Instructions for Xafina lyophilisate for solution for injection 8 mg vial No. 5
Composition
active ingredient: lornoxicam;
1 vial contains 8 mg of lornoxicam;
Excipients: mannitol (E 421), trometamol, disodium edetate, water for injections.
Dosage form
Lyophilisate for solution for injection.
Main physicochemical properties: lyophilized mass of yellow color.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Oxycodone. ATX code M01A C05.
Pharmacological properties
Pharmacodynamics.
Lornoxicam is a nonsteroidal anti-inflammatory drug with analgesic and anti-inflammatory properties, belonging to the oxicam class. The mechanism of action of lornoxicam is mainly associated with inhibition of prostaglandin synthesis (inhibition of the enzyme cyclooxygenase), which causes desensitization of peripheral nociceptors and inhibition of inflammation. A central effect on nociceptors, which is not associated with anti-inflammatory action, is also assumed. Lornoxicam does not affect vital signs (e.g. body temperature, respiratory rate, heart rate, blood pressure, ECG, spirometry).
The analgesic properties of lornoxicam have been successfully demonstrated in several clinical studies during the drug development process.
Due to local irritation of the gastrointestinal tract and systemic ulcerogenic effects associated with inhibition of prostaglandin (PG) synthesis, the use of lornoxicam, like other nonsteroidal anti-inflammatory drugs (NSAIDs), often leads to the development of gastrointestinal complications.
Pharmacokinetics.
Absorption. Lornoxicam in the form of a lyophilisate for injection of 8 mg is intended for intravenous and intramuscular administration. The maximum concentration in the blood plasma (Cmax) after intramuscular administration of the drug is achieved after approximately 0.4 hours. The absolute bioavailability [calculated by the area under the pharmacokinetic curve "concentration - time" (AUC)] after intramuscular administration of the drug is 97%.
Distribution: Lornoxicam is present in plasma in an unchanged form and in the inactive form of its hydroxylated metabolite. The binding of lornoxicam to plasma proteins is 99% and is independent of its concentration. It is also detected in synovial fluid after repeated administration.
Biotransformation. Lornoxicam is extensively metabolized in the liver by hydroxylation, primarily to the inactive 5-hydroxylornoxicam. Lornoxicam is metabolized by cytochrome CYP2C9. The metabolism of this enzyme due to genetic polymorphisms can be slow or intense in different individuals, which can lead to a marked increase in plasma levels of lornoxicam in individuals with slow metabolism. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized. Approximately 2/3 is excreted through the liver, and 1/3 by the kidneys as an inactive compound.
Lornoxicam did not induce hepatic enzymes in animal models. In clinical studies, no accumulation of lornoxicam was observed after multiple administration of the recommended doses. These results were confirmed by data from the 1-year safety and efficacy monitoring studies.
Elimination. The elimination half-life of the parent compound is 3–4 hours. After oral administration, approximately 50% is excreted in the feces and 42% in the urine, mainly as 5-hydroxylornoxicam. The elimination half-life of 5-hydroxylornoxicam is approximately 9 hours after parenteral administration of the drug once or twice daily. There is no evidence that the elimination rate changes with repeated doses.
In elderly patients (over 65 years of age), clearance is reduced by 30–40%. Apart from the reduction in clearance, there are no significant changes in the kinetic profile of lornoxicam in elderly patients.
There is no significant change in the kinetic profile of lornoxicam in patients with renal or hepatic insufficiency, with the exception of accumulation in patients with chronic liver disease after 7 days of therapy with daily doses of 12 mg and 16 mg.
Indication
For the short-term symptomatic treatment of acute mild to moderate pain in adults.
Contraindication
- Hypersensitivity to lornoxicam or to other components of the drug;
- thrombocytopenia;
- hypersensitivity (symptoms similar to those of asthma, rhinitis, angioedema or urticaria) to other NSAIDs, including acetylsalicylic acid;
- severe heart failure;
- gastrointestinal bleeding, cerebrovascular or other bleeding;
- history of gastrointestinal bleeding or perforation related to previous NSAID therapy;
- active recurrent gastric ulcer/bleeding or history of recurrent gastric ulcer/bleeding (two or more separate episodes of proven ulceration or bleeding);
- severe liver failure;
- severe renal failure (serum creatinine level > 700 μmol/l);
- III trimester of pregnancy (see section "Use during pregnancy or breastfeeding").
