Lornoxicam

Pharmacological properties

lornoxicam - NSAIDs with painkillers and anti-inflammatory properties - belongs to the class of oxycams. the mechanism of action of lornoxicam is mainly associated with inhibition of prostaglandin synthesis (inhibition of cog enzyme), which leads to desensitization of peripheral nociceptors and inhibition of inflammation. a central effect on nociceptors that is not associated with an anti-inflammatory effect is also suggested. lornoxicam does not affect vital signs (e.g. body temperature, respiratory rate, heart rate, hell, ecg, spirometry). the analgesic properties of lornoxicam have been successfully demonstrated in several clinical studies during the development of the drug.

Due to local gastrointestinal irritation and systemic ulcerogenic activity associated with inhibition of prostaglandin synthesis (PG), the use of lornoxicam and other NSAIDs often leads to the development of gastrointestinal complications.

Pharmacokinetics Absorption. Lornoxicam is rapidly and almost completely absorbed from the digestive tract. C_max achieved 1-2 hours after taking the drug. The bioavailability of lornoxicam is 90–100%. The effect of the first passage was not noted. The average elimination half-life is 3-4 hours.

With concomitant use of lornoxicam with food C_max decreases by about 30% and Tmax increases from 1.5 to 2.3 hours. Lornoxicam absorption (calculated according to the area under the concentration / time pharmacokinetic curve (AUC) can be reduced to 20%.

Lornoxicam 8 mg powder for injection is intended for intravenous and / m administration. C_max in blood plasma after i / m administration of the drug is achieved after 0.4 hours. Bioavailability (calculated by AUC) after i / m administration of the drug is 97%.

Distribution. In blood plasma, lornoxicam is in an unchanged state and in an inactive form of its hydroxylated metabolite. The binding of lornoxicam to plasma proteins is 99% and does not depend on its concentration.

Biotransformation. Lornoxicam is actively metabolized in the liver by hydroxylation, first into inactive 5-hydroxylornoxicam. Lornoxicam undergoes biotransformation with the participation of cytochrome CYP 2C9. The metabolism of this enzyme due to genetic polymorphism can be slowed down or intense in different individuals, which can lead to a marked increase in plasma lornoxicam levels in individuals with a slowed metabolism. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized. About ⅔ is excreted through the liver and¹/₃ - through the kidneys as an inactive compound.

In studies on animal models, lornoxicam did not induce hepatic enzyme induction. Based on the results of clinical studies, no data were obtained on the accumulation of lornoxicam after repeated administration in recommended doses. These results are confirmed by monitoring the safety and efficacy of drugs for 1 year of study.

T_½ the starting material is 3-4 hours. After oral administration, about 50% is excreted in the feces and 42% through the kidneys, mainly in the form of 5-hydroxylornoxicam. T_½ 5-hydroxylornoxicam is about 9 hours after parenteral use of the drug 1 or 2 times a day.

In elderly patients (over 65 years), clearance is reduced by 30-40%. In addition to reducing clearance, there are no significant changes in the kinetic profile of lornoxicam in the elderly.

There is no significant change in the kinetic profile of lornoxicam in patients with renal or hepatic insufficiency, with the exception of cumulation, in people with chronic liver disease, after 7 days of therapy with daily doses of 12 and 16 mg.

Indications

Short-term treatment of acute pain of mild to moderate degree.

For tablets also: symptomatic relief of pain and inflammation in osteoarthritis; symptomatic relief of pain and inflammation in rheumatoid arthritis.

Application

Tablets

For all patients, the appropriate dosage regimen should be based on an individual response to treatment.

Pain

The dose of lornoxicam is 8–16 mg / day, divided into 2–3 doses. The maximum recommended daily dose is 16 mg.

Osteoarthritis and Rheumatoid Arthritis

An initial dose of 12 mg of lornoxicam is recommended, divided into 2–3 doses. The maintenance dose should not exceed 16 mg / day.

Xefocam tablets, film-coated, are taken orally with a sufficient amount of water.

Elderly patients (over 65), except for persons with impaired liver or kidney function: dose adjustment is not required, but lornoxicam should be used with caution due to the likelihood of adverse reactions from the gastrointestinal tract.

Renal failure. For patients with mild to moderate renal failure, the maximum recommended daily dose is 12 mg, divided into 2-3 doses.

Liver failure. For patients with moderate liver failure, the maximum recommended daily dose is 12 mg, divided into 2-3 doses (see SPECIAL INSTRUCTIONS).

