Xefocam (Tablets, Lyophilisate) Instructions for Use

ATC Code

M01AC05 (Lornoxicam)

Active Substance

Lornoxicam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic drugs; non-steroidal anti-inflammatory and antirheumatic drugs; oxicams

Pharmacological Action

NSAID, belongs to the class of oxicams. It has a pronounced analgesic and anti-inflammatory effect.

The mechanism of action is based on the suppression of prostaglandin synthesis (inhibition of the COX enzyme), leading to the suppression of inflammation.

Lornoxicam does not affect the main parameters of the body’s condition: body temperature, respiratory rate, heart rate, blood pressure, ECG data, spirometry.

The analgesic effect of lornoxicam is not associated with a narcotic effect.

The drug Xefocam does not have an opiate-like effect on the central nervous system and, unlike narcotic analgesics, does not depress respiration and does not cause drug dependence.

Due to the presence of a locally irritating effect on the gastrointestinal tract and a systemic ulcerogenic effect associated with the suppression of prostaglandin synthesis, gastrointestinal complications are frequent adverse effects during treatment with NSAIDs.

Pharmacokinetics

Absorption

Lornoxicam is rapidly and almost completely absorbed from the gastrointestinal tract. C_max in plasma is reached in approximately 1-2 hours. The absolute bioavailability is approximately 90-100%. It is not subject to the first-pass effect through the liver.

When lornoxicam is taken simultaneously with food, C_max decreases by approximately 30% and T_max increases from 1.5 hours to 2.3 hours. The absorption of lornoxicam (calculated by AUC) may decrease by up to 20%.

Distribution

The degree of binding of lornoxicam to plasma proteins is about 99% and is independent of concentration.

Lornoxicam is also found in synovial fluid after repeated administration.

Metabolism

Lornoxicam is extensively metabolized in the liver, mainly through hydroxylation to the inactive 5′-hydroxylornoxicam. The biotransformation of lornoxicam is carried out by the isoenzyme CYP2C9.

Due to the polymorphism of the gene encoding this enzyme, there are people with slow and fast metabolism of the drug, which may lead to a significant increase in the level of lornoxicam in the plasma in individuals with slow metabolism. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized: approximately 2/3 of the drug is excreted by the liver, and 1/3 by the kidneys as an inactive metabolite.

Excretion

The T_1/2 of lornoxicam averages from 3 to 4 hours.

After oral administration, approximately 50% of the drug is excreted in the feces and 42% by the kidneys, mainly as 5′-hydroxylornoxicam. The T_1/2 of 5′-hydroxylornoxicam is approximately 9 hours after parenteral administration 1 or 2 times/day. There is no evidence that the elimination rate changes with repeated dose administration.

Pharmacokinetics in special patient groups

In elderly patients (over 65 years of age), the clearance of the drug is reduced by 30-40%.

In patients with impaired liver or kidney function, no significant changes in the kinetics of lornoxicam are observed, except for accumulation in patients with chronic liver diseases after 7 days of treatment at a daily dose of 12 mg or 16 mg.

Indications

• Short-term treatment of mild to moderate acute pain syndrome in adults;
• Symptomatic treatment of pain and inflammation associated with osteoarthritis in adults;
• Symptomatic treatment of pain and inflammation associated with rheumatoid arthritis in adults.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally with a sufficient amount of liquid.

Doses and administration regimen for all patients should be based on the individual response to the drug.

The risk of adverse events can be significantly reduced by using the drug at the lowest effective dose for the shortest period necessary to relieve symptoms.

Pain

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

Osteoarthritis and rheumatoid arthritis

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

Special patient groups

Lornoxicam is not intended for use in children and adolescents under 18 years of age, because data on safety and efficacy are insufficient.

No special dose adjustment is required for elderly patients (over 65 years of age) if there is no impairment of renal or hepatic function, however, the drug should be used with caution, since gastrointestinal adverse events are less well tolerated in this age group.

For patients with mild and moderate renal impairment, the maximum recommended dose is 12 mg and should be divided into 2 or 3 doses. Lornoxicam is contraindicated in patients with severe renal failure.

For patients with moderate hepatic impairment, the maximum recommended dose is 12 mg and should be divided into 2 or 3 doses. Lornoxicam is contraindicated in patients with severe hepatic failure.

