Instructions for Ketonal Duo hard capsules 150 mg blister No. 20
Composition
active ingredient: ketoprofen;
1 capsule contains ketoprofen 150 mg;
excipients:
capsule contents: microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium, polysorbate 80, methacrylate copolymer (type B), methacrylate copolymer (type A), triethyl citrate, talc, iron oxide yellow (E 172), colloidal anhydrous silicon dioxide;
capsule shell: gelatin, titanium dioxide (E 171), indigo carmine (E 132).
Dosage form
Modified-release capsules are hard.
Main physicochemical properties: capsules with a transparent body and a blue cap, containing white and yellow pellets.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. 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. Ketonal® Duo capsules are a new dosage form that differs from conventional capsules in the way the active substance is released. The capsules contain two types of pellets: standard (white) and coated (yellow). Ketoprofen is released quickly from the white pellets (60% of the total amount) and slowly from the yellow pellets (40% of the total amount), which provides an immediate and prolonged effect of the drug.
After oral administration of Ketonal® Duo capsules, ketoprofen is rapidly absorbed in the digestive tract. The bioavailability of ketoprofen is 90%.
Food intake does not affect the overall bioavailability of ketoprofen, but reduces the rate of absorption. Fatty food increases the time to reach maximum concentration, but does not reduce the bioavailability and maximum concentration of ketoprofen in blood plasma. Simultaneous administration of drugs that reduce the acidity of gastric juice does not affect the rate and volume of ketoprofen absorption. The maximum plasma concentration - 9036.64 ng/ml - is reached within 1.76 hours.
Distribution. The degree of binding to blood proteins is 99%. The volume of distribution is 0.1 l/kg. Ketoprofen penetrates into the synovial fluid and reaches a concentration there that is 30% of the plasma concentration. Although the concentration of ketoprofen in the synovial fluid is somewhat lower than in blood plasma, it is more stable (up to 30 hours), so pain syndrome and joint stiffness are reduced for a long time.
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. About 80% of the administered dose of ketoprofen is excreted in the urine, usually (over 90%) as a glucuronide, about 10% in the feces. There are no active metabolites of ketoprofen. The plasma clearance of ketoprofen is approximately 0.08 l/kg/h.
In patients with renal insufficiency, the elimination of ketoprofen is slowed down, the half-life is increased by 1 hour. In patients with hepatic insufficiency, 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, postoperative pain, pain from tumor metastases to the bone, algodysmenorrhea.
Contraindication
Hypersensitivity to ketoprofen or to any of the excipients of the drug. Ketonal® Duo is 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.
Do not use for the treatment of perioperative pain during coronary artery bypass graft surgery.
Chronic dyspepsia in history; active phase or relapse of gastric or duodenal ulcer or ulceration/perforation (two or more separate cases) in history; gastrointestinal bleeding/perforation/ulcers in history associated with previous NSAID treatment; cerebrovascular or other bleeding; tendency to hemorrhage; hemorrhagic diathesis; severe liver or kidney dysfunction, severe renal failure; bronchial asthma and rhinitis in history. III trimester of pregnancy.
Interaction with other medicinal products and other types of interactions
Concomitant use of ketoprofen with other NSAIDs and salicylates, including selective cyclooxygenase-2 inhibitors, should be avoided. The risk of gastrointestinal bleeding/ulceration is increased.
Anticoagulants (heparin, warfarin), drugs that inhibit platelet aggregation
(ticlopidine, clopidogrel) when used with ketoprofen increase the risk of gastrointestinal bleeding.
When used simultaneously with lithium preparations, lithium excretion is reduced, and its concentration in blood plasma increases to toxic levels.
Severe, sometimes fatal, toxicity has occurred after the use of ketoprofen with methotrexate (doses above 15 mg/week). The toxicity is due to an increase and prolongation of the plasma concentration of methotrexate.
Concomitant use with ketoprofen requires precautions
Diuretics may increase the risk of nephrotoxicity of NSAIDs. Patients receiving diuretics should be rehydrated before prescribing ketoprofen and renal function should be closely monitored during treatment.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists when used with ketoprofen in patients with impaired renal function (e.g. dehydrated patients, elderly patients) increase the risk of nephrotoxicity with the possibility of developing acute renal failure.
