Ketonal solution for injections 100mg/2ml in ampoules 2ml №10

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Transparent solution from colorless to slightly yellowish color, practically without visible inclusions. The main active ingredient Release formAmpoule 2 ml of dark glass. 10 ampoules with leaflet in a cardboard box. DosageSpecial instructions Do not mix tramadol and ketoprofen in the same infusion fluid due to the formation of sediment. Infusion bottles should be wrapped in black paper or aluminum foil as ketoprofen is light sensitive. Pharmacological action Pharmacodynamics Mechanism of action Ketoprofen inhibits the synthesis of prostaglandins and leukotrienes by blocking the cyclooxygenase enzyme (at least two isoenzymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)), which catalyzes the synthesis of prostaglandins in the metabolism of arachidonic acid. Ketoprofen stabilizes lysosomal membranes in vitro and in vivo, inhibits the synthesis of leukotrienes in vitro at high concentrations and has anti-bradykinin activity. The mechanism of antipyretic action of ketoprofen is unknown. Perhaps ketoprofen inhibits the synthesis of prostaglandins in the central nervous system (most likely in the hypothalamus). In some women, ketoprofen reduces the symptoms of primary dysmenorrhea, probably by suppressing the synthesis and / or effectiveness of prostaglandins. Pharmacokinetics Absorption Mean plasma levels measured 5 minutes after the start of intravenous infusion of 100 mg of ketoprofen and 4 minutes after the end of administration are 26.4 ± 5.4 μg / ml. Bioavailability – 90%. In most patients with intramuscular injection, ketoprofen was detected in the blood after 15 minutes, and the peak plasma concentration was reached 2 hours after administration. The bioavailability of ketoprofen when injected increases linearly with increasing dose of the drug. Distribution Ketoprofen is 99% bound to plasma proteins, predominantly to albumin. The volume of distribution in tissues is 0.1-0.2 l / kg. Ketoprofen penetrates into the synovial fluid. Three hours after the appointment of 100 mg of ketoprofen, its plasma concentration is about 3 μg / ml, and the concentration in the synovial fluid is 1.5 μg / ml. After nine hours, its plasma concentration is about 0.3 μg / ml, and the concentration in the synovial fluid is 0.8 μg / ml. This means that ketoprofen slowly penetrates into the synovial fluid and is also slowly excreted from it, against the background of a continuing decrease in plasma concentration. Equilibrium concentrations of ketoprofen are established 24 hours after its administration. In elderly patients, the equilibrium concentration was reached after 8.7 hours and was 6.3 μg / ml. Already 15 minutes after a single intramuscular injection, ketoprofen was found in the synovial fluid, and its peak concentration was reached after 2 hours (1.3 μg / ml). Metabolism Ketoprofen is extensively metabolized by hepatic microsomal enzymes. It binds to glucuronic acid and is excreted from the body in this form. After oral administration, its plasma clearance is 1.16 ml / min / kg. Due to its rapid metabolism, its biological half-life is only two hours. Since ketoprofen is metabolized primarily in the liver, liver failure may cause a prolongation of the half-life, in these circumstances it is necessary to take into account the possible cumulation. Withdrawal Up to 80% of ketoprofen is excreted in the urine, mainly (over 90%) as ketoprofen glucuronide, and about 10% is excreted in the feces. In patients with renal insufficiency, ketoprofen is excreted more slowly, and its biological half-life is increased by an hour. Pharmacokinetics in special groups of patients In patients with hepatic insufficiency, ketoprofen may accumulate in tissues. Its metabolism and elimination is slowed down in the elderly. This is clinically significant only in patients with reduced renal function. Incompatibility Do not mix tramadol and ketoprofen in the same vial due to the formation of sediment. Infusion bottles should be wrapped in black paper or aluminum foil as ketoprofen is light sensitive. Indications for use Symptomatic treatment of acute painful episodes occurring in the course of inflammatory diseases of the musculoskeletal system. Dosage and administration For parenteral use. Recommended dose The maximum daily dose is 200 mg. It is recommended not to prescribe injections for longer than 3 days. Upon reaching a satisfactory response, Ketonal is prescribed in the form for oral administration. Intramuscular administration Intramuscularly administered one ampoule (100 mg) once or twice a day. The drug can, if necessary, be combined with ketoprofen in the form for oral administration, rectal or transdermal