Adverse effects can be minimized by using the lowest effective dose of the drug for the shortest period of time sufficient to control symptoms.

Lyophilisate

IV, IM.

The solution for IV and IM administration is prepared immediately before administration by dissolving the contents of one vial (8 mg of lornoxicam) with water for injections (2 ml).

After preparing the solution, the needle is replaced. IM injections are given with a long needle.

The solution prepared in this way is administered IV or IM for postoperative pain and IM for an acute attack of lumbago/sciatica.

The duration of IV administration of the solution should be at least 15 seconds, IM – at least 5 seconds.

The drug Xefocam lyophilisate for the preparation of solution for IV and IM administration is used only for the relief of acute pain syndrome, if oral administration of the drug is not possible.

The recommended single dose: 8 mg IV or IM. The daily dose should not exceed 16 mg. Some patients may require an additional 8 mg dose within the first 24 hours.

The minimum effective dose should be used for the shortest possible course.

For all patients, doses and administration regimen should be based on the individual response to treatment. The risk of adverse events can be significantly reduced by using the drug at the lowest effective dose for the shortest period necessary to relieve symptoms.

No special dose adjustment is required for elderly patients over 65 years of age if there is no impairment of renal or hepatic function. The drug should be used with caution, since gastrointestinal adverse events are less well tolerated in this age group.

Patients with mild or moderate renal impairment may require dose adjustment. Lornoxicam is contraindicated in patients with severe renal failure.

Patients with moderate hepatic impairment may require dose adjustment. Lornoxicam is contraindicated in patients with severe hepatic failure.

Lornoxicam is not intended for use in children and adolescents under 18 years of age, because data on its safety and efficacy are insufficient.

Adverse Reactions

The most common adverse reactions associated with the use of NSAIDs are noted from the gastrointestinal tract: peptic ulcers, perforation or gastrointestinal bleeding may develop, sometimes fatal, especially in elderly patients. After the use of NSAIDs, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis or Crohn’s disease have been reported. In rarer cases, gastritis was observed.

Approximately 20% of patients receiving Lornoxicam may develop adverse reactions. The most common are nausea, vomiting and diarrhea, dyspeptic symptoms, indigestion, abdominal pain.

Cases of edema, arterial hypertension and heart failure have been reported in connection with the use of NSAIDs.

Results of clinical studies and epidemiological data suggest that the use of NSAIDs (especially long-term and high-dose use) may be associated with an increased risk of cardiovascular thrombotic complications (e.g., myocardial infarction, stroke).

In isolated cases, in patients with chickenpox, serious infectious complications of the skin and soft tissues may develop.

The table below lists adverse reactions that were observed in more than 0.05% of patients out of 6417 who received treatment in clinical studies.

Adverse reactions are grouped by frequency of occurrence according to the following classification: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data).

If signs of liver damage appear (skin itching, yellowing of the skin, nausea, vomiting, abdominal pain, dark urine, increased levels of liver transaminases), the drug should be discontinued and a doctor should be consulted.

If any of the indicated side effects worsen or the patient notices any other side effects, they should inform the doctor.

Contraindications

• Hypersensitivity to lornoxicam or any of the excipients;
• Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose or paranasal sinuses, rhinitis, angioedema, urticaria and intolerance to acetylsalicylic acid and other NSAIDs (including in history);
• Thrombocytopenia;
• Hemorrhagic diathesis or bleeding disorders, as well as those who have undergone operations associated with a risk of bleeding or incomplete hemostasis;
• The period after coronary artery bypass grafting;
• Decompensated heart failure;
• Erosive and ulcerative changes in the gastric or duodenal mucosa, active gastrointestinal bleeding; cerebrovascular or other bleeding;
• History of gastrointestinal bleeding or ulcer perforation associated with NSAID use;
• Active peptic ulcer or history of recurrent peptic ulcer;
• Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) in the acute phase;
• Severe hepatic failure;
• Severe renal failure (serum creatinine level more than 700 µmol/l), progressive kidney diseases, confirmed hyperkalemia;
• Pregnancy;
• Breastfeeding period;
• Lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
• Age under 18 years (due to insufficient clinical experience).