Concomitant use with corticosteroids increases the risk of gastrointestinal ulceration or bleeding.
When ketoprofen is used concomitantly with methotrexate (doses below 15 mg/week), blood cell counts should be monitored weekly. In patients with impaired renal function and elderly patients, monitoring should be performed more frequently.
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; diuretics increase the risk of nephrotoxicity of NSAIDs.
The use of ketoprofen together with thrombolytics and selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.
Concomitant administration of probenecid may lead to a significant decrease in the clearance of ketoprofen from blood plasma.
Ketoprofen binds to blood proteins; when used simultaneously with other drugs that bind to proteins, for example, anticoagulants, sulfonamides, hydantoins, dose adjustment may be required to prevent increased levels of these drugs due to competition for binding to blood plasma proteins.
Potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists, nonsteroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus and trimethoprim may cause hyperkalemia.
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, 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.
It should be taken into account that the effectiveness of intrauterine contraceptives may be reduced when used simultaneously with ketoprofen. It is also possible to enhance the hypoglycemic effect of oral hypoglycemic drugs.
Ketoprofen may reduce glomerular filtration rate and increase serum concentrations of cardiac glycosides.
Aluminum compounds with a neutralizing effect do not reduce the absorption of ketoprofen.
Cases of acute hepatic failure have been observed in patients with renal impairment who have received concomitant treatment with tenofovir disoproxil and high doses or multiple NSAIDs. Appropriate monitoring of renal function should be performed when NSAIDs and tenofovir disoproxil are co-administered.
Application features
Special precautions.
Undesirable effects (especially from the digestive tract and cardiovascular system) can be avoided by taking the minimum effective dose for the shortest time necessary to relieve symptoms.
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).
The concomitant use of ketoprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.
The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID dose, in patients with a history of ulcer, especially if complicated by haemorrhage or perforation, in the elderly, in patients with low body weight, as well as in patients with impaired platelet function and in patients taking anticoagulants or platelet aggregation inhibitors. These patients should be started on the lowest dose. In such patients, combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be used.
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.
Gastrointestinal bleeding, ulceration or perforation, in some cases fatal, have been reported with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disease. If bleeding or ulceration occurs in patients receiving ketoprofen, therapy should be discontinued.
Epidemiological data suggest that ketoprofen may be associated with a high risk of severe gastrointestinal toxicity, as is the case with some other NSAIDs, particularly at high doses. Clinical trials and epidemiological data also suggest that the use of some NSAIDs (particularly at high doses and in long-term treatment) is associated with an increased risk of arterial thrombosis (e.g. myocardial infarction or stroke). There is insufficient evidence to exclude such a risk with ketoprofen.
In isolated cases, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with NSAIDs. The risk of such reactions is highest at the beginning of therapy (in most cases, such reactions occur in the first months of treatment). Ketoprofen should be discontinued at the first appearance of skin rashes, lesions of the mucous membranes or other signs of hypersensitivity.
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 an increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There are insufficient data to exclude such a risk for ketoprofen.
Precautions.
NSAIDs should be prescribed with caution to patients with gastrointestinal disorders such as gastritis and duodenitis, ulcerative colitis, Crohn's disease in history, as their condition may be exacerbated.
The drug should be used with caution in patients with 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.
At the beginning of treatment, renal function should be monitored in patients with heart failure, chronic renal failure, nephrosis, liver dysfunction, cirrhosis, disorders of water metabolism (e.g. dehydration due to diuretic use, hypovolemia after surgery), especially in elderly patients. In such patients, the appointment of ketoprofen may cause a decrease in renal blood flow due to inhibition of prostaglandin synthesis. In the initial period of treatment, the amount of diuresis and other indicators of renal function should be carefully monitored. Impaired renal function may cause edema and an increase in the concentration of non-protein nitrogen in serum.
In patients with heart failure, especially the elderly, increased manifestation of adverse reactions may be observed due to fluid and sodium retention in the body. In such patients, cardiac and renal function should be monitored.
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.