administration. Intravenous administration Ketoprofen infusion should be carried out only in a hospital setting. The infusion lasts for 0.5-1 hour. Infusion can be carried out no more than two days in a row. Short-term intravenous infusion From 100 to 200 mg of ketoprofen, diluted in 100 ml of 0.9% sodium chloride solution, is administered over 0.5-1 hour. Continuous intravenous infusion Ketoprofen 100 to 200 mg diluted in 500 ml infusion solution (0.9% sodium chloride solution, Ringer’s lactate, glucose) is administered over 8 hours. Ketoprofen can be combined with centrally acting analgesics. It can be mixed in one vial with morphine: 10-20 mg of morphine and 100 (up to 200) mg of ketoprofen are diluted in 500 ml of 0.9% sodium chloride solution for injection or Ringer’s lactate. Undesirable effects can be minimized if the drug is taken at the lowest effective dose for the shortest possible time necessary to relieve symptoms. The maximum daily dose of ketoprofen (regardless of dosage form) is 200 mg. Before starting treatment at a dose of 200 mg of ketoprofen per day, the benefits and possible risks should be carefully weighed. The use of higher doses is not recommended. Elderly patients In the elderly, adverse reactions are more likely to have severe consequences. Treatment of the elderly is recommended to start with the lowest effective dose available. Patients with impaired renal function In patients with mild impaired renal function (creatinine clearance below 0.33 ml / s (20 ml / min)) the dose of ketoprofen is reduced. Ketoprofen is contraindicated in patients with severe renal impairment. Patients with impaired liver function In patients with chronic liver disease with reduced serum albumin, the dose of ketoprofen should be reduced. Ketoprofen is contraindicated in patients with severe hepatic impairment. Children The safety and efficacy of ketoprofen in children has not been studied. Use during pregnancy and lactation Pregnancy Inhibition of prostaglandin synthesis may have a negative effect on pregnancy and / or development of the embryo / fetus. According to epidemiological data, the use of prostaglandin synthesis inhibitors in early pregnancy is associated with an increased risk of miscarriage, the development of heart defects and gastroschisis. The absolute risk of developing congenital malformations of the cardiovascular system increased from less than 1% to about 1.5%. It is believed that the risk increases with increasing dose and duration of treatment. The administration of a prostaglandin synthesis inhibitor in animals led to an increase in the number of miscarriages before and after implantation and to an increase in embryo-fetal mortality. In addition, an increased frequency of various congenital anomalies, including cardiovascular, has been described in the administration of a prostaglandin synthesis inhibitor to animals during the period of organogenesis. In the first and second trimesters of pregnancy, ketoprofen should not be prescribed unless absolutely necessary. If ketoprofen is used by a woman who is trying to conceive or is in the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. In the third trimester of pregnancy, all inhibitors of prostaglandin synthesis can have the following effects on the fetus: – cardiopulmonary toxicity (with premature closure of the Botalla duct and the development of pulmonary hypertension); – impaired renal function, up to the development of renal failure with oligohydroamnios; At the end of pregnancy, prostaglandin synthesis inhibitors can affect the mother and newborn as follows: – the likelihood of prolonged bleeding time – an antiplatelet effect that can be observed even at very low doses of the drug; – inhibition of the contractile activity of the uterus, leading to a delay in the onset of labor and their lengthening. Therefore, the use of ketoprofen in the third trimester of pregnancy is contraindicated. Breast-feeding Data on the penetration of the drug into milk in humans are not available. It is not recommended to prescribe ketoprofen to nursing mothers. Precautions Avoid concomitant use of the drug with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Undesirable effects can be minimized if the drug is taken at the lowest effective dose for the shortest possible time necessary to relieve symptoms. The elderly are more likely to experience adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal. Patients should be warned that this drug may cause drowsiness, dizziness or convulsions and advised not to drive or operate machines when these symptoms occur. Patients should be warned about the possible occurrence of visual impairment. In this case, you should not drive vehicles or work with mechanisms. Gastrointestinal bleeding, ulceration, and