Lornado

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LORNADO (LORNADO)

Composition:

active substance: lornoxicam;

1 vial contains lornoxicam 8 mg;

excipients: mannitol (E 421), tromethamine, disodium edetate;

1 ampoule (2 ml) of solvent contains water for injections.

Medicinal form. Lyophilisate for solution for injection.

Main physico-chemical properties:

lyophilisate – yellow lyophilized powder;

solvent – colorless clear solution;

reconstituted solution – clear greenish-yellow solution practically free from particles.

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. Its mechanism of action is primarily related to inhibition of prostaglandin synthesis (inhibition of the enzyme cyclooxygenase), resulting in desensitization of peripheral nociceptors and inhibition 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 its development.

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

Pharmacokinetics

Absorption

Lornoxicam in the form of 8 mg powder for injection is intended for intravenous and intramuscular administration. After intramuscular administration, maximum plasma concentration (Cmax) of 8 mg lornoxicam is reached in approximately 0.4 hours. Absolute bioavailability (calculated from 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 by hydroxylation, predominantly into the inactive metabolite 5-hydroxy-lornoxicam. Lornoxicam undergoes biotransformation involving cytochrome CYP2C9. Due to genetic polymorphism, individuals with slow and extensive metabolism of this enzyme exist, which may result in a marked increase in plasma levels of lornoxicam in individuals with slow metabolism. The hydroxylated metabolite has no pharmacological activity. Lornoxicam is completely metabolized. Approximately two-thirds is excreted via the liver and one-third via the kidneys as inactive compounds. Studies in animal models have shown that lornoxicam does not induce hepatic enzymes. Clinical studies have not shown evidence of accumulation of lornoxicam after repeated administration of recommended doses. The absence of accumulation has been 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, 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.

Special Patient Populations

Elderly Patients

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

Patients with Hepatic and/or Renal Impairment

There is no significant 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 acute mild to moderate pain in adults.

Contraindications

• Hypersensitivity to the active substance and/or to any of the excipients of the medicinal product.
• Hypersensitivity (symptoms similar to those observed in asthma, rhinitis, angioedema or urticaria) to other NSAIDs, including acetylsalicylic acid.
• Gastrointestinal bleeding, cerebrovascular or other hemorrhages.
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Active recurrent peptic ulcer/gastrointestinal bleeding or history of recurrent peptic ulcer/gastrointestinal bleeding (two or more distinct documented episodes of ulceration or bleeding).
• Thrombocytopenia.
• Severe heart failure.
• Severe hepatic impairment.
• Severe renal impairment (plasma creatinine level > 700 µmol/L).
• Third trimester of pregnancy (see section "Use during pregnancy or lactation").

Special precautions

The injection solution is prepared immediately before use (the contents of 1 vial (8 mg of lyophilisate) are dissolved in water for injections (2 mL)). The appearance of the reconstituted medicinal product is a clear greenish-yellow solution practically free from particles.

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

Interaction with other medicinal products and other types of interactions

The following interactions may occur when used concomitantly with lornoxicam.

Cimetidine

Concomitant use may increase plasma levels of lornoxicam, potentially increasing the risk of adverse effects of lornoxicam (no interactions were observed between lornoxicam and ranitidine or between lornoxicam and antacids).

Anticoagulants

Concomitant use 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 recommended when these medicinal products are used concomitantly.

Phenprocoumon

Concomitant use may reduce the effectiveness of phenprocoumon treatment.

Heparin

Concomitant use may increase the risk of bleeding and the risk of spinal/epidural hematoma during spinal or epidural anesthesia (see section "Special warnings and precautions for use").

Angiotensin-converting enzyme (ACE) inhibitors

Concomitant use may reduce the effect of ACE inhibitors.

Diuretics

Concomitant use may reduce the diuretic and antihypertensive effects of loop, thiazide, and potassium-sparing diuretics (increased risk of hyperkalemia and nephrotoxicity).

Beta-adrenergic blockers

Concomitant use may reduce the antihypertensive effect of beta-blockers.

Angiotensin II receptor blockers

Concomitant use may reduce the antihypertensive effect of angiotensin II receptor blockers.

Digoxin

Concomitant use may reduce renal clearance of digoxin, increasing the risk of digoxin toxicity.

Corticosteroids

Concomitant use may increase the risk of gastrointestinal ulcers or bleeding (see section "Special warnings and precautions for use").

Quinolone antibacterial agents (e.g., levofloxacin, ofloxacin)

Concomitant use may increase the risk of seizures.

Antiplatelet agents (e.g., clopidogrel)

Concomitant use increases the risk of bleeding (see section "Special warnings and precautions for use").

Other NSAIDs

Concomitant use increases the risk of gastrointestinal bleeding or ulcers.

Methotrexate

Concomitant use increases methotrexate plasma levels, leading to increased toxicity. Careful monitoring of the patient is recommended when these medicinal products are used concomitantly.

