INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSEFOKAM® (XEFOCAM®)

Composition:

Active substance: lornoxicam;

1 tablet of 4 mg or 8 mg contains 4 mg or 8 mg of lornoxicam, respectively;

Excipients: magnesium stearate; povidone; sodium croscarmellose; microcrystalline cellulose; lactose monohydrate; polyethylene glycol 6000; titanium dioxide (E 171); talc; hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated film-coated tablets, white to yellowish in color, with an imprint «L04» on 4 mg tablets and «L08» on 8 mg tablets.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Oxicams. ATC code M01A C05.

Pharmacological Properties

Pharmacodynamics

Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and anti-inflammatory properties, belonging to the oxicam class. The mechanism of action of lornoxicam is primarily related to inhibition of prostaglandin synthesis (inhibition of the enzyme cyclooxygenase), leading to desensitization of peripheral nociceptors and suppression of inflammation. A central effect on nociceptors, unrelated to its anti-inflammatory action, is also presumed. Lornoxicam does not affect vital parameters (such as 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's development.

Due to local gastrointestinal irritation and systemic ulcerogenic effects associated with inhibition of prostaglandin (PG) synthesis, administration of lornoxicam, like other NSAIDs, frequently leads to gastrointestinal complications.

Pharmacokinetics

Absorption. Lornoxicam is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration (Cmax) is reached within 1–2 hours after administration. Absolute bioavailability of lornoxicam is 90–100%. No first-pass effect has been observed. When lornoxicam is administered with food, Cmax is reduced by approximately 30%, and Tmax increases from 1.5 hours to 2.3 hours. Absorption of lornoxicam (calculated as the area under the plasma concentration-time curve (AUC)) may be reduced by up to 20%.

Distribution. In plasma, lornoxicam is present in unchanged form and as its inactive hydroxylated metabolite. Plasma protein binding of lornoxicam is 99% and is independent of its concentration. It is also detected in synovial fluid after repeated administration.

Metabolism. Lornoxicam is actively metabolized in the liver via hydroxylation, primarily into the inactive metabolite 5-hydroxy-lornoxicam. This process involves the cytochrome CYP2C9 enzyme. Due to genetic polymorphism, individuals may exhibit either slow or extensive metabolism of this enzyme, which may result in significantly increased plasma levels of lornoxicam in slow metabolizers. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized. Approximately two-thirds are excreted via the liver and one-third via the kidneys as inactive compounds.

In animal models, lornoxicam did not induce hepatic enzymes. Clinical studies have not shown evidence of lornoxicam accumulation after repeated administration of recommended doses, as confirmed by safety and efficacy monitoring data from studies lasting up to 1 year.

Elimination. The elimination half-life of the parent compound is 3–4 hours. After oral administration, approximately 50% is excreted in feces and 42% via the kidneys, primarily as 5-hydroxy-lornoxicam. The elimination half-life of 5-hydroxy-lornoxicam is approximately 9 hours after parenteral administration once or twice daily. There is no evidence that elimination rate changes with repeated dosing.

In elderly patients (over 65 years of age), clearance is reduced by 30–40%. Apart from reduced clearance, there are no significant changes in the kinetic profile of lornoxicam in elderly patients.

There is no substantial change in the pharmacokinetic profile of lornoxicam in patients with renal or hepatic impairment, except for accumulation observed in patients with chronic liver disease after 7 days of therapy with daily doses of 12 mg and 16 mg.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of mild to moderate acute pain in adults.
Symptomatic treatment of pain and inflammation in osteoarthritis in adults.
Symptomatic treatment of pain and inflammation in rheumatoid arthritis in adults.

Contraindications.