Adverse reactions can be minimized by taking the drug at the lowest effective dose and the shortest period necessary to control symptoms (see SPECIAL INSTRUCTIONS).

Injections

This dosage form of the drug is intended to initiate therapy and to quickly achieve an analgesic effect or in case of impossibility of using oral drugs or suppositories. For all patients, the appropriate dosage regimen should be based on an individual response to treatment.

For in / in and / m introduction.

The recommended dose is 8 mg IV or IM. Some patients require an additional dose of 8 mg in the first 24 hours. The maximum daily dose is 16 mg.

The duration of the on / in the introduction of the solution should be at least 15 s, in / m - at least 5 s After preparation of solution, the needle should be replaced.

For a / m injection, a long needle is required, which provides a deep introduction. The medicine is intended for single use only. Solution for injection should be prepared immediately before use (the contents of 1 bottle (8 mg of lyophilisate) should be dissolved with water for injection (2 ml)).

Elderly patients (over 65 years old), except for persons with impaired liver or kidney function, dose adjustment is not required, but lornoxicam should be used with caution due to the likelihood of adverse reactions from the gastrointestinal tract.

Renal failure. Patients with mild to moderate renal failure require a dose reduction.

Liver failure. Patients with a moderate degree of liver failure require a dose reduction.

Adverse reactions can be minimized by taking the drug at the lowest effective dose and the shortest period necessary to control symptoms (see SPECIAL INSTRUCTIONS).

Reconstituted solution: the chemical and physical stability of the restored solution was demonstrated for 24 hours at a temperature of 2–8 ° С. From a microbiological point of view, the drug should be used immediately. In case of non-use immediately, the term and storage conditions of the restored solution before its use are the responsibility of the user.

Contraindications

• Hypersensitivity to lornoxicam or other components of the drug; thrombocytopenia; hypersensitivity (symptoms similar to those with ba, rhinitis, angioedema or urticaria) to other NSAIDs, including acetylsalicylic acid; severe heart failure; gastrointestinal bleeding, cerebrovascular or other bleeding; a history of gastrointestinal bleeding or ulcer perforation associated with previous NSAID therapy; active recurrent peptic ulcer / bleeding or history of recurrent peptic ulcer / bleeding (2 or more separate proven episodes of ulcer or bleeding); severe liver failure; severe renal failure (plasma creatinine level 700 μmol / l); iii trimester of pregnancy (see use during pregnancy and lactation).

Side effects

Most often, adverse reactions of NSAIDs were associated with the gastrointestinal tract. when using NSAIDs, peptic ulcers, perforation, or gastrointestinal bleeding may occur, which sometimes ends fatally, especially in the elderly (see special instructions). nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, blood vomiting, ulcerative stomatitis, exacerbation of colitis and Crohns disease have been reported in the treatment of NSAIDs. gastritis was less common.

It is believed that ≈20% of patients treated with lornoxicam may experience side effects. The most common side effects of lornoxicam are nausea, dyspepsia, indigestion, abdominal pain, vomiting, diarrhea. These symptoms were generally observed in 10% of patients participating in the study. Edema, hypertension, and heart failure have been reported in the treatment of NSAIDs.

Clinical studies and epidemiological data show that the use of certain NSAIDs, especially at high doses and for a long time, may be associated with an increased risk of arterial thrombotic events, such as myocardial infarction or stroke (see SPECIAL INSTRUCTIONS).

Serious infectious complications from the skin and soft tissues were reported exclusively during the course of chickenpox.

Undesirable effects by frequency of occurrence are classified into the following categories: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000), unknown (frequency cannot be estimated from the available data).

Infections and infestations: rarely - pharyngitis.

On the part of the blood and lymphatic system: rarely - anemia, thrombocytopenia, leukopenia, an increase in the duration of bleeding; very rarely - ecchymosis. NSAIDs can cause class-specific, potentially severe hematologic disorders, such as neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

On the part of the immune system: rarely - hypersensitivity reactions, anaphylactoid reactions and anaphylaxis.

Metabolic disorders: infrequently - loss of appetite, changes in body weight.

Mental disorders: infrequently - insomnia, depression; rarely - anxiety, nervousness, agitation.

From the nervous system: often - mild and transient headache, dizziness; rarely - drowsiness, paresthesia, taste disturbances (dysgeusia), tremor, migraine; very rarely - aseptic meningitis in patients with systemic lupus erythematosus and mixed connective tissue disease (see SPECIAL INSTRUCTIONS).

From the side of the organ of vision: infrequently - conjunctivitis; rarely - visual impairment.