Special safety precautions
The solution for injection is prepared immediately before use [the contents of 1 vial (8 mg of lyophilisate) are dissolved in water for injection (2 ml)]. The appearance of the medicinal product after reconstitution is a clear yellow solution, practically free of particles.
If there are visible signs of deterioration of the medicinal product, it should be disposed of in accordance with current requirements.
Interaction with other medicinal products and other types of interactions
When used simultaneously with lornoxicam, the following interactions are possible:
- Cimetidine: increased plasma concentration of lornoxicam, which increases the risk of adverse effects of lornoxicam (no interaction between lornoxicam and ranitidine or lornoxicam and antacids has been identified).
- Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4). The international normalized ratio should be closely monitored.
- Phenprocoumon: the effectiveness of phenprocoumon treatment is reduced.
- Heparin: NSAIDs increase the risk of bleeding and spinal/epidural hematoma when used concomitantly with heparin during spinal or epidural anesthesia (see section "Special warnings and precautions for use").
- ACE inhibitors: the effect of ACE inhibitors may be reduced.
- Diuretics: weakening of the diuretic and hypotensive effect of loop, thiazide and potassium-sparing diuretics (increased risk of hyperkalemia and nephrotoxicity).
- Beta-adrenergic blockers: reduced hypotensive effect.
- Angiotensin II receptor blockers: reduction of the hypotensive effect.
- Digoxin: decreased renal clearance of digoxin, increasing the risk of digoxin toxicity.
- Corticosteroids: increased risk of gastrointestinal ulcers or bleeding (see section "Special warnings and precautions for use").
- Quinolone antibacterial agents (e.g. levofloxacin, ofloxacin): increased risk of seizures.
- Antiplatelet drugs (e.g. clopidogrel): increased risk of bleeding (see section "Special warnings and precautions for use").
- Other NSAIDs: increased risk of gastrointestinal bleeding or ulcers.
- Methotrexate: increased serum concentrations of methotrexate, leading to increased toxicity. Careful monitoring is required when used concomitantly.
- Selective serotonin reuptake inhibitors (SSRIs): increased risk of bleeding (see section "Special warnings and precautions for use").
- Lithium preparations: NSAIDs reduce the renal clearance of lithium, thus serum lithium concentrations may exceed the threshold for toxicity. Serum lithium levels should be monitored, especially at the beginning of treatment, during dose adjustments and during discontinuation of treatment.
- Cyclosporine: increased serum cyclosporine concentrations. Possible increased nephrotoxicity of cyclosporine due to effects mediated by renal prostaglandins. Renal function should be monitored during combination therapy.
- Sulfonylurea derivatives (e.g. glibenclamide): increased risk of hypoglycemia.
- Known inducers and inhibitors of CYP2C9 isoenzymes: lornoxicam [like other NSAIDs metabolized by cytochrome P450 2C9 (CYP2C9 isoenzyme)] interacts with known inducers and inhibitors of CYP2C9 isoenzymes (see section "Biotransformation").
- Tacrolimus: increased risk of nephrotoxicity due to decreased renal prostacyclin synthesis. Renal function should be monitored during combination therapy (see section 4.4).
- Pemetrexed: NSAIDs may reduce the renal clearance of pemetrexed, resulting in increased renal and gastrointestinal toxicity and myelosuppression.
Application features
Lornoxicam reduces platelet aggregation and prolongs bleeding time. Therefore, caution should be exercised when prescribing to patients with an increased tendency to bleed.
Lornoxicam should be prescribed only after careful assessment of the expected benefit of therapy and the possible risk to the following patients:
- Patients with renal impairment: Lornoxicam should be used with caution in patients with mild (serum creatinine level 150-300 μmol/l) and moderate renal insufficiency (serum creatinine level 300-700 μmol/l) due to the important role of prostaglandins in maintaining renal blood flow (see section "Method of administration and dosage"). In case of deterioration of renal function, treatment with Lornoxicam should be discontinued.
- Patients after major surgery, with heart failure, those taking diuretics or drugs that can cause kidney damage should have their renal function carefully monitored (see section "Interaction with other medicinal products and other types of interactions").