Hypersensitivity to lornoxicam or to any component of the medicinal product;
thrombocytopenia;
hypersensitivity (symptoms resembling those seen in asthma, rhinitis, angioedema, or urticaria) to other NSAIDs, including acetylsalicylic acid;
severe heart failure;
gastrointestinal bleeding, cerebrovascular or other hemorrhages;
history of gastrointestinal bleeding or perforation associated with previous NSAID therapy;
active recurrent peptic ulcer/gastrointestinal bleeding or recurrent peptic ulcer/gastrointestinal bleeding in history (two or more distinct episodes of proven ulceration or bleeding);
severe hepatic impairment;
severe renal impairment (serum creatinine level > 700 µmol/L);
third trimester of pregnancy (see section "Use during pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with lornoxicam:

Cimetidine: increases plasma concentration of lornoxicam, which may increase the risk of adverse effects of lornoxicam (no interactions between lornoxicam and ranitidine or between lornoxicam and antacids have been observed).
Anticoagulants: NSAIDs may enhance the effect of anticoagulants, e.g., warfarin (see section "Special precautions for use"). Careful monitoring of the international normalized ratio (INR) is required.
Phenprocoumon: reduced effectiveness of phenprocoumon treatment.
Heparin: nonsteroidal anti-inflammatory drugs increase the risk of bleeding and the development of spinal/epidural hematoma when used concomitantly with heparin during spinal or epidural anesthesia (see section "Special precautions for use").
ACE inhibitors: may reduce the effect of ACE inhibitors.
Diuretics: reduced diuretic and antihypertensive effect of loop, thiazide, and potassium-sparing diuretics (increased risk of hyperkalemia and nephrotoxicity).
Beta-blockers: reduced antihypertensive effect.
Angiotensin II receptor blockers: reduced antihypertensive effect.
Digoxin: reduced renal clearance of digoxin, increasing the risk of digoxin toxicity.
Corticosteroids: increased risk of gastrointestinal ulcers or bleeding (see section "Special precautions for use").
Quinolone antibacterial agents (e.g., levofloxacin, ofloxacin): increased risk of seizures.
Antiplatelet agents (e.g., clopidogrel): increased risk of bleeding (see section "Special precautions for use").
Other NSAIDs: increased risk of gastrointestinal bleeding or ulcers.
Methotrexate: increased methotrexate concentration in blood serum, leading to increased toxicity. Close monitoring is required during concomitant use.
Selective serotonin reuptake inhibitors (SSRIs): increased risk of bleeding (see section "Special precautions for use").
Lithium preparations: NSAIDs reduce renal clearance of lithium, thus serum lithium concentration may exceed the toxicity threshold. Serum lithium levels should be monitored, especially at the beginning of treatment, during dose adjustment, and upon discontinuation of therapy.
Cyclosporine: increased cyclosporine concentration in serum. Possible increase in cyclosporine nephrotoxicity due to effects mediated by renal prostaglandins. Renal function should be monitored during combination therapy.
Sulfonylurea derivatives (e.g., glyburide): 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 "Special precautions for use").
Pemetrexed: NSAIDs may reduce renal clearance of pemetrexed, resulting in increased renal and gastrointestinal toxicity and myelosuppression.

Since food intake slows the absorption of lornoxicam, Xefocam® tablets should not be taken with food when a rapid onset of therapeutic effect (pain relief) is required.

Food intake reduces absorption by approximately 20% and increases Tmax (see section "Pharmacological properties. Pharmacokinetics").

Special precautions for use.

Lornoxicam reduces platelet aggregation and prolongs bleeding time. Therefore, caution is required when prescribing to patients with increased susceptibility to bleeding.

Lornoxicam should be prescribed only after careful assessment of the expected therapeutic benefit and potential risks in the following patient groups:

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 "Dosage and administration"). If renal function worsens, lornoxicam therapy should be discontinued.
Patients after extensive surgical procedures, with heart failure, or those taking diuretics or agents that may cause renal damage, require careful monitoring of renal function (see section "Interaction with other medicinal products and other forms of interaction").
Patients with coagulation disorders should undergo careful clinical evaluation and laboratory monitoring (e.g., activated partial thromboplastin time).
Patients with hepatic insufficiency (e.g., liver cirrhosis) should undergo regular laboratory testing after administration of the drug at doses of 12–16 mg/day due to the potential for accumulation of lornoxicam in the body (increased AUC) (see section "Pharmacological properties. Pharmacokinetics"). However, no significant differences in pharmacokinetic parameters have been observed in patients with hepatic insufficiency compared to healthy volunteers.
During long-term treatment (over 3 months) with NSAIDs, regular monitoring of renal and liver function and hematology is recommended.
Elderly patients (aged 65 years and older) should be monitored for renal and liver function. Use with caution after surgical procedures.