From the side of the organ of hearing and balance: infrequently - vertigo, tinnitus.

From the cardiovascular system: infrequently - palpitations, tachycardia, edema, heart failure, facial redness; rarely - hypertension, hot flashes, hemorrhages, hematomas.

From the respiratory system: infrequently - rhinitis; rarely - dyspnea, cough, bronchospasm.

From the digestive system: often - nausea, abdominal pain, dyspepsia, diarrhea, vomiting; infrequently - constipation, flatulence, belching, dry mouth, gastritis, stomach ulcer, abdominal pain, abdominal pain in the upper abdomen, duodenal ulcer, ulcers of the oral mucosa; rarely - melena, vomiting with blood, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, ulcer perforation, gastrointestinal bleeding.

On the part of the liver and biliary tract: infrequently - an increase in the level of hepatic enzymes (AlAT, AsAT); very rarely - toxic effect on the liver, as a result of which the development of liver failure, hepatitis, jaundice, cholestasis is possible.

On the part of the skin and subcutaneous tissues: infrequently - rash, itching, increased sweating, erythematous rash, urticaria, angioedema, alopecia; rarely - dermatitis, eczema, purpura; very rarely - edema and bullous reactions, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal system and connective tissue: infrequently - arthralgia; rarely - bone pain, muscle cramps, myalgia.

From the kidneys and urinary tract: rarely - nocturia, impaired urination, increased levels of urea nitrogen and creatinine in the blood; very rarely, lornoxicam can cause acute renal failure in individuals with kidney disease, which depends on renal prostaglandins, which play an important role in maintaining renal blood flow (see SPECIAL INSTRUCTIONS). Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, is a class-specific effect of NSAIDs.

General violations: infrequently - malaise, swelling of the face; rarely - asthenia.

special instructions

In the following disorders, the drug can be prescribed only after a careful assessment of the ratio of the expected benefit of the therapy / possible risk.

Lornoxicam should be used with caution in patients with mild renal insufficiency (serum creatinine level - 150-300 mmol / l) and moderate renal failure (serum creatinine level - 300-700 micromol / l) due to the important role of prostaglandins in maintaining renal blood flow. In case of impaired renal function, drug treatment should be discontinued.

Individuals after extensive surgery, with heart failure, taking diuretics or drugs that can cause kidney damage, should carefully monitor kidney function.

Patients with blood clotting disorders are advised to conduct a thorough clinical study and evaluate laboratory parameters (e.g., activated partial thrombin time).

After using the drug at a dose of 12–16 mg / day, it is recommended that persons with liver failure (for example, cirrhosis) regularly conduct laboratory tests in connection with the possibility of accumulation of lornoxicam in the body (increased AUC). But deviations of pharmacokinetic parameters in patients with liver failure compared with healthy volunteers were not detected.

With prolonged treatment (3 months), it is recommended to assess the state of the blood (determination of hemoglobin), renal function (determination of creatinine) and liver enzymes.

Elderly people (over 65) are advised to monitor renal and hepatic function and use the drug with caution after surgery.

The combined use of lornoxicam with other NSAIDs, including selective COX-2 inhibitors, should be avoided.

Undesirable reactions can be minimized by taking the lowest effective dose for the short period necessary to control the symptoms of the disease.

When using any NSAIDs at any time during treatment, the occurrence (with / without warning symptoms or serious gastrointestinal disturbances in the anamnesis) of gastrointestinal bleeding, ulcers or perforation may be fatal.

The risk of gastrointestinal bleeding, ulcers or perforation increases with increasing doses of NSAIDs in patients with a history of ulcers, especially complicated bleeding or perforation (see CONTRAINDICATIONS), as well as in the elderly.These groups of patients should with extreme caution begin treatment with the drug in the lowest therapeutic doses.

With caution, NSAIDs should be used to treat the above groups of patients and those taking concomitantly low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications (see INTERACTIONS). For patients in need of such combination therapy, treatment can be carried out against the background of the simultaneous use of protective agents (for example misoprostol or proton pump inhibitors). Clinical observation at regular intervals is recommended.

Patients with a history of toxic effects on the gastrointestinal tract, especially the elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) in the initial stages of treatment. With extreme caution, it is prescribed to patients who are simultaneously using medicines that can increase the risk of ulcers or bleeding, for example, oral corticosteroids, anticoagulants - warfarin, selective serotonin reuptake inhibitors, or antithrombotic drugs - acetylsalicylic acid (see INTERACTIONS).