- Patients with hepatic insufficiency (e.g. cirrhosis) are recommended to have regular laboratory tests after using the drug at a dose of 12-16 mg per day due to the possibility of accumulation of lornoxicam in the body (increased AUC) (see section "Pharmacological properties. Pharmacokinetics"). However, no deviations in pharmacokinetic parameters were found in patients with hepatic insufficiency compared to healthy volunteers.
- Elderly people (over 65 years of age) are advised to monitor kidney and liver function. Use with caution after surgical interventions.
Concomitant use of NSAIDs.
The concomitant use of lornoxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Minimizing adverse reactions.
Adverse reactions can be minimized by taking the lowest effective dose of the drug for the shortest period necessary to control the symptoms of the disease (see section "Method of administration and dosage" and the information below on gastrointestinal and cardiovascular risks).
Gastrointestinal bleeding, ulcers and perforations.
Gastrointestinal bleeding, ulceration or perforation, which may be fatal, may occur with any NSAID at any time during treatment (with or without warning symptoms or a history of serious gastrointestinal disorders).
The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID dose in patients with a history of ulceration, especially complicated by bleeding or perforation (see section 4.3), and in the elderly. In these patient groups, treatment with the drug should be initiated with particular caution at the lowest therapeutic dose (see section 4.2).
NSAIDs should be used with caution in the above patient groups and in patients taking concomitant low-dose acetylsalicylic acid or other medicinal products that increase the risk of gastrointestinal complications (see section 4.5). For patients requiring such concomitant therapy, treatment may be carried out with concomitant protective agents (e.g. misoprostol or proton pump inhibitors). Regular clinical monitoring is recommended.
Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) during the initial stages of treatment.
Particular caution should be exercised when prescribing the drug to patients who are concomitantly taking medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants - warfarin, selective serotonin reuptake inhibitors or antithrombotic drugs - acetylsalicylic acid (see section "Interaction with other medicinal products and other types of interactions").
If gastrointestinal bleeding or ulceration occurs in patients taking lornoxicam, treatment should be discontinued.
NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as their condition may worsen.
Elderly patients.
Elderly patients are at increased risk of adverse reactions to NSAIDs, including gastrointestinal bleeding and perforation, which can be fatal (see Contraindications).
Cardiovascular and cerebrovascular effects.
Patients with a history of hypertension and/or mild to moderate congestive heart failure should be monitored, as NSAID therapy may be associated with phenomena such as fluid retention and edema.
There are clinical studies and epidemiological data that suggest that the use of some NSAIDs, especially long-term therapy and the use of high doses, increases the risk of arterial thrombotic events (such as myocardial infarction or stroke). There are insufficient data to exclude such a risk with lornoxicam.
Lornoxicam should only be prescribed to patients with uncontrolled hypertension, chronic heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disorders after careful evaluation of the indications. Evaluation is also required before prescribing long-term treatment to patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking).
Concomitant treatment with NSAIDs and heparin increases the risk of spinal/epidural hematoma during spinal or epidural anesthesia (see section "Interaction with other medicinal products and other types of interactions").
Very rarely, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, some of which have been fatal, have been reported with NSAIDs (see section 4.8). The risk of such reactions is highest at the beginning of treatment, with most occurring within the first month of treatment. Lornoxicam should be discontinued at the first appearance of skin rash, mucosal lesions or other signs of hypersensitivity.
Respiratory disorders.
Use with caution in patients with bronchial asthma, including a history of it, as NSAIDs may provoke bronchospasm in such patients.
Systemic lupus erythematosus and mixed connective tissue disease.
Use with caution in patients with systemic lupus erythematosus and mixed connective tissue disease, as the risk of developing aseptic meningitis is increased.
Nephrotoxicity.
Concomitant treatment with NSAIDs and tacrolimus increases the risk of nephrotoxicity due to decreased renal prostacyclin synthesis. Renal function should be closely monitored during such combination therapy (see section 4.5).
Laboratory abnormalities.
Like other NSAIDs, lornoxicam may cause occasional elevations in transaminases, serum bilirubin, blood urea and creatinine, and other laboratory abnormalities. If laboratory abnormalities are significant and persist for a long time, treatment should be discontinued and appropriate investigation should be performed.
Fertility.
Lornoxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is therefore not recommended in women attempting to conceive. Lornoxicam should be discontinued in women who have difficulty conceiving or who are undergoing investigation of infertility (see section 4.6).