Masking of symptoms of underlying infections: Ketonal® Duo, like other NSAIDs with analgesic, anti-inflammatory and antipyretic properties, may mask the symptoms of an infectious disease, which may delay the initiation of appropriate treatment and thereby complicate the course of the disease. Such cases have been observed with bacterial community-acquired pneumonia and bacterial complications of chickenpox. When Ketonal® Duo is used to relieve pain in an infection, monitoring of the infectious disease is recommended. In outpatient settings, the patient should consult a doctor if symptoms persist or worsen.
Ketoprofen should be prescribed with particular caution to the elderly, especially those with impaired liver or kidney function; such patients should reduce the dose of the drug. During long-term treatment with ketoprofen, it is necessary to monitor blood morphology and liver and kidney function.
Isolated cases of jaundice and hepatitis have been reported in association with ketoprofen treatment.
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 impair female reproductive function and should not be used by women attempting to conceive. Ketoprofen should be discontinued in women who are unable to conceive or are undergoing infertility evaluation.
Patients with chronic bronchial asthma, rhinitis, sinusitis and/or nasal polyposis are at increased risk of developing allergies to acetylsalicylic acid and other NSAIDs. Ketoprofen may cause asthma attacks and bronchospasm, especially in individuals with hypersensitivity to acetylsalicylic acid and other NSAIDs.
Patients with uncontrolled arterial hypertension, chronic heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ketoprofen after careful monitoring. Patients with risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and smoking should also be carefully examined before starting long-term treatment.
Patients with hypersensitivity to sunlight or a history of phototoxic reactions should also be carefully monitored when using ketoprofen.
Treatment with ketoprofen should be discontinued if visual disturbances, such as blurred vision, occur.
The drug contains lactose, so it should not be prescribed to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
The drug should be discontinued before major surgical interventions.
Ketoprofen should be used with caution in people who abuse alcohol.
Elderly: Ketoprofen absorption is not altered, only the half-life of the drug is prolonged (3 hours) and renal and plasma clearance is reduced. Elderly patients have an increased incidence of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. After 4 weeks of treatment, monitoring for gastrointestinal bleeding should be performed.
Patients with renal insufficiency: renal and plasma clearance is reduced, and the half-life is prolonged in proportion to the severity of renal insufficiency.
Patients with hepatic insufficiency: plasma clearance and half-life are unchanged; the amount of drug not bound to proteins increases almost twofold.
Use during pregnancy or breastfeeding
Pregnancy.
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® Duo 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® Duo for several days, starting from the 20th week of gestation. Ketonal® Duo 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);
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 contraindicated 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, convulsions may occur), it is recommended to refrain from driving or operating other mechanisms.
Method of administration and doses
Doses should be selected individually, depending on the patient's condition and response to treatment.
The recommended dose is 150 mg (1 capsule) per day.
The duration of treatment depends on the severity and course of the disease, but side effects can be minimized by using the lowest effective dose for the shortest possible time. The lowest effective dose should be used for the shortest time necessary to relieve symptoms (see section "Special instructions").
When combined administration of different forms of the drug (capsules, tablets, suppositories, injection solution), the maximum daily dose of ketoprofen should not exceed 200 mg.
Take the capsules during meals, drinking water or milk (at least 100 ml).
To prevent the negative effects of ketoprofen on the mucous membranes of the gastrointestinal tract, you can simultaneously take antacids and proton pump inhibitors after consulting a doctor.
Elderly patients. Elderly patients are at increased risk of adverse reactions and, if NSAID therapy is prescribed, it is recommended to use the lowest effective dose of ketoprofen. After 4 weeks of treatment, monitoring for gastrointestinal bleeding is mandatory.
Children.
The drug should not be used in children.
Overdose
Symptoms: tinnitus, disorientation, agitation, suffocation, headache, dizziness, drowsiness, hypotension or hypertension, nausea, vomiting, diarrhea, abdominal pain, bloody vomiting, respiratory depression, convulsions, epigastric pain, black stools, impaired consciousness. In severe intoxication, gastrointestinal bleeding (melena, hematemesis), impaired renal function, renal failure; rarely, coma.