In case of bleeding or gastrointestinal ulcers in patients taking lornoxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohns disease), since their condition may worsen. In elderly people, the incidence of adverse reactions with the use of NSAIDs, in particular gastrointestinal bleeding and perforation, increases, which can lead to death (see CONTRAINDICATIONS). Caution is advised to use the drug in patients with AH and / or history of heart failure, since NSAIDs may cause swelling and fluid retention in the body.

It is necessary to observe patients with AH and / or congestive heart failure of mild to moderate severity, as NSAID therapy may be accompanied by such phenomena as fluid retention and edema. There are clinical studies and epidemiological data that suggest that the use of certain NSAIDs (especially long-term therapy and at high doses) may be associated with a slight increase in the risk of arterial thrombotic events (for example, myocardial infarction or stroke). There is not enough data to exclude such a risk when taking lornoxicam.

For patients with uncontrolled hypertension, chronic heart failure, coronary heart disease, peripheral artery disease and / or cerebrovascular disorders, lornoxicam should be prescribed only after a thorough evaluation of the indications. Evaluation is also required before prescribing long-term treatment to individuals with risk factors for cardiovascular disease (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking). Combined treatment with NSAIDs and heparin increases the risk of spinal / epidural hematoma with spinal or epidural anesthesia (see INTERACTIONS).

Very rarely, against the background of the use of NSAIDs, skin reactions occur, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, sometimes some of them end fatally (see ADVERSE EFFECTS). The risk of developing such reactions is highest at the beginning of treatment: in most cases, such reactions occur in the 1st month of taking the drug. Lornoxicam should be discontinued at the first sign of a skin rash, mucosal lesions, and other manifestations of hypersensitivity.

Use with caution to people with AD or with a given medical history, since NSAIDs provoke bronchospasm in these patients.

In patients with systemic lupus erythematosus and mixed connective tissue disease, the risk of developing aseptic meningitis may increase.

Lornoxicam inhibits platelet aggregation, increasing blood clotting time.

The drug should be used with caution in patients with a tendency to bleeding.

Concomitant treatment with NSAIDs and tacrolimus may increase the risk of nephrotoxicity due to weakened prostacyclin synthesis in the kidneys. With such combination therapy, it is necessary to carefully monitor renal function.

Like other NSAIDs, lornoxicam can cause an episodic increase in transaminases, bilirubin in the blood serum, as well as an increase in the blood concentration of urea and creatinine, as well as other laboratory deviations from the norm. If the deviations of laboratory parameters are significant and continue for a long time, treatment must be stopped and the necessary research carried out.

The drug contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency or malabsorption of glucose-galactose should not use the drug.

Lornoxicam, like other drugs that suppress COX / prostaglandin synthesis, can reduce fertility, so it is not recommended for women planning pregnancy. Women who have problems with pregnancy or who are being examined due to infertility need to stop taking lornoxicam.

In the presence of chickenpox, in exceptional cases severe infectious lesions of the skin and soft tissues may develop. By this time, the effect of NSAIDs on the worsening of these infectious diseases cannot be ruled out. It is recommended to avoid the use of lornoxicam with existing chickenpox.

Use during pregnancy or lactation. Pregnancy. Lornoxicam is contraindicated in the third trimester of pregnancy. There are no clinical data on the use of lornoxicam in the I – II trimesters of pregnancy and during childbirth, so the drug is not recommended for use during this period.

There is insufficient data regarding the use of lornoxicam for pregnant women. Animal studies have shown reproductive toxicity.

Suppression of prostaglandin synthesis may adversely affect pregnancy and / or embryo / fetal development. Data from epidemiological studies indicate an increased risk of miscarriage, as well as the development of heart defects with the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases with increasing doses and duration of therapy. In animals, the use of inhibitors of prostaglandin synthesis leads to an increase in pre- and post-implantation death of the fetus and embryo-fetal mortality. Prostaglandin synthesis inhibitors should not be used in the first and second trimesters of pregnancy. Application is possible only if absolutely necessary.

In the III trimester of pregnancy with the use of any inhibitors of prostaglandin synthesis, such effects on the fetus are possible:

• cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function, which can progress to renal failure with the manifestation of oligohydroamnion.

The pregnant woman and the fetus at the end of pregnancy may be exposed to such effects from the use of prostaglandin synthesis inhibitors:

• possibly an increase in the duration of bleeding;
• suppression of contractile function of the uterus, which can lead to a delay or increase in the duration of labor.

Thus, the use of lornoxicam is contraindicated in the III trimester of pregnancy (see CONTRAINDICATIONS).

