Xefocam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSEFOCAM® (XEFOCAM®)

Composition:

Active substance: lornoxicam;

1 vial contains 8 mg of lornoxicam;

Excipients: mannitol (E 421), trometamol, disodium edetate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: yellowish solid mass.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs. Oxicams. ATC code M01A C05.

Pharmacological properties.

Pharmacodynamics.

Lornoxicam is a non-steroidal anti-inflammatory agent 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 inhibition of inflammation. A central effect on nociceptors, unrelated to anti-inflammatory action, is also presumed. Lornoxicam does not affect vital parameters (e.g., body temperature, respiratory rate, heart rate, blood pressure, ECG, spirometry).

Analgesic properties of lornoxicam have been successfully demonstrated in several clinical studies during drug development.

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

Pharmacokinetics.

Absorption.
Lornoxicam in the form of an 8 mg injection powder is intended for intravenous and intramuscular administration. Maximum plasma concentration (Cmax) after intramuscular administration is reached approximately within 0.4 hours. Absolute bioavailability (calculated based on the area under the plasma concentration-time curve (AUC)) after intramuscular administration is 97%.

Distribution.
In plasma, lornoxicam is present in unchanged form and as the inactive form of its hydroxylated metabolite. Protein binding of lornoxicam to plasma proteins 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 inactive 5-hydroxy-lornoxicam. Lornoxicam undergoes biotransformation involving cytochrome CYP2C9. The metabolism of this enzyme may be slow or extensive in different individuals due to genetic polymorphism, potentially leading to a significant increase in plasma levels of lornoxicam in individuals with slow metabolism. 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. Based on clinical study results, there is no evidence of accumulation of lornoxicam after repeated administration of recommended doses. These findings were confirmed by safety and efficacy monitoring data from 1-year studies.

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 kidneys, mainly 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), 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 kinetic 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.

Contraindications.

• Hypersensitivity to lornoxicam or to any component of the medicinal product;
• thrombocytopenia;
• hypersensitivity (symptoms similar to those seen in 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 associated with prior NSAID therapy;
• active recurrent gastric/duodenal ulcer or bleeding, or history of recurrent gastric/duoden/ulcer or bleeding (two or more separate episodes of confirmed 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 breastfeeding").

Special precautions. The injection solution should be prepared immediately before use (the contents of 1 vial (8 mg lyophilisate) are dissolved in water for injections (2 mL)). The appearance of the reconstituted preparation is a clear yellow solution, free from visible particles.

If visible signs of deterioration of the medicinal product are present, it should be disposed of according to local requirements.

Interaction with other medicinal products and other types of interactions.

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 warnings and 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 occurrence of 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: 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: 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 antibiotics (e.g., levofloxacin, ofloxacin): increased risk of seizures.
• Antiplatelet agents (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 concentration 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 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 treatment.
• Cyclosporine: increased serum concentration of cyclosporine. 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 "Metabolism").
• Tacrolimus: increased risk of nephrotoxicity due to decreased renal prostacyclin synthesis. Renal function should be monitored during combination therapy (see section "Special warnings and precautions for use").
• Pemetrexed: NSAIDs may reduce renal clearance of pemetrexed, thereby increasing renal, gastrointestinal toxicity, and myelosuppression.

Special precautions for use.

Lornoxicam reduces platelet aggregation and prolongs bleeding time. Therefore, caution should be exercised when prescribing to patients with an increased risk of bleeding.

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

• Patients with renal impairment: lornoxicam should be used with caution in patients with mild (serum creatinine 150–300 μmol/L) and moderate renal insufficiency (serum creatinine 300–700 μmol/L) due to the important role of prostaglandins in maintaining renal blood flow (see section "Dosage and administration"). If renal function deteriorates, 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").
• In patients with coagulation disorders, careful clinical evaluation and laboratory monitoring (e.g., activated partial thromboplastin time) are recommended.
• In patients with hepatic insufficiency (e.g., liver cirrhosis), regular laboratory testing is recommended after administration of the drug at doses of 12–16 mg per day due to the potential for lornoxicam accumulation in the body (increased AUC) (see section "Pharmacological properties. Pharmacokinetics"). However, no deviations in pharmacokinetic parameters have been observed in patients with hepatic insufficiency compared to healthy volunteers.
• Elderly patients (aged 65 years and older) should be monitored for renal and hepatic 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 information below regarding gastrointestinal and cardiovascular risks).

Gastrointestinal bleeding, ulcers, and perforation.

During treatment with any NSAID, gastrointestinal bleeding, ulceration, or perforation may occur at any time during therapy, with or without warning symptoms, and even in patients without prior history of gastrointestinal disorders. These events may be fatal.

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

NSAIDs should be used with caution in treating these patient groups and in patients concurrently taking low-dose acetylsalicylic acid or other agents 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 administered with concomitant use of 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 the drug to patients who are concurrently using medications 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 cautiously in patients with a history of gastrointestinal disorders (e.g., ulcerative colitis, Crohn’s disease), as their condition may worsen.

Elderly patients.

In elderly patients, the frequency of adverse reactions during NSAID use increases, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "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 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 is 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 evaluation of indications. Such evaluation is also required before initiating long-term treatment in patients with risk factors for cardiovascular disease (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 have been reported during NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some of which have been fatal (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 drug use. 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 this condition, 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 and 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 renal prostacyclin synthesis. Renal function should be closely monitored during such 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.