perforation Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, is described for all NSAIDs and may occur at any time during treatment, with or without prior symptoms or severe gastrointestinal disease. tract in history. According to epidemiological data, the use of ketoprofen may be associated with a high risk of severe gastrointestinal toxicity, which is characteristic of some other NSAIDs, especially when taking high doses. The risk of gastrointestinal bleeding, ulcers or perforation increases with increasing doses of NSAIDs, in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in the elderly. Treatment of these patients should be initiated at the lowest available dose. For these patients, as well as for patients taking low doses of acetylsalicylic acid together or other drugs that increase the risk of gastrointestinal complications, combination therapy with protective drugs (eg, misoprostol or proton pump blockers) should be considered. Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially at the start of treatment. Particular caution should be observed when co-administered with drugs that can increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (eg, warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid. If patients develop gastrointestinal bleeding or ulcers during treatment with Ketonal, treatment with the drug should be discontinued. NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as they may experience exacerbations of these diseases. Risk of gastrointestinal bleeding: The relative risk increases in patients with low body weight. If gastrointestinal bleeding or ulcers occur, treatment should be stopped immediately. Cardiovascular and cerebrovascular effects Patients with a history of arterial hypertension and / or congestive heart failure of mild to moderate severity require appropriate monitoring and consultation, since fluid retention and edema have been reported with the use of NSAIDs. Clinical studies and epidemiological data suggest that the use of some non-selective NSAIDs (especially at high doses and in long-term treatment) may be associated with a slight increase in the risk of arterial thrombosis (eg, myocardial infarction or stroke). There are insufficient data to rule out such a risk for ketoprofen. Patients suffering from bronchial asthma in combination with chronic rhinitis, chronic sinusitis and/or nasal polyposis are more likely to experience allergic reactions after taking acetylsalicylic acid and/or non-steroidal anti-inflammatory drugs than other patients. The appointment of the drug can cause an attack of bronchial asthma or bronchospasm, especially in patients with allergies to acetylsalicylic acid or NSAIDs. In patients with heart failure, cirrhosis and nephrotic syndrome, as well as in patients taking diuretics, and in patients with chronic renal failure, especially the elderly, renal function should be carefully monitored at the beginning of treatment. In such patients, the appointment of ketoprofen can cause a decrease in renal blood flow due to inhibition of prostaglandin synthesis and lead to decompensation of renal function. In patients with abnormal liver function tests or a history of liver disease, blood transaminase levels should be monitored periodically, especially during prolonged therapy. Treatment should be discontinued if visual disturbances occur, such as blurred vision. With caution appoint persons suffering from alcohol dependence. Severe skin reactions (some of them fatal) associated with the use of NSAIDs, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, are extremely rarely described. The greatest risk of developing these reactions is at the beginning of the course of treatment; in most cases, reactions occur in the first month of treatment. Ketonal should be discontinued at the first appearance of a skin rash, mucosal lesions, or other signs of hypersensitivity. With prolonged treatment, it is necessary to control the number of blood cells, as well as the function of the liver and kidneys. Like all non-steroidal anti-inflammatory drugs, ketoprofen, due to its anti-inflammatory, analgesic or antipyretic effect, can mask signs of the development of infectious diseases, such as fever. Before extensive surgical interventions, the drug must be canceled. Hyperkalemia on the background of diabetes mellitus or concomitant therapy with potassium-sparing drugs. Under these circumstances, potassium levels need to be checked regularly. For severe pain, ketoprofen can be used in combination with morphine derivatives. In women, non-selective NSAIDs can reduce fertility. Therefore, they are not recommended for women trying to get pregnant. In women who have difficulty becoming pregnant or who are being investigated for