With caution

• In case of increased tendency to bleeding;
• In case of mild (serum creatinine 150-300 µmol/l) or moderate (serum creatinine 300-700 µmol/l) renal impairment;
• In case of blood clotting system disorders;
• In case of hepatic impairment (e.g., liver cirrhosis);
• In patients over 65 years of age;
• In patients with a history of gastrointestinal diseases;
• With simultaneous use of drugs that may increase the risk of ulcers and bleeding (oral corticosteroids);
• Anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors and antiplatelet agents (e.g., acetylsalicylic acid);
• In patients with risk factors for the development of cardiovascular diseases;
• In patients with active bronchial asthma or a history of it;
• In patients with systemic lupus erythematosus (SLE);
• In patients with mixed connective tissue diseases.

Use in Pregnancy and Lactation

Pregnancy

The drug is contraindicated during pregnancy, since there are no clinical data on its use during pregnancy. Suppression of prostaglandin synthesis may have a negative effect on the course of pregnancy and/or fetal development.

Epidemiological data indicate an increased risk of spontaneous abortion and fetal heart defects after the use of prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with increasing dose and duration of treatment.

In animals, the administration of a prostaglandin synthesis inhibitor led to an increase in the frequency of pre- and post-implantation loss of embryos and embryonic death at various stages of pregnancy.

In the first and second trimesters of pregnancy, prostaglandin synthesis inhibitors should be used only in cases of extreme necessity. The use of prostaglandin synthesis inhibitors in the third trimester of pregnancy may lead to toxic effects on the fetal heart and lungs (premature closure of the ductus arteriosus and the development of pulmonary hypertension), as well as to renal failure and, consequently, a decrease in the amount of amniotic fluid.

The use of NSAIDs by women at 20 weeks of gestation or later may lead to the development of oligohydramnios and/or kidney pathology in newborns (neonatal renal dysfunction). The use of prostaglandin synthesis inhibitors in late pregnancy may cause prolongation of bleeding time in the mother and fetus, as well as suppression of uterine contractility, which may delay or prolong labor. At the end of pregnancy, prostaglandin synthesis inhibitors may cause prolongation of bleeding time in the mother and fetus, as well as suppression of uterine contractions, which may lead to post-term pregnancy or an increase in the duration of labor.

Breastfeeding period

There are no data on whether Lornoxicam passes into human breast milk.

Lornoxicam is found in the breast milk of female rats in relatively high concentrations. Lornoxicam should not be used in women who are breastfeeding.

Fertility

The use of lornoxicam, like any drug that inhibits COX and prostaglandin synthesis, may impair fertility and is not recommended for women planning a pregnancy. In women experiencing conception difficulties or undergoing infertility examination, the possibility of discontinuing lornoxicam should be considered.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic failure.

In case of hepatic impairment (liver cirrhosis), the drug should be prescribed only after a careful assessment of the expected benefit of therapy and the possible risk.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (serum creatinine level more than 700 µmol/l), progressive kidney diseases.

In case of mild renal impairment (serum creatinine 150-300 µmol/l) and moderate renal impairment (serum creatinine 300-700 µmol/l), the drug should be prescribed only after a careful assessment of the expected benefit of therapy and the possible risk.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

The drug should be prescribed with caution to elderly patients (over 65 years of age).

Special Precautions

Lornoxicam inhibits platelet aggregation and prolongs bleeding time, so it should be prescribed with caution in case of increased tendency to bleeding.

Lornoxicam should be used only after a careful assessment of the expected benefit of therapy and the possible risk in patients with mild renal impairment (serum creatinine 150-300 µmol/l) and moderate renal impairment (serum creatinine 300-700 µmol/l), because the maintenance of renal blood flow depends on the level of renal prostaglandins. The use of lornoxicam should be discontinued in case of deterioration of renal function during treatment.

Renal function should be monitored in patients

• Who have undergone extensive surgery;
• With heart failure;
• Receiving simultaneous treatment with diuretics or drugs with proven or suspected nephrotoxicity.

Lornoxicam should also be used only after a careful assessment of the expected benefit of therapy and the possible risk

In patients with blood clotting system disorders: thorough clinical monitoring and assessment of laboratory parameters, such as aPTT, is recommended;

In patients with hepatic impairment (liver cirrhosis): clinical monitoring and assessment of laboratory parameters are recommended, because during treatment with lornoxicam at a daily dose of 12-16 mg, accumulation of the drug (increase in AUC) is possible. In addition, hepatic failure does not appear to affect the pharmacokinetic parameters of lornoxicam compared to healthy subjects;

In patients receiving long-term treatment (more than 3 months) – when taking NSAIDs, kidney and liver function, as well as hematological parameters, should be regularly monitored.

