Ksefokam lyophilisate for the preparation of a solution for intravenous and intramuscular injection 8mg No. 5

NameKsefokam lyof-t d / application solution for IV and IM injection 8mg per vial. in pack. No. 5 Main active ingredient Lornoxicam Release form Filizat Dosage 8 mg Pharmacological properties Pharmacodynamics Mechanism of action Lornoxicam belongs to the NSAIDs of the oxicam class with pronounced analgesic properties. Lornoxicam has a complex mechanism of action, which is based on the suppression of prostaglandin synthesis (inhibition of the activity of cyclooxygenase isoenzymes), which leads to desensitization of peripheral pain receptors and, accordingly, to inhibition of inflammation. It also suggests a central effect on pain perception independent of anti-inflammatory effects. Pharmacodynamic properties Lornoxicam does not affect the vital signs of the body (for example, body temperature, respiratory rate, heart rate, blood pressure, ECG, spirometry). Clinical efficacy and safety The analgesic effects of lornoxicam have been successfully demonstrated in several clinical trials during drug development. In treatment with lornoxicam, as with other NSAIDs, common side effects are gastrointestinal complications due to local irritation of the gastrointestinal tract and systemic ulcerogenic effects, which are mediated by inhibition of prostaglandin synthesis. Pharmacokinetics Absorption Ksefokam 8 mg powder for injection is intended for the preparation of a solution for intravenous and intramuscular administration. After intramuscular administration, peak plasma concentrations are reached after approximately 0.4 hours. Absolute bioavailability (calculated by AUC) after intramuscular injection is 97%. Distribution Lornoxicam is present in plasma unchanged, as well as in the form of a hydroxylated metabolite. The degree of binding of lornoxicam to plasma proteins is 99% and does not depend on concentration. Biotransformation Lornoxicam undergoes extensive hepatic metabolism, primarily through hydroxylation to the inactive metabolite 5-hydroxylornoxicam. The CYP2C9 isoenzyme is involved in the biotransformation of lornoxicam. Due to genetic polymorphism for this enzyme, there are slow and fast metabolizers, therefore, slow metabolizers can experience significantly increased plasma levels of lornoxicam. The hydroxylated metabolite does not show pharmacological activity. Lornoxicam is completely metabolized, with approximately 2/3 being excreted by the liver and approximately 1/3 by the kidneys in the form of an inactive substance. In animal studies, lornoxicam did not induce liver enzymes. In clinical studies, no accumulation of lornoxicam was observed after repeated use at recommended doses. This result is supported by drug monitoring data from one-year studies. Withdrawal The average half-life of the parent substance is 3-4 hours. After oral administration, approximately 50% is excreted in the feces and 42% by the kidneys, mainly in the form of 5-hydroxylornoxicam. The elimination half-life of 5-hydroxylornoxicam after a single or double daily parenteral dose is approximately 9 hours. In elderly patients over 65 years of age, clearance is reduced by 30-40%. Other than a reduction in clearance, there were no significant changes in the kinetic profile of lornoxicam in elderly patients. There are no significant changes in the kinetic profile of lornoxicam in patients with renal or hepatic insufficiency, except for cumulation in patients with chronic liver disease after 7 days of treatment with a daily dose of 12 mg and 16 mg. Indications for use Short-term therapy of acute pain syndrome of mild to moderate intensity. Route of administration and doses Dosage regimen This particular route of administration of the drug should be used only if rapid relief of pain is necessary or if oral or rectal administration is not possible. As a general rule, therapy should include only one injection just to start therapy. For all patients, the appropriate dosage regimen should be based on the individual’s response to treatment. Pain syndrome Recommended dose: 8 mg intravenously or intramuscularly. The maximum daily dose should not exceed 16 mg. Some patients may require additional administration of 8 mg during the first 24 hours. Features of use in special groups of patients Children and adolescents Lornoxicam is not recommended for use in children and adolescents under 18 years of age due to the lack of data on safety and efficacy. Elderly Patients For elderly patients over 65 years of age, no special dose adjustment is required, except in cases of existing impaired renal and hepatic function. Lornoxicam should be administered with caution, since this group of patients is more difficult to tolerate adverse reactions from the gastrointestinal tract (see section “Precautions”). Renal impairment In patients with mild to moderate renal impairment, dose reduction should be considered (see Precautions section). Hepatic impairment In patients with moderate hepatic impairment, dose reduction should be considered (see Precautions section). The risk of adverse effects can be minimized by using the lowest effective dose for the shortest possible course needed to control symptoms (see Precautions section). Method of application The solution is administered intravenously or intramuscularly. The duration of intravenous administration of the solution should be at least 15 seconds, intramuscular – at least 5 seconds. After preparing the solution, the needle is replaced. Intramuscular injections are made with a long enough needle for deep intramuscular injection. For further instructions on handling the drug before use, see the section “Precautions for Disposal and Other Instructions for Use”. The drug is intended for single use only. Use in Pregnancy and Lactation Pregnancy Lornoxicam is contraindicated in the third trimester of pregnancy and should not be used in the first and second trimesters of pregnancy and during childbirth, as there are no clinical data on treatment during pregnancy. Sufficient data on the use of lornoxicam in pregnant women are not available. Experimental animal studies have demonstrated the reproductive toxicity of the drug. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Data from epidemiological studies indicate an increased risk of miscarriage and cardiac malformations after the use of prostaglandin synthesis inhibitors in early pregnancy. The risk is expected to increase with increasing dose and duration of treatment. In animals, administration of a prostaglandin synthesis inhibitor resulted in increased pre- and post-implantation loss and increased embryofetal mortality. Prostaglandin synthesis inhibitors should not be used during the first and second trimesters of pregnancy unless clearly needed. During the third trimester of pregnancy, prostaglandin synthesis inhibitors can lead to fetal cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension) and cause renal impairment that may progress to renal failure with oligohydramnios. In late maternal and neonatal pregnancy, prostaglandin synthesis inhibitors may prolong bleeding time and suppress uterine contractions, which may delay or prolong labor. Therefore, the use of lornoxicam is contraindicated in the third trimester of pregnancy (see section “Contraindications”). Breast-feeding There are no data on the excretion of lornoxicam into the mother’s milk. In lactating rats, relatively high concentrations of lornoxicam pass into the mother’s milk. Therefore, lornoxicam should not be used in breastfeeding women. Precautions In the following cases, lornoxicam should be prescribed only after a careful assessment of the benefit-risk ratio: severe renal insufficiency: lornoxicam should be used with caution in patients with mild (serum creatinine 150-300 µmol/l) and moderate (serum creatinine 300-700 µmol/l) renal failure due to the dependence of the maintenance of renal blood flow on the level of renal prostaglandins. If renal function worsens during treatment, treatment with lornoxicam should be discontinued. Patients undergoing major surgery, with heart failure, during treatment with diuretics or concomitant treatment with drugs with known or suspected nephrotoxic effects: it is necessary to monitor renal function. Patients with coagulation disorders blood: careful clinical observation and laboratory monitoring (eg, APTT) is recommended. hepatic insufficiency (eg, with cirrhosis of the liver): in patients with impaired liver function, close clinical observation and laboratory monitoring should be considered, since after applying daily doses of 12-16 mg, accumulation of lornoxicam (increased AUC) may occur. In other cases, impaired liver function is unlikely to affect the pharmacokinetics of lornoxicam compared to healthy individuals. Long-term treatment (more than 3 months): regular laboratory tests of blood (hemoglobin), kidney function (creatinine) and liver enzymes are recommended. Elderly patients over 65 years: monitoring of kidney and liver function is recommended. It is recommended to use with caution in elderly patients after surgery. The simultaneous use of lornoxicam with NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided. Undesirable reactions can be minimized by using the minimum effective dose for the shortest period necessary to control symptoms (see section “Dosage and administration” and also below: gastrointestinal and cardiovascular risks). Gastrointestinal bleeding, ulceration, and perforation: Gastrointestinal bleeding, ulceration, or perforation, which can be fatal, has been