Fertility.

Lornoxicam, like other agents 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 during chickenpox. At present, the potential influence of NSAIDs on the worsening of these infections cannot be excluded. The use of lornoxicam is not recommended during 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 with the use of prostaglandin synthesis inhibitors during early pregnancy. The risk increases with higher dose 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. Use is only justified in cases of extreme necessity.

Administration 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 ductus arteriosus constriction has been reported after drug use during the second trimester, which typically resolves after stopping treatment. Therefore, lornoxicam should not be used during the first and second trimesters unless absolutely necessary. If lornoxicam is used by a woman trying to conceive or during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible. Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to lornoxicam for several days starting from the 20th gestational week. Lornoxicam should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

• Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function (see above).

The mother and fetus near term may be affected as follows by prostaglandin synthesis inhibitors:

• Possible prolongation of 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. Relatively high concentrations of lornoxicam are excreted in 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. Women experiencing difficulty conceiving or undergoing infertility evaluation should consider discontinuing lornoxicam.

Ability to influence reaction speed when driving or operating machinery.
If dizziness and/or drowsiness occur after taking lornoxicam, driving or operating machinery should be avoided.

Method of Administration and Dosage

This pharmaceutical form of the drug is intended for initiating therapy and when rapid achievement of analgesic effect is required, or when oral administration of drugs is not possible. In general, treatment should include only one injection to initiate therapy. For all patients, the appropriate dosage regimen 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").

This pharmaceutical form is intended for intravenous and intramuscular administration.

The recommended dose is 8 mg administered intravenously or intramuscularly. The daily dose should not exceed 16 mg. Some patients may require an additional dose of 8 mg within the first 24 hours.

The duration of intravenous administration of the solution should be at least 15 seconds; intramuscular administration should last at least 5 seconds.

After preparing the solution, the needle should be replaced.

For intramuscular injection, a long needle ensuring deep injection is required.

The diluted medicinal product is intended for single use only.

The injection solution should be prepared immediately before use (the contents of 1 vial (8 mg of lyophilisate) should be dissolved in 2 ml of water for injections). After preparation, a clear yellow solution should be obtained. If the medicinal product shows signs of deterioration, it should be disposed of according to local requirements.

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 in this patient group, as gastrointestinal adverse reactions are less well tolerated in elderly patients.

Renal impairment. Patients with mild to moderate renal impairment require a reduced dose of the drug. Lornoxicam is contraindicated in patients with severe renal impairment (see section "Contraindications").

Hepatic impairment. Patients with moderate hepatic impairment require a reduced dose of the drug. Lornoxicam is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Children.
The drug is not recommended for use in children under 18 years of age due to insufficient clinical 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 expected following lornoxicam overdose may include nausea, vomiting, and central nervous system symptoms (dizziness, visual disturbances). In severe cases, ataxia (progressing to coma and seizures), liver and kidney injury, and potentially impaired blood coagulation may occur.

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. Currently, no specific antidote is known. For the treatment of gastrointestinal disorders, for example, a prostaglandin analogue or ranitidine may be used.

Adverse Reactions

The most common adverse reactions associated with NSAIDs involved the gastrointestinal tract. Peptic ulcers, perforation, or gastrointestinal bleeding may occur during NSAID therapy, sometimes resulting in fatal outcomes, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbations of colitis and 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 effects. The most commonly reported adverse effects 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 trials and epidemiological data suggest that the use of certain NSAIDs, especially 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 Warnings and Precautions for Use").

Very rarely, serious skin and soft tissue infections have been reported during varicella (chickenpox) infection.

Adverse effects are classified by frequency of occurrence as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Infections and infestations

Rare: pharyngitis

Blood and lymphatic system disorders

Rare: anemia, thrombocytopenia, leukopenia, prolonged bleeding time

Very rare: ecchymosis. NSAIDs may cause potentially severe hematological disorders specific to this class of drugs, including 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, paresthesia, taste disturbances (dysgeusia), tremor, migraine

Very rare: aseptic meningitis in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (see section "Special Warnings and Precautions for Use")

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 Warnings and Precautions for Use")

Rare: hypertension, hot flushes, hemorrhage, hematoma

Respiratory, thoracic and mediastinal 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 ulceration

Rare: melena, hematemesis, stomatitis, esophagitis, gastroesophageal reflux, dysphagia, aphthous stomatitis, glossitis, peptic ulcer perforation, gastrointestinal hemorrhage

Hepatobiliary disorders

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

Very rare: hepatotoxicity, which may lead to liver failure, hepatitis, jaundice, and 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, 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 Warnings and Precautions for Use"). Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, is a class-specific effect of NSAIDs.

General disorders and administration site conditions

Uncommon: malaise, facial edema

Rare: asthenia

Shelf life
3 years

Reconstituted solution: chemical and physical stability of the reconstituted solution has been demonstrated for 24 hours at 2–8 °C. From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and storage conditions prior to use are the responsibility of the user.

Incompatibilities
This medicinal product should not be mixed with other medicinal products except as specified in the instructions for medical use.

Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children!

Packaging
5 vials in a cardboard box.

Prescription status
Prescription only.

Manufacturer
Takeda Austria GmbH, Austria

Address of the manufacturer and location of business operations
St. Peter-Strasse 25, 4020 Linz, Austria