Treatment: gastric lavage and use of activated charcoal. Symptomatic and supportive therapy to compensate for dehydration, control diuresis and correct acidosis, if present. In case of renal failure, hemodialysis should be performed. H2-receptor antagonists, proton pump inhibitors, prostaglandins alleviate the dangerous effects of ketoprofen on the digestive tract. There is no specific antidote.
Side effects
The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 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: rare - hemorrhagic anemia; infrequent - hemolysis, purpura; frequency unknown - thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, hemolytic anemia, neutropenia.
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: respiratory system reactivity, including bronchial asthma and its exacerbation, bronchospasm or dyspnea (especially in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs); rare - angioedema and anaphylaxis, hypersensitivity, anaphylactic reactions, including shock.
On the part of the psyche: frequent - nervousness, terrible dreams; rare - delirium with visual and auditory hallucinations, disorientation; rare - mood swings, speech disorders.
Nervous system: common - headache, asthenia, dizziness, paresthesia, drowsiness, discomfort, weakness, increased fatigue, vertigo; uncommon - convulsions; rare - speech disorders, dysgeusia; rare - pseudotumor cerebri; frequency unknown - depression; confusion, hallucinations, malaise; there have been reports of aseptic meningitis (especially in patients with autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as occipital muscle rigidity, nausea, vomiting, fever, disorientation.
On the part of the organs of vision: frequent - visual impairment; rare - conjunctivitis; rare - blurred vision; frequency unknown - optic neuritis, retinal hemorrhages, changes in retinal pigmentation.
Cardiovascular system: frequent - edema; infrequent - heart failure, hypertension, vasodilation; frequency unknown - tachycardia, congestive heart failure, peripheral vascular disease, vasodilation, arrhythmia, myocardial infarction, atrial fibrillation, vasculitis.
The use of some NSAIDs (especially at high doses for long periods) may be associated with an increased risk of arterial thrombotic complications (e.g. myocardial infarction or stroke) (see section "Special warnings and precautions for use").
On the part of the respiratory system: infrequent - hemoptysis, shortness of breath, pharyngitis, rhinitis; rare - bronchospasm (mainly in patients with hypersensitivity to acetylsalicylic acid and other NSAIDs), bronchial asthma attacks, laryngeal edema (signs of anaphylactic reaction); frequency unknown - shortness of breath.
From the digestive tract: very common - dyspepsia; common - nausea, abdominal pain, diarrhea, constipation, flatulence, anorexia, vomiting, stomatitis; rare - gastritis, gastrointestinal ulcer; rare - colitis, intestinal perforation (as a complication of diverticula), exacerbation of ulcerative colitis or Crohn's disease, enteropathy with perforation, stenosis; frequency unknown - melena, hematemesis. Peptic ulcers, perforation or gastrointestinal bleeding may occur. There have been reports of a case of rectal perforation in an elderly woman. Enteropathy may be accompanied by minor bleeding with protein loss. 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.
Hepatobiliary system: rare - increased serum bilirubin and transaminase levels, severe liver dysfunction accompanied by jaundice and hepatitis; frequency unknown - hepatitis, cholestatic hepatitis, jaundice.
Skin: frequent - skin rashes; infrequent - alopecia, eczema, purpura-like rashes, itching, increased sweating, urticaria, exfoliative dermatitis; rare - photosensitivity, photodermatitis; rare - bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, exfoliative and bullous dermatosis, erythema multiforme, angioedema.
On the part of the urinary system: rare - abnormalities in renal function, acute renal failure, interstitial nephritis, nephrotic syndrome, acute pyelonephritis, abnormal renal function tests.
Reproductive system: infrequent - menometrorrhagia.
General disorders: rare - edema; frequency unknown - taste disturbance.
Laboratory indicators: very common - deviations from the norm of liver function tests, increased levels of transaminases, bilirubin in serum due to disorders associated with diabetes; uncommon - weight gain, during treatment with NSAIDs, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) significantly increase. Ketoprofen reduces platelet aggregation, thereby prolonging bleeding time.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 capsules in a blister; 2 (10 ´ 2) blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Lek Pharmaceutical Company Ltd., Slovenia (series release).
Location of the manufacturer and address of its place of business
Verovškova Street 57, Ljubljana 1526, Slovenia.