infertility, discontinuation of ketoprofen should be considered. Information on excipients Ketonal, solution for injection The drug contains 12.3% (by volume) ethanol (96%). Each 2 ml of solution contains 200 mg of ethanol, which is equivalent to 5 ml of beer or 2 ml of wine per dose. Harmful to people with alcohol dependence. The content of ethanol (alcohol) should be considered when used in pregnant and breastfeeding women, children and patients at risk, for example, with liver disease or suffering from epilepsy. The drug contains benzyl alcohol (E1519) (40 mg / ampoule), so it should not be prescribed to premature and newborn babies. In children under 3 years of age, it can cause toxic and anaphylactoid reactions. The drug contains sodium in an amount of less than 1 mmol/ampoule (23 mg) and is therefore considered to be sodium-free. Therapy with an injectable form of Ketonal should be carried out under close medical supervision. After the acute pain episode has been eliminated, it is advisable to switch to other forms of ketoprofen, which are less likely to cause serious reactions. Intramuscular administration of Ketonal for long periods is recommended in a hospital and under medical supervision. Interaction with other drugs Not recommended combinations of drugs Other NSAIDs (including selective cyclooxygenase-2 inhibitors) and high doses of salicylates: increased risk of ulcers and bleeding in the gastrointestinal tract. Anticoagulants (heparin and warfarin) and inhibitors of platelet aggregation (eg ticlopidine, clopidogrel): increased risk of bleeding. If necessary, joint use requires close medical supervision. Lithium: Risk of increased plasma lithium levels, which can sometimes reach toxic levels due to decreased renal excretion of lithium. If necessary, the concentration of lithium in plasma should be carefully monitored and the dose of lithium should be adjusted during and after treatment with NSAIDs. Methotrexate at doses greater than 15 mg/week Increased risk of hematotoxicity of methotrexate, especially if used at high doses (>15 mg/week), probably due to displacement of methotrexate from protein binding and reduced renal clearance. Between the end or start of treatment with ketoprofen and treatment with methotrexate, at least 12 hours should elapse. Combinations requiring caution Diuretics Patients taking diuretics, especially those with dehydration, have an increased risk of renal failure due to a decrease in renal blood flow due to inhibition of prostaglandin synthesis. Such patients should be adequately hydrated prior to co-administration of such drugs, and renal function should be monitored at the start of treatment. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists In patients with impaired renal function (eg, patients with dehydration or the elderly), the concomitant use of an ACE inhibitor or angiotensin II receptor antagonist and drugs that inhibit cyclooxygenase may cause additional deterioration renal function, including possible acute renal failure. Methotrexate at doses below 15 mg / week In the first weeks of combined treatment, it is necessary to monitor the detailed blood picture once a week. In case of any impairment of renal function and in elderly patients, monitoring should be carried out more often. Corticosteroids: increased risk of ulcers or bleeding in the gastrointestinal tract. Pentoxifylline Increases the risk of bleeding. More frequent clinical monitoring and more frequent control of bleeding time are needed. Combinations to consider Antihypertensive drugs (beta-blockers, ACE inhibitors, diuretics) Ketoprofen reduces the effect of antihypertensive drugs (inhibition of vasodilatory prostaglandins). Thrombolytics: increased risk of bleeding. Selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding. Probenecid: Co-administration of probenecid may significantly reduce the plasma clearance of ketoprofen. Combinations that should also be noted Cyclosporine, tacrolimus: risk of additive nephrotoxicity, especially in elderly patients. Risk associated with hyperkalemia A number of drugs and entire therapeutic classes of drugs can contribute to the development of hyperkalemia, for example, potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus and trimethoprim. The development of hyperkalemia may depend on the presence of additional factors. The risk is increased when the above drugs are used concomitantly. Risk associated with antiplatelet activity Interactions may occur with the simultaneous use of certain drugs that prevent platelet aggregation: tirofiban, eptifibaride, abciximab and iloprost. The simultaneous use of several antiplatelet agents increases the risk of bleeding. Contraindications Hypersensitivity to ketoprofen or any of the excipients of