reported with all NSAIDs. They have occurred with or without warning symptoms or a history of serious gastrointestinal complications at any time during therapy. The risk of gastrointestinal bleeding, ulcers or perforation is higher with increasing dose of NSAIDs, in patients with a history of ulcers, especially if it was complicated by bleeding or perforation (see section “Contraindications”), and in elderly patients. In these patients, treatment should be initiated at the lowest possible dose. For these patients and for patients who require concomitant treatment with low doses of acetylsalicylic acid or other medicinal products that may increase the risk of adverse reactions from the gastrointestinal tract, combination therapy with protective agents (eg, misoprostol or proton pump inhibitors) should be considered. Patients with a history of gastrointestinal toxicity, especially the elderly, should report all unusual abdominal symptoms (especially signs of gastrointestinal bleeding); especially at the beginning of treatment. Caution should be exercised in patients concomitantly taking drugs that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (such as warfarin), selective serotonin reuptake inhibitors or antiplatelet agents (such as acetylsalicylic acid) (see section “Interaction with other medicines”). If gastrointestinal bleeding or ulceration occurs in patients taking lornoxicam, treatment should be interrupted. NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as their use may exacerbate the disease (see section “Side Effects”). In elderly patients, there is an increased incidence of adverse reactions to NSAIDs, primarily gastrointestinal bleeding and perforation, which can be fatal (see section “Contraindications”). Adequate monitoring and instruction of patients with arterial hypertension and / or heart failure in history is necessary, since fluid retention and edema have been described in connection with NSAID therapy. Clinical studies and epidemiological data indicate that the use of some NSAIDs (particularly at high doses and as part of long-term treatment) may be associated with a small increase in the risk of arterial thrombotic complications (eg, myocardial infarction and stroke). There are insufficient data to rule out such a risk for lornoxicam. The use of lornoxicam in patients with uncontrolled hypertension, congestive heart failure, established coronary artery disease, peripheral arterial disease and/or cerebrovascular disease should be undertaken only after a careful assessment of the benefits and risks. Such an assessment should be made before initiating long-term treatment in patients with cardiovascular risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking). Simultaneous treatment with NSAIDs and heparin in connection with spinal or epidural anesthesia increases the risk of spinal / epidural hematomas (see section “Interaction with other drugs”). Severe, sometimes fatal skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), have very rarely been described in connection with the use of NSAIDs (see section “Side Effects”). The highest risk for such reactions exists at the beginning of therapy, in most cases in the first month of treatment. At the first occurrence of skin rash, mucosal lesions or other signs of increased individual sensitivity, lorinoxicam should be discontinued. Caution should be given to patients suffering from bronchial asthma or with a history of asthma, as it has been reported that NSAIDs can cause bronchospasm in such patients. Patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease may have an increased risk of aseptic meningitis. Lornoxicam reduces platelet aggregation and prolongs bleeding time; therefore, caution should be exercised when prescribing to patients with a tendency to bleed. The combined use of NSAIDs and tacrolimus may increase the risk of nephrotoxicity due to reduced synthesis of prostacyclin in the kidneys. In patients receiving such combination therapy, renal function should be carefully monitored. As with most NSAIDs, there have been reports of increases in serum transaminases, bilirubin, or other liver function tests, as well as increases in creatinine and blood urea nitrogen, and other laboratory changes. If these abnormalities become significant or persist, the use of lornoxicam should be discontinued and an appropriate evaluation should be carried out. The use of lornoxicam, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may adversely affect fertility and is therefore not recommended for use in women planning pregnancy. For women who have difficulty becoming pregnant or who are undergoing investigation for infertility, discontinuation of lornoxicam should be considered. In exceptional cases, the occurrence of chickenpox can lead to serious