Varicella.
In the presence of chickenpox, severe skin and soft tissue infections may develop in exceptional cases. At this time, the effect of NSAIDs on the worsening of these infectious diseases cannot be excluded. It is recommended to avoid the use of lornoxicam in the presence of chickenpox.
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy. Lornoxicam is contraindicated in the third trimester of pregnancy (see section "Contraindications"). There are no clinical data on the use of lornoxicam in the first and second trimesters of pregnancy and during labor, therefore the drug is not recommended for use during this period.
There are no adequate data from the use of lornoxicam in pregnant women. Animal studies have shown reproductive toxicity.
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryo/fetal development. Epidemiological studies have shown an increased risk of miscarriage and heart defects when prostaglandin synthesis inhibitors are used in early pregnancy. The risk increases with increasing dose and duration of therapy. In animals, the use of prostaglandin synthesis inhibitors has been shown to increase the incidence of pre- and post-implantation fetal death and embryo-fetal lethality. Prostaglandin synthesis inhibitors should not be used in the first and second trimesters of pregnancy. They should only be used if clearly necessary.
During the third trimester of pregnancy, the use of any prostaglandin synthesis inhibitors may have the following effects on the fetus:
- cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
- impaired renal function, which may progress to renal failure with the development of oligohydramnios.
The pregnant woman and fetus at the end of pregnancy may be exposed to the following effects of the use of prostaglandin synthesis inhibitors:
- increased bleeding duration;
- suppression of uterine contractile function, which may lead to a delay or increase in the duration of labor.
Therefore, the use of lornoxicam is contraindicated in the third trimester of pregnancy (see section "Contraindications").
Breastfeeding. There are no data on the excretion of lornoxicam in human milk. Relatively high concentrations of lornoxicam are excreted in the milk of rats. Lornoxicam should not be used during breastfeeding.
Fertility: The use of lornoxicam, as with any medicinal product that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. If a woman has difficulty conceiving or is undergoing investigation of infertility, discontinuation of lornoxicam should be considered.
Ability to influence reaction speed when driving vehicles or other mechanisms
If you experience dizziness and/or drowsiness as a result of taking lornoxicam, you should not drive or operate other machinery.
Method of administration and doses
This formulation of lornoxicam is intended for initiation of therapy when rapid analgesic effect is required or when oral administration is not possible. In general, treatment should consist of only one injection to initiate therapy. For all patients, the appropriate dosage regimen should be based on the individual response to treatment. Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
This dosage form is intended for intravenous and intramuscular administration.
The recommended dose is 8 mg intravenously or intramuscularly. The daily dose should not exceed 16 mg. Some patients require an additional 8 mg dose in the first 24 hours.
The duration of intravenous administration of the solution should be at least 15 seconds, intramuscular administration - at least 5 seconds.
After preparing the solution, the needle should be replaced.
Intramuscular injection requires a long needle to ensure deep insertion.
The diluted medicinal product is intended for single use only.
The solution for injection should be prepared immediately before use. The contents of 1 vial (8 mg of lyophilisate) should be dissolved in water for injections (2 ml). After preparation, a clear yellow solution should be obtained. If the medicinal product shows signs of deterioration, it should be disposed of in accordance with local requirements.
Elderly patients (over 65 years of age) without impaired liver or kidney function do not require dose adjustment, but lornoxicam should be used with caution, since gastrointestinal adverse reactions are less well tolerated by this category of patients.
Renal impairment: Patients with mild to moderate renal impairment require a reduced dose. Lornoxicam is contraindicated in patients with severe renal impairment (see Contraindications).
Hepatic impairment: Patients with moderate hepatic impairment require a reduced dose. Lornoxicam is contraindicated in patients with severe hepatic impairment (see Contraindications).
Children.
It is not recommended for use in children under 18 years of age due to insufficient clinical data on the efficacy and safety of the drug.
Overdose
There are currently no data on overdose that would allow us to determine its consequences or to suggest specific treatment. However, it is expected that the following symptoms may occur as a result of an overdose of lornoxicam: nausea, vomiting, cerebral symptoms (dizziness, visual disturbances). In severe cases, ataxia (with the development of coma and convulsions), liver and kidney damage, and blood clotting disorders are possible.