The period of breastfeeding. There is no data on the excretion of lornoxicam in human breast milk.Relatively high concentrations of lornoxicam are excreted in the milk of lactating rats. Therefore, lornoxicam should not be used during breastfeeding.

Children. Lornoxicam is not recommended for use in children under the age of 18 due to a lack of clinical data on the effectiveness and safety of the drug.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. In case of dizziness and / or drowsiness due to the administration of lornoxicam, one should not drive vehicles or work with other mechanisms.

Interactions

The simultaneous use of lornoxicam and the following medicines:

• cimetidine: increased plasma concentration of lornoxicam (no interaction between lornoxicam and ranitidine or lornoxicam and antacids);
• anticoagulants: NSAIDs may increase the severity of the action of anticoagulants (e.g. warfarin - see SPECIAL INSTRUCTIONS). Careful monitoring of PIM should be carried out;
• fenprokumon: the effectiveness of treatment with fenprokumon decreases;
• heparin: NSAIDs increase the risk of spinal / epidural hematoma while using heparin during spinal or epidural anesthesia (see SPECIAL INSTRUCTIONS);
• ACE inhibitors: may reduce the severity of ACE inhibitors;
• diuretics: weakening the diuretic and hypotensive effect of loop, thiazide and potassium-sparing diuretics;
• β-adrenergic blockers: weakening of the hypotensive effect;
• angiotensin II receptor blockers: a decrease in the hypotensive effect;
• digoxin: decrease in renal clearance of digoxin;
• corticosteroids: increased risk of gastrointestinal ulcers or bleeding (see SPECIAL INSTRUCTIONS);
• quinolone antibacterial agents: increased risk of seizures;
• antiplatelet drugs: the risk of gastrointestinal bleeding increases (see SPECIAL INSTRUCTIONS);
• other NSAIDs: increased risk of gastrointestinal bleeding;
• methotrexate: an increase in the concentration of methotrexate in blood plasma, which leads to an increase in its toxicity. With simultaneous use, careful monitoring is necessary;
• SSRIs: increased risk of gastrointestinal bleeding (see SPECIAL INSTRUCTIONS);
• lithium preparations: NSAIDs reduce the renal clearance of lithium, so the concentration of serum lithium may exceed the toxicity threshold. It is necessary to control the level of lithium in the blood serum, especially at the beginning of treatment, with dose adjustment and discontinuation of treatment;
• cyclosporine: increased serum cyclosporine concentration. Possible increased nephrotoxicity of cyclosporine, due to effects mediated by renal prostaglandins. With combination therapy, it is necessary to monitor renal function;
• sulfonylurea derivatives (e.g. glibenclamide): increased risk of hypoglycemia;
• well-known inducers and inhibitors of CYP 2C9 isoenzymes: lornoxicam (like other NSAIDs dependent on cytochrome P450 2C9 (CYP 2C9 isoenzyme)) interacts with known inducers and inhibitors of CYP 2C9 isoenzymes (see Biotransformation);
• tacrolimus: increased risk of nephrotoxicity due to decreased synthesis of prostacyclin in the kidneys. With combination therapy, it is necessary to monitor renal function (see SPECIAL INSTRUCTIONS);
• pemetrexed: NSAIDs may decrease renal clearance of pemetrexed, resulting in increased renal and gastrointestinal toxicity and myelosuppression.

Since food slows down the absorption of lornoxicam, Xefocam tablets should not be taken with food if it is necessary to quickly begin their effective action (pain relief).

Eating reduces absorption by ≈20% and increases Tmax.

Incompatibility.The drug in the form of a solution for injection should not be mixed with other drugs, with the exception of those indicated in the instructions for use.

Overdose

Currently, there are no data on overdose that would allow to determine its consequences or offer specific treatment. The following symptoms may occur as a result of an overdose of lornoxicam: nausea, vomiting, cerebral symptoms (dizziness, blurred vision). in severe cases: ataxia, with a transition to a coma and convulsions; damage to the liver and kidneys; blood clotting disorder is possible. with a real or suspected overdose, the use of the drug should be discontinued. thanks to a short t½, lornoxicam is rapidly excreted. dialysis is ineffective. there is currently no specific antidote. regular emergency measures, including gastric lavage, must be taken. based on general principles, only the use of activated carbon when taken immediately after an overdose of lornoxicam can lead to a decrease in the absorption of the drug. for the treatment of gastrointestinal disorders, for example, a prostaglandin analog or ranitidine can be used.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° c.

UA / CVM / 1018/0009