Concomitant use of NSAIDs.

Concomitant administration 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").

Minimization of adverse reactions.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Dosage and administration" and the gastrointestinal and cardiovascular risks described below).

Gastrointestinal bleeding, ulcers, and perforations.

During treatment with any NSAID, gastrointestinal bleeding, ulceration, or perforation may occur at any time, with or without warning symptoms or a history of serious gastrointestinal disorders, and may be fatal.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses in patients with a history of peptic ulcers, especially those complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. These patient groups should start treatment with the lowest therapeutic dose (see section "Dosage and administration").

NSAIDs should be used with caution in treating these patient groups and in patients concurrently taking low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal complications (see section "Interaction with other medicinal products and other forms of interaction"). For patients requiring such concomitant therapy, treatment may be combined with protective agents (e.g., misoprostol or proton pump inhibitors). Regular clinical monitoring is recommended.

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding) at the beginning of treatment.

Particular caution is required when prescribing lornoxicam to patients who are concurrently using drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

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 disorders (e.g., ulcerative colitis, Crohn's disease), as their condition may worsen.

Elderly patients.

The frequency of adverse reactions during NSAID use, including gastrointestinal bleeding and perforation, increases in elderly patients and may lead to fatal outcomes (see section "Contraindications").

Cardiovascular and cerebrovascular effects.

Patients with a history of hypertension and/or mild to moderate heart failure should be monitored, as NSAID therapy may be associated with fluid retention and edema.

Clinical studies and epidemiological data suggest that the use of some NSAIDs, particularly long-term therapy and high doses, may be associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There are insufficient data to exclude such a risk with lornoxicam.

Lornoxicam should be prescribed to patients with uncontrolled hypertension, chronic heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disorders only after careful assessment of benefits versus risks. Such an assessment is also required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Concomitant use of NSAIDs and heparin increases the risk of spinal/epidural hematoma during spinal or epidural anesthesia (see section "Interaction with other medicinal products and other forms of interaction").

Skin disorders.

Very rarely, severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during NSAID use, sometimes with fatal outcomes (see section "Adverse reactions"). The risk of such reactions is highest at the beginning of treatment, with most cases occurring within the first month of therapy. Lornoxicam should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

Respiratory disorders.

Use with caution in patients with bronchial asthma or a history of asthma, as NSAIDs have been reported to provoke bronchospasm in such patients.

Systemic lupus erythematosus and mixed connective tissue disease.

Use with caution in patients with systemic lupus erythematosus or mixed connective tissue disease, as there may be an increased risk of aseptic meningitis.

Nephrotoxicity.

Concomitant use of NSAIDs and tacrolimus may increase the risk of nephrotoxicity due to reduced prostacyclin synthesis in the kidneys. Renal function should be closely monitored during combination therapy (see section "Interaction with other medicinal products and other forms of interaction").

Laboratory abnormalities.

Like other NSAIDs, lornoxicam may cause transient elevations in serum transaminases and bilirubin, as well as increased blood urea and creatinine levels and other laboratory parameter deviations. If laboratory abnormalities are significant and persistent, treatment should be discontinued and appropriate investigations performed.

Lactose.

The product contains lactose. It should not be administered to patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Fertility.

Lornoxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for women attempting to conceive. Women experiencing difficulty conceiving or undergoing infertility evaluation should discontinue lornoxicam (see section "Use during pregnancy or breastfeeding").