In case of actual or suspected overdose, the drug should be discontinued. Due to its short half-life, lornoxicam is rapidly eliminated from the body. It is not dialyzable. There is currently no specific antidote. For the treatment of gastrointestinal disorders, a prostaglandin analogue or ranitidine can be used.
Adverse reactions
The most common adverse reactions to NSAIDs have been related to the gastrointestinal tract. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, especially in the elderly, may occur with NSAIDs (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported with NSAIDs. Gastritis has been observed less frequently.
Approximately 20% of patients treated with lornoxicam experienced adverse events. The most common adverse events were nausea, dyspepsia, indigestion, abdominal pain, vomiting, and diarrhea. These symptoms were generally observed in less than 10% of patients in the study.
Edema, hypertension, and heart failure have been reported with NSAID treatment.
Clinical trials and epidemiological data show that the use of some NSAIDs, especially at high doses and with prolonged use, increases the risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special warnings and precautions for use").
Exceptionally, serious infectious complications of the skin and soft tissues have been reported during the course of chickenpox.
Adverse reactions are classified according to the following frequency: very common (> 1/10); common (> 1/100, 1/10); uncommon (> 1/1000, 1/100); rare (> 1/10000, 1/1000); very rare (1/10000), unknown (frequency cannot be estimated from the available data).
Infections and infestations: Rare: pharyngitis.
Blood and lymphatic system disorders Rare: Anaemia, thrombocytopenia, leukopenia, prolonged bleeding time Very rare: ecchymosis NSAIDs can cause potentially severe haematological disorders specific to this class of medicinal products, such as neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.
Immune system disorders: Rare: hypersensitivity, including anaphylactoid reactions and anaphylaxis.
Metabolic and nutritional disorders: Uncommon: loss of appetite, weight changes.
Nervous system disorders: Common: mild and transient headache, dizziness. Rare: drowsiness, paresthesia, dysgeusia, tremor, migraine. Very rare: aseptic meningitis in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (see section 4.4).
On the part of the organs of vision. Common: conjunctivitis. Rare: visual impairment.
Hearing and balance disorders: Uncommon: vertigo, tinnitus.
Cardiovascular system: Uncommon: palpitations, tachycardia, edema, heart failure, facial flushing (see section "Special warnings and precautions for use"). Rare: hypertension, hot flashes, hemorrhages, hematomas.
Respiratory system: Uncommon: rhinitis. Rare: dyspnoea, cough, bronchospasm.
From the digestive system: often: nausea, abdominal pain, dyspepsia, diarrhea, vomiting.
Uncommon: constipation, flatulence, eructation, dry mouth, gastritis, gastric ulcer, abdominal pain upper, duodenal ulcer, oral mucosal ulcer. Rare: melena, haematemesis, stomatitis, oesophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, peptic ulcer perforation, gastrointestinal bleeding.
Hepatobiliary disorders: Uncommon: increased liver enzymes (alanine aminotransferase, aspartate aminotransferase). Very rare: toxic effects on the liver, which may lead to liver failure, hepatitis, jaundice, cholestasis.
Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus, increased sweating, erythematous rash, urticaria, angioedema, alopecia. Rare: dermatitis, eczema, purpura. Very rare: edema and bullous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Uncommon: arthralgia. Rare: bone pain, muscle spasms, myalgia.
Renal and urinary disorders: Rare: nocturia, urinary disorders, increased blood urea nitrogen and creatinine. Very rare: lornoxicam may cause acute renal failure in patients with renal disease, where renal prostaglandins play an important role in maintaining renal blood flow (see section "Special warnings and precautions for use"). Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, is an effect specific to NSAIDs.
General disorders: Uncommon: malaise, facial oedema. Rare: asthenia.
Expiration date
2 years.
Reconstituted solution: Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 2–8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
Incompatibility
This medicinal product should not be mixed with other medicinal products except those mentioned in the “Method of administration and dosage” section of this leaflet.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
1 or 5 bottles of dark glass of class I, sealed with a rubber stopper under an aluminum cap, complete with instructions for medical use of the medicinal product in a cardboard box.
Vacation category
According to the recipe.
Producer
Swiss Parenterals Ltd.
Location of the manufacturer and address of its place of business
808, 809 & 810, Kerala Industrial Estate, G.I.D.C., Hp. Bavla, Dist. Ahmedabad – 382220, India.