infectious complications of the skin and soft tissues. So far, it cannot be ruled out that NSAIDs may contribute to the worsening of these infections. Therefore, it is advisable to avoid the use of lornoxicam in varicella. Interactions with other drugs Concomitant use of lornoxicam with: cimetidine: leads to increased plasma concentrations of lornoxicam (no interactions between lornoxicam and ranitidine or between lornoxicam and antacids have been found). precautions”). Control of INR is indicated. Phenprocoumon: Decreased effectiveness of treatment with phenprocoumon. Heparin: NSAIDs, when used simultaneously with heparin in connection with spinal or epidural anesthesia, increase the risk of spinal or epidural hematomas (see the Precautions section). ACE inhibitors: the antihypertensive effect of ACE inhibitors may diuretics: decreased diuretic and antihypertensive action of loop, thiazide and potassium-sparing diuretics. angiotensin II receptor blockers: decreased antihypertensive effect; digoxin: decreased renal clearance of digoxin. corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section “Precautions “”). quinolone antibiotics: increased risk of seizures. antiplatelet agents: increased risk of gastrointestinal bleeding (see section “Precautions”). other NSAIDs: increased risk of gastrointestinal bleeding. methotrexate: higher the given level of methotrexate in serum. This can lead to increased toxicity. If concomitant therapy is necessary, attention should be paid to careful monitoring. Selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding (see Precautions section). Lithium: NSAIDs suppress renal clearance of lithium and thus may increase serum lithium concentrations blood beyond the limits of toxicity. Therefore, it is necessary to monitor the level of lithium in serum, especially at the time of initiation of treatment, when adjusting the dose or discontinuing treatment. cyclosporine: an increase in the concentration of cyclosporine in the blood serum. Renal toxicity of ciclosporin may be enhanced by effects that are mediated by renal prostaglandins. With joint therapy, it is necessary to monitor renal function. Sulfonylureas (for example, glibenclamide): increased risk of hypoglycemia. Known inducers and inhibitors of CYP2C9 isoenzymes: Lornoxicam (like other NSAIDs dependent on cytochrome P450 2C9 (CYP2C9 isoenzyme) interacts with known inducers and inhibitors CYP2C9 isoenzymes (see section “Biotransformation”). tacrolimus: increased risk of renal toxicity due to a decrease in the synthesis of prostacyclin in the kidneys. When used together, it is necessary to monitor renal function (see section “Precautions”). pemetrexedom: NSAIDs may reduce renal clearance of pemetrexed and thus increase renal and gastrointestinal toxicity and lead to myelosuppression. ma, rhinitis, angioedema or urticaria) to other non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid; severe heart failure; gastrointestinal bleeding, cerebral hemorrhage or other bleeding; history of gastrointestinal bleeding or perforation associated with prior NSAID therapy; history of acute peptic ulcer/bleeding or recurrent peptic ulcer/bleeding (2 or more overt episodes of confirmed ulceration or bleeding); severe liver failure; severe renal failure (serum creatinine >700 µmol/l); third trimester of pregnancy ( cm. section “Period of pregnancy and breastfeeding”) Composition One vial contains: lornoxicam 8 mg. Overdose There are currently no data on acute overdose with lornoxicam to describe the consequences of overdose or to recommend specific therapies. However, in case of an overdose of lornoxicam, the following symptoms should be expected: nausea and vomiting, cerebral symptoms (dizziness, blurred vision). Serious symptoms are ataxia up to coma and seizures, liver and kidney damage, and possibly coagulation disorders. In case of actual or suspected overdose, the drug should be discontinued. Lornoxicam is rapidly eliminated from the body due to its short half-life. Lornoxicam is not removed by dialysis. The specific antidote is still unknown. Gastrointestinal disorders, for example, can be treated with prostaglandin analogs or ranitidine. Side effects The most common adverse reactions of NSAIDs are reactions from the gastrointestinal tract. Possible development of peptic ulcers, perforation or gastrointestinal bleeding, in some cases, life-threatening, especially in elderly patients (see section “Precautions”). After the use of NSAIDs, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, vomiting of blood, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease were noted (see section “Precautions”). In more rare cases, gastritis developed. About 20% of patients taking lornoxicam may experience adverse reactions. When taking lornoxicam, the most common adverse reactions were nausea, dyspepsia, indigestion, abdominal pain, vomiting and diarrhea. In general, the available results of clinical studies indicate the development of these symptoms in less than 10% of patients. In the treatment of NSAIDs, cases of edema, arterial hypertension, and heart failure have been reported. Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and in long-term treatment) may increase the risk of arterial thrombosis (eg, myocardial infarction or stroke) (see section “Precautions”). Chicken pox can rarely cause severe infectious complications of the skin and soft tissues. The following are data on adverse reactions that were detected in more than 0.05% of 6417 patients after the use of the drug lornoxicam during phase II, III and IV clinical trials. Adverse reactions are classified depending on the frequency of occurrence: very often (? 1/10); often (?1/100, <1/10); infrequently (?1/1000, <1/100), rarely (?1/10000, <1/1000), very rarely (<1/10000), the frequency is unknown (cannot be estimated from the available data). Infectious and parasitic diseases: Rare: pharyngitis. Blood and lymphatic system disorders: Rare: anemia, thrombocytopenia, leukopenia, prolonged bleeding time. Very rare: extensive bleeding into the skin or mucous membranes (ecchymosis). Cases of severe disorders of the hematopoietic system, such as neutropenia, agranulocytosis, aplastic anemia and hemolytic anemia, caused by NSAIDs have been reported. Immune system disorders: Rare: hypersensitivity, anaphylactoid and anaphylactic reactions. Metabolic and nutritional disorders: Uncommon: anorexia, weight change. Mental disorders: Uncommon: insomnia, depression. Rare: confusion, irritability, agitation. Nervous system disorders: Often: mild and transient headache, dizziness. Rare: drowsiness, paresthesia, dysgeusia, tremor, migraine. Very rare: aseptic meningitis in patients with SLE and mixed connective tissue diseases (see Precautions section). On the part of the organ of vision: Infrequently: conjunctivitis. Rare: visual disturbances. On the part of the organ of hearing and labyrinth: Infrequently: dizziness, tinnitus. Cardiac disorders: Uncommon: palpitations, tachycardia, edema, heart failure. Vascular disorders: Uncommon: hyperemia, edema. Rare: arterial hypertension, hot flashes, bleeding, hematoma. Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis. Rarely: shortness of breath, cough, bronchospasm. Gastrointestinal disorders: Often: nausea, abdominal pain, dyspepsia, diarrhea, vomiting. Uncommon: constipation, flatulence, belching, dry mouth, gastritis, stomach ulcer, upper abdominal pain, duodenal ulcer, ulcerative stomatitis. Rare: melena, hematemesis, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, perforated peptic ulcer, gastrointestinal bleeding. Liver and biliary tract disorders: Uncommon: Increased liver function tests (ALT or ACT). Very rare: hepatotoxicity, which may manifest as liver failure; hepatitis, jaundice and cholestasis. Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus, hyperhidrosis, rash erythematous, urticaria and angioedema, alopecia. Rare: dermatitis, eczema, purpura. Very rare: edema and bullous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis. Muscular, skeletal and connective tissue disorders: Uncommon: arthralgia. Rare: bone pain, muscle spasm, myalgia. Renal and urinary tract disorders: Rare: nocturia, urination disorders, increased levels of urea nitrogen and creatinine in the blood. Very rare: Lornoxicam may cause acute renal failure in patients with a history of impaired renal function, since the maintenance of renal blood flow depends on the level of renal prostaglandins (see section "Precautions"). The development of nephrotoxicity in various forms (including nephritis and nephrotic syndrome) is associated with the use of NSAIDs (class-specific effect). General disorders and reactions at the injection site: Infrequently: malaise, swelling of the face. Rare: asthenia. Reporting suspected adverse reactions It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. If an adverse reaction occurs that is indicated in this package leaflet or not mentioned in it, patients are advised to contact their doctor. Medical professionals are encouraged to report any suspected adverse drug reactions to the Republican Unitary Enterprise "Center for Expertise and Testing in Health Care" (see section "Send information about adverse reactions to the address"). Storage conditions Store at a temperature not exceeding 25 ° C in a place protected from light. Keep out of the reach of children. See the storage conditions of the prepared solution in the section "Expiry date". application for Ksefokam lyophilisate for solution preparation for intravenous and intramuscular administration 8mg No. 5