Chickenpox.

In rare cases, severe skin and soft tissue infections may develop in patients with chickenpox. The potential influence of NSAIDs on worsening such infections cannot currently be excluded. The use of lornoxicam is not recommended in patients with active chickenpox.

Use during pregnancy or breastfeeding.

Pregnancy. Lornoxicam is contraindicated during the third trimester of pregnancy (see section "Contraindications"). There are no clinical data on the use of lornoxicam during the first and second trimesters of pregnancy or during labor; therefore, the drug is not recommended during these periods.

There are insufficient data on the use of lornoxicam in pregnant women. Animal studies have shown reproductive toxicity.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects when prostaglandin synthesis inhibitors are used in early pregnancy. The risk increases with higher doses and duration of therapy. In animals, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryofetal mortality. Prostaglandin synthesis inhibitors should not be used during the first and second trimesters of pregnancy unless absolutely necessary.

Use of lornoxicam from the 20th week of pregnancy may cause oligohydramnios due to impaired fetal renal function. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug. Additionally, fetal arterial duct constriction has been reported after drug use in the second trimester, which mostly resolves after stopping treatment. Therefore, lornoxicam should not be used during the first and second trimesters unless clearly necessary. If lornoxicam is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of lornoxicam exposure starting from the 20th gestational week. Lornoxicam should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, the use of any prostaglandin synthesis inhibitor may affect the fetus as follows:

Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
Renal dysfunction (see above).

The mother and fetus near term may be affected as follows when prostaglandin synthesis inhibitors are used:

Prolonged bleeding time, anti-aggregatory effect (which may occur even at very low doses), and increased bleeding time;
Inhibition of uterine contractility, which may lead to delayed or prolonged labor.

Therefore, the use of lornoxicam is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding period. There are no data on the excretion of lornoxicam into human breast milk. High concentrations of lornoxicam are excreted into the milk of lactating rats. Lornoxicam should not be used during breastfeeding.

Fertility.

The use of lornoxicam, like any drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for women attempting to conceive. For women experiencing difficulty conceiving or undergoing infertility evaluation, discontinuation of lornoxicam should be considered.

Ability to affect reaction speed when driving or operating machinery. If dizziness and/or drowsiness occur after taking lornoxicam, patients should not drive or operate machinery.

Method of Administration and Dosage

The appropriate dosage regimen for all patients should be based on individual response to treatment. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Pain

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

Osteoarthritis and rheumatoid arthritis

Recommended initial daily dose is 12 mg of lornoxicam, divided into 2–3 doses.

The maintenance dose should not exceed 16 mg per day.

Film-coated tablets of Xefoсam® should be taken with sufficient amount of water.

Elderly patients (over 65 years of age) without impaired liver or kidney function do not require dose adjustment; however, lornoxicam should be used with caution, as gastrointestinal adverse reactions are less well tolerated in this patient group.

Renal impairment. In patients with mild to moderate renal impairment, the maximum recommended daily dose is 12 mg, divided into 2–3 doses. Lornoxicam is contraindicated in patients with severe renal impairment (see section "Contraindications").

Hepatic impairment. In patients with moderate hepatic impairment, the maximum recommended daily dose is 12 mg, divided into 2–3 doses (see section "Special Warnings and Precautions for Use"). Lornoxicam is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Children. Lornoxicam is not recommended for use in children under 18 years of age due to insufficient data on efficacy and safety.

Overdose.

Currently, there are no data on lornoxicam overdose sufficient to determine its consequences or to recommend specific treatment. However, symptoms following overdose may include: nausea, vomiting, and central nervous system symptoms (dizziness, visual disturbances). In severe cases, ataxia (progressing to coma and convulsions), liver and kidney damage may occur; blood coagulation disorders are also potentially possible.