In patients over 65 years of age – monitoring of liver and kidney function is recommended. Use with caution in elderly patients in the postoperative period.

Concomitant use with NSAIDs

Concomitant use with other NSAIDs, including selective COX-2 inhibitors, should be avoided.

Minimizing adverse effects

Adverse effects can be minimized by using the lowest effective dose of the drug for the shortest period of time sufficient to control symptoms.

Gastrointestinal bleeding, ulcer, gastrointestinal perforation

Gastrointestinal bleeding, ulceration, and perforation can occur during the use of any NSAID and can be fatal. Warning symptoms or a history of serious gastrointestinal pathology may be absent.

The risk of bleeding, ulceration, or gastrointestinal perforation increases with higher doses of NSAIDs, in patients with a history of peptic ulcer disease, especially if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest possible dose. In these patients, as well as in patients receiving therapy with low doses of acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered. Regular assessment of the condition of such patients is recommended.

Patients with a history of gastrointestinal side effects, especially the elderly, should be instructed to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the initial stage of treatment.

Lornoxicam should be used with caution when taken concomitantly with drugs that may increase the risk of ulceration and bleeding, such as oral corticosteroids (e.g., prednisolone), anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, sertraline) and antiplatelet agents (e.g., acetylsalicylic acid).

If gastrointestinal bleeding or ulceration occurs during treatment with lornoxicam, the treatment should be discontinued.

NSAIDs should be prescribed with caution to patients with a history of gastrointestinal pathology (ulcerative colitis, Crohn’s disease), as the patient’s condition may worsen.

Elderly patients

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal.

Cardiovascular and cerebrovascular diseases

Patients with a history of or current arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and consultation, as cases of fluid retention and edema development have been reported with the use of NSAIDs.

Clinical and epidemiological study data indicate that some NSAIDs, especially in high doses and with long-term use, may increase the risk of arterial thromboembolic complications (e.g., myocardial infarction or stroke). There is insufficient data to rule out such a risk for lornoxicam.

Patients with uncontrolled hypertension, congestive heart failure, established coronary artery disease, peripheral arterial disease, or cerebrovascular disease, as well as in the presence of risk factors for cardiovascular diseases, such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking, should use Lornoxicam only after a thorough assessment of the expected benefit of therapy and the possible risk.

When NSAIDs and heparin are used concomitantly during spinal or epidural anesthesia, the risk of hematoma formation increases.

Skin diseases

In very rare cases, severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, are possible.

The risk of such reactions is highest at the start of therapy – the development of the reaction is observed in the first month of treatment in most cases. Lornoxicam should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Respiratory diseases

The drug should be used with caution in patients with active or a history of bronchial asthma, as it is known that NSAIDs can provoke bronchospasm in such patients.

Systemic lupus erythematosus and mixed connective tissue diseases

Caution should be exercised when using lornoxicam in patients with systemic lupus erythematosus (SLE) and mixed connective tissue diseases, as there may be an increased risk of aseptic meningitis.

Nephrotoxicity

Concomitant use of NSAIDs and tacrolimus may lead to an increased risk of nephrotoxic effects due to inhibition of prostacyclin synthesis in the kidneys.

During combination therapy with these drugs, kidney function should be carefully monitored.

Varicella

In rare cases, the varicella zoster virus can cause severe infectious complications of the skin and soft tissues. The role of NSAIDs in the worsening of these infectious complications cannot currently be ruled out. It is recommended to avoid the use of lornoxicam in infections caused by the varicella zoster virus.

Laboratory parameters

As with most NSAIDs, cases of increased activity of serum aminotransferases, serum bilirubin levels or other biochemical parameters of liver function, as well as increased levels of serum creatinine and urea and other deviations in laboratory parameters have been reported. If any of these deviations is significant or persists for a long time, lornoxicam should be discontinued and appropriate investigations should be performed.

Lactose

This medicinal product contains lactose monohydrate. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Effect on ability to drive vehicles and operate machinery

Patients who experience dizziness and/or drowsiness during treatment with lornoxicam should refrain from driving vehicles and operating machinery.