the drug. The drug is also contraindicated in the following cases: a history of bronchial asthma, urticaria, rhinitis, bronchospasm or allergic-type reactions after the use of ketoprofen or similar active substances, such as other nonsteroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) or salicylates (eg, acetylsalicylic acid); severe heart failure; treatment of pain in the perioperative period during coronary artery bypass grafting (CABG); peptic ulcer in the active phase, as well as gastrointestinal bleeding, ulcer or perforation in history; gastrointestinal, cerebrovascular or other active bleeding; chronic dyspepsia in history; severe impairment of kidney function; severe liver dysfunction; predisposition to bleeding; last trimester of pregnancy; children; bleeding disorder or current anticoagulant treatment. Composition Each 2 ml solution for injection (1 ampoule) contains 100 mg of ketoprofen. Excipients: propylene glycol, ethanol (12.3 vol%), benzyl alcohol, sodium hydroxide (for pH correction), water for injection. Overdose In adults, the main symptoms of overdose are headache, dizziness, drowsiness, nausea, vomiting, diarrhea and abdominal pain. In severe intoxication, hypotension, respiratory depression and gastrointestinal bleeding are observed. The patient is immediately hospitalized and treated symptomatically. The specific antidote is unknown. Side effects If severe side effects occur, treatment should be discontinued. Adverse effects are distributed according to the classes of organ systems and according to the frequency of occurrence. The frequency of adverse effects is classified as follows: very common (≥ 1/10), frequent (≥ 1/100, <1/10), infrequent (≥ 1/1000, <1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10 000), frequency not established (cannot be established from the available data). When using ketoprofen, the following undesirable effects were reported. Blood and lymphatic system disorders - Rare: posthemorrhagic anemia; - Frequency not established: agranulocytosis, thrombocytopenia, rare cases of leukopenia. Immune system disorders - Frequency not established: anaphylactic reactions (including shock). Psychiatric disorders - Frequency not established: Mood variability. Nervous system disorders - Uncommon: headache, dizziness, drowsiness; - Frequency not established: convulsions. Violations of the organ of vision - Rare: blurred vision. Hearing and labyrinth disorders - Rare: ringing in the ears (tinnitus). Cardiac disorders - Frequency not established: heart failure. Vascular disorders - Frequency not established: arterial hypertension. Respiratory, thoracic and mediastinal disorders - Rare: bronchial asthma; - Frequency not established: bronchospasm (especially in patients with established hypersensitivity to acetylsalicylic acid and other NSAIDs), rhinitis. Gastrointestinal disorders - Frequent: nausea, vomiting; - Infrequent: constipation, diarrhea, gastritis; - Rare: stomatitis, peptic ulcer; - Frequency not established: gastrointestinal bleeding and perforation, gastrointestinal discomfort, stomach pain and rare examples of colitis, tarry stools and hematemesis. The most common adverse reactions include reactions from the gastrointestinal tract. Possible development of peptic ulcers, perforations and bleeding in the gastrointestinal tract, which sometimes, especially in elderly patients, can be fatal. Hepatic and biliary tract disorders - Rare: hepatitis, elevated transaminase levels, elevated serum bilirubin due to hepatitis. Skin and subcutaneous tissue disorders - Uncommon: rash, itching. - Frequency not established: photosensitivity reaction, alopecia, urticaria, angioedema, bullous skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, exacerbation of chronic urticaria. Renal and urinary tract disorders - Frequency not established: acute renal failure, tubulointerstitial nephritis, nephritic syndrome, water / sodium retention with possible development of edema, hyperkalemia, organic kidney damage that can cause acute renal failure: there have been reports of isolated cases of acute tubular necrosis and papillary necrosis. General disorders and disorders at the injection site - Infrequent: edema. - Frequency not established: reported cases of pain and burning at the injection site. Clinical studies and epidemiological data suggest that the use of some non-selective NSAIDs (especially at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombosis (eg, myocardial infarction or stroke). Edema, high blood pressure and heart failure have been reported in association with treatment with non-selective NSAIDs. Storage conditions Keep out of the reach of children. Store at a temperature not exceeding 25°C. 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