In cases of actual or suspected overdose, administration of the drug should be discontinued. Due to the short elimination half-life, lornoxicam is rapidly eliminated from the body. It is not dialyzable. There is currently no specific antidote. Standard emergency measures should be implemented. According to general principles, only the administration of activated charcoal, if taken immediately after overdose, may reduce drug absorption. For the treatment of gastrointestinal disturbances, a prostaglandin analogue or ranitidine may be used, for example.

Side effects.

The most common adverse reactions to NSAIDs are gastrointestinal in nature. Peptic ulcers, perforation, or gastrointestinal bleeding may occur during NSAID therapy, sometimes resulting in fatal outcomes, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis or Crohn’s disease have been reported during treatment with NSAIDs. Gastritis has been observed less frequently.

Approximately 20% of patients treated with lornoxicam may experience adverse events. The most commonly reported adverse events include nausea, dyspepsia, digestive disturbances, abdominal pain, vomiting, and diarrhea. These symptoms were generally observed in less than 10% of patients participating in clinical studies.

Edema, arterial hypertension, and heart failure have been reported during NSAID therapy.

Clinical studies and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and during prolonged treatment, may be associated with an increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

Rarely, serious skin and soft tissue infections have been reported during the course of varicella (chickenpox).

Adverse reactions are classified by frequency as follows: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), not known (cannot be estimated from available data).

Infections and infestations.

Rare: pharyngitis.

Blood and lymphatic system disorders.

Uncommon: anemia, thrombocytopenia, leukopenia, prolonged bleeding time.

Very rare: ecchymosis. NSAIDs may cause potentially severe hematological disorders specific to this class of drugs, such as neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia.

Immune system disorders.

Rare: hypersensitivity, including anaphylactoid reactions and anaphylaxis.

Metabolism and nutrition disorders.

Uncommon: loss of appetite, weight changes.

Psychiatric disorders.

Uncommon: insomnia, depression.

Rare: confusion, nervousness, restlessness.

Nervous system disorders.

Common: mild and transient headache, dizziness.

Rare: somnolence, paraesthesia, taste disturbances (dysgeusia), tremor, migraine.

Very rare: aseptic meningitis in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (see section "Special precautions").

Eye disorders.

Common: conjunctivitis.

Rare: visual disturbances.

Ear and labyrinth disorders.

Uncommon: vertigo, tinnitus.

Cardiovascular disorders.

Uncommon: palpitations, tachycardia, edema, heart failure, facial flushing (see section "Special precautions").

Rare: hypertension, hot flushes, hemorrhage, hematomas.

Respiratory system disorders.

Uncommon: rhinitis.

Rare: dyspnea, cough, bronchospasm.

Gastrointestinal disorders.

Common: nausea, abdominal pain, dyspepsia, diarrhea, vomiting.

Uncommon: constipation, flatulence, belching, dry mouth, gastritis, gastric ulcer, upper abdominal pain, duodenal ulcer, oral mucosal ulcers.

Rare: melena, vomiting blood, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, perforation of peptic ulcer, gastrointestinal bleeding.

Hepatobiliary disorders.

Uncommon: increased levels of liver enzymes (ALT, AST).

Very rare: hepatotoxicity, which may lead to liver failure, hepatitis, jaundice, or cholestasis.

Skin and subcutaneous tissue disorders.

Uncommon: rash, pruritus, increased sweating, erythematous rash, urticaria, angioneurotic edema, alopecia.

Rare: dermatitis, eczema, purpura.

Very rare: swelling and bullous reactions such as erythema multiforme, 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 levels.

Very rare: lornoxicam may cause acute renal failure in patients with conditions dependent on renal prostaglandins, which play an important role in maintaining renal blood flow (see section "Special precautions"). Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, is an effect specific to NSAIDs.

General disorders.

Uncommon: malaise, facial edema.

Rare: asthenia.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children!

Packaging. 10 tablets per blister. 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Takeda GmbH, manufacturing site Oranienburg, Germany / Takeda GmbH Betriebsstätte Oranienburg, Germany.

Manufacturer's address. Lehnitzstrasse 70-98, 16515 Oranienburg, Germany.