Overdose

Currently, there are no data on overdose that would allow assessment of its consequences or suggest specific treatment.

Symptoms in case of overdose of the drug Xefocam, nausea and vomiting, cerebral symptoms (dizziness, visual disturbances, ataxia, progressing to coma and convulsions) may be observed. Changes in liver and kidney function, and blood clotting disorders are possible.

Treatment in case of actual or suspected overdose, administration of the drug should be discontinued. Due to the short T_1/2, Lornoxicam is rapidly eliminated from the body. Dialysis is not effective. To date, the existence of a specific antidote is unknown. Standard emergency measures, including gastric lavage, should be provided. Based on general principles, the use of activated charcoal only if taken immediately after taking Xefocam may reduce drug absorption. Prostaglandin analogues or ranitidine may be used to treat gastrointestinal disorders.

Drug Interactions

When Xefocam is used concomitantly with cimetidine, the plasma concentration of lornoxicam increases, which may increase the risk of lornoxicam side effects. No interaction with ranitidine and antacid preparations has been identified.

When Xefocam is used concomitantly with anticoagulants (e.g., warfarin) or platelet aggregation inhibitors, bleeding time may increase (increased risk of bleeding, INR monitoring required).

Concomitant use with phenprocoumon reduces its therapeutic effectiveness.

When NSAIDs and heparin are used concomitantly with spinal or epidural anesthesia, the risk of spinal or epidural hematomas increases.

Concomitant use with ACE inhibitors may lead to a decrease in the antihypertensive effect of the ACE inhibitor.

Concomitant use with beta-blockers reduces the antihypertensive effect of beta-blockers.

Concomitant use with angiotensin II receptor blockers reduces the antihypertensive effect of angiotensin II receptor blockers.

Xefocam reduces the diuretic effect and antihypertensive effect of “loop” and thiazide diuretics, as well as potassium-sparing diuretics (increased risk of hyperkalemia and nephrotoxicity).

Xefocam reduces the renal clearance of digoxin, which increases the risk of digoxin toxicity.

When used concomitantly with quinolone antibiotics (e.g., levofloxacin, ofloxacin), the risk of convulsive syndrome increases.

When used concomitantly with antiplatelet agents (e.g., clopidogrel), the risk of bleeding increases.

When used concomitantly with other NSAIDs, the risk of peptic ulcer or gastrointestinal bleeding increases.

When used concomitantly with corticosteroids, the risk of peptic ulcer or gastrointestinal bleeding increases.

Lornoxicam increases the serum concentration of methotrexate. This may lead to increased toxicity. If concomitant use of these drugs is necessary, careful patient monitoring is required.

When Xefocam and selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, sertraline) are used concomitantly, the risk of bleeding increases.

Xefocam may cause an increase in the C_max of lithium in plasma and thereby enhance the known side effects of lithium. Constant monitoring of serum lithium ion concentration is necessary, especially at the initial stage of treatment, when changing the dose, and when discontinuing treatment.

Xefocam increases the nephrotoxicity of cyclosporine. The nephrotoxicity of cyclosporine may be enhanced due to the effect of lornoxicam on the synthesis of renal prostaglandins. When drugs are used concomitantly, kidney function should be monitored.

When Xefocam is used concomitantly with sulfonylurea derivatives (e.g., glibenclamide), the risk of hypoglycemia increases.

When the drug is used concomitantly with cefamandole, cefoperazone, cefotetan, valproic acid, the risk of bleeding increases.

When drugs that are inducers and inhibitors of the CYP2C9 isoenzyme are used concomitantly, Lornoxicam (like other NSAIDs metabolized by the CYP2C9 isoenzyme) interacts with its inducers and inhibitors.

When used concomitantly with tacrolimus, the risk of nephrotoxicity increases due to inhibition of prostacyclin synthesis in the kidneys. When drugs are used concomitantly, kidney function should be monitored.

NSAIDs may reduce the renal clearance of pemetrexed, leading to increased nephrotoxicity and gastrointestinal toxicity of the drug, as well as suppression of hematopoiesis.

If Xefocam film-coated tablets are taken with food, the absorption of lornoxicam is slowed. Therefore, the drug should not be taken with food if a rapid onset of action (pain relief) is required.

Taking with food may reduce the absorption of lornoxicam by approximately 20% and increase T_max.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.