a complication of diverticulosis), melaena, haematemesis, stomatitis, gastric or duodenal ulcer, exacerbation of ulcerative colitis or Crohn’s disease, enteropathy with perforation, stenosis, pancreatitis. Peptic ulcers, gastrointestinal perforation or gastrointestinal haemorrhage may occur. Enteropathy may be associated with occult bleeding and protein loss. Gastrointestinal discomfort, stomach pain, and rarely colitis may occur.

There have been reports of rectal perforation in an elderly woman.

Ulceration, haemorrhage or perforation may develop in 1% of patients within 3–6 months of treatment or in 2–4% of patients after 1 year of treatment with NSAIDs.

Hepatobiliary system:
Frequency not known – severe liver function disorders, accompanied by jaundice and hepatitis.

Skin and subcutaneous tissue:
Common – skin rashes, pruritus; uncommon – alopecia, eczema, purpura-like rashes, increased sweating, urticaria, exacerbation of chronic urticaria, exfoliative dermatitis; rare – photosensitivity, photoallergic dermatitis; frequency not known – bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

Renal and urinary system:
Frequency not known – acute renal failure, interstitial nephritis, nephrotic syndrome, acute pyelonephritis, organic kidney damage, acute tubular necrosis, acute papillary necrosis; fluid and sodium retention, hyperkalaemia.

Reproductive system:
Uncommon – menometrorrhagia.

Metabolic and nutritional disorders:
Frequency not known – hyponatraemia, hyperkalaemia.

Laboratory findings:
Very common – deviations from normal levels of liver transaminases (ALT, AST), increased serum bilirubin levels.

Injection site reactions:
Uncommon – burning sensation and/or pain at injection site, swelling; frequency not known – injection site reaction known as Nicolau syndrome.

Ketoprofen reduces platelet aggregation, thereby prolonging bleeding time.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibility.

Do not mix tramadol and ketoprofen in the same vial due to precipitate formation.

Packaging.

2 ml solution in an ampoule; 5 ampoules in a blister pack; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

Manufacturer's address and place of business.

Verovškova 57, 1526 Ljubljana, Slovenia.