Selective serotonin reuptake inhibitors (SSRIs)

Concomitant use increases the risk of bleeding (see section "Special warnings and precautions for use").

Lithium preparations

Concomitant use reduces renal clearance of lithium, potentially resulting in plasma lithium concentrations exceeding the toxic threshold. Plasma lithium levels should be monitored when these medicinal products are used concomitantly, especially at the beginning of treatment, during dose adjustments, and upon discontinuation of therapy.

Cyclosporine

Concomitant use may increase cyclosporine plasma levels and its nephrotoxicity, due to effects mediated by renal prostaglandins. Careful monitoring of renal function is recommended when these medicinal products are used concomitantly.

Sulfonylurea derivatives (e.g., glyburide)

Concomitant use increases the 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

Concomitant use increases the risk of nephrotoxicity due to reduced renal prostacyclin synthesis. Renal function should be monitored when these medicinal products are used concomitantly (see section "Special warnings and precautions for use").

Pemetrexed

Concomitant use may reduce renal clearance of pemetrexed, thereby increasing renal, gastrointestinal toxicity, and myelosuppression.

Special precautions for use

Lornoxicam inhibits platelet aggregation, thereby prolonging blood clotting time. The medicinal product should be used with caution in patients with a tendency to bleeding.

The medicinal product should be administered only after careful assessment of the expected therapeutic benefit versus potential risk in the following conditions:

• Patients with renal impairment: the medicinal product should be used with caution in patients with mild (plasma creatinine level 150–300 µmol/L) and moderate renal insufficiency (plasma creatininе level 300–700 µmol/L) due to the important role of prostaglandins in maintaining renal blood flow (see section "Method of administration and dosage"). In case of renal function impairment, the use of the medicinal product should be discontinued.
• Patients after extensive surgical procedures, with heart failure, or those taking diuretics or medicinal products that may cause renal damage: renal function should be closely monitored during treatment (see section "Interaction with other medicinal products and other forms of interaction").
• Patients with coagulation disorders: careful clinical monitoring and laboratory assessment (e.g., activated partial thromboplastin time) are recommended during treatment.
• Patients with hepatic insufficiency (e.g., liver cirrhosis): regular laboratory testing is recommended when administering lornoxicam at a dose of 12–16 mg per day due to the potential for accumulation of lornoxicam 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): monitoring of renal and hepatic function is recommended during treatment. Use with caution after surgical procedures.

Concomitant use with other NSAIDs

Avoid concomitant administration of the medicinal product with other NSAIDs, including selective cyclooxygenase-2 inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Minimizing adverse reactions

Adverse reactions can be minimized by using the lowest effective dose of lornoxicam for the shortest duration necessary to control disease symptoms (see section "Method of administration and dosage" and the information below regarding gastrointestinal and cardiovascular risks).

Gastrointestinal bleeding, ulcers, and perforations

During treatment with any NSAID (including lornoxicam), gastrointestinal bleeding, ulcers, or perforations 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, ulcers, or perforations 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. Treatment in such patients should be initiated with particular caution and at the lowest therapeutic doses (see section "Method of administration and dosage").

The medicinal product should be used with caution in 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 administered with concomitant gastroprotective agents, such as misoprostol or proton pump inhibitors (see section "Interaction with other medicinal products and other forms of interaction"). Clinical monitoring at regular intervals is recommended.

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

The medicinal product should be used with particular caution in patients concurrently taking drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents, including acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking lornoxicam, the medicinal product should be discontinued.

The medicinal product 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 (see section "Adverse reactions").

Elderly patients

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

Cardiovascular and cerebrovascular effects

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should be closely monitored during treatment, as NSAID therapy may lead to fluid retention and edema.

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

The medicinal product should be administered only after careful evaluation of benefits versus risks in patients with uncontrolled arterial hypertension, chronic heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disorders. Such evaluation is also required before prolonged treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Concomitant use of lornoxicam with 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 may occur during lornoxicam treatment, sometimes with fatal outcomes (see section "Adverse reactions"). The risk of such reactions is highest at the beginning of treatment: most cases occur within the first month of lornoxicam use. The medicinal product should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

Respiratory disorders

The medicinal product should be used 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

During lornoxicam use in patients with systemic lupus erythematosus or mixed connective tissue disease, the risk of aseptic meningitis may increase.

Nephrotoxicity

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

Laboratory abnormalities

During lornoxicam treatment, transient elevations in transaminases and plasma bilirubin, as well as increased plasma urea and creatinine levels and other laboratory parameter deviations from normal may occur. If laboratory abnormalities are significant and persistent, the medicinal product should be discontinued and appropriate investigations initiated.

Fertility

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

Chickenpox

In rare cases, severe skin and soft tissue infections may develop in patients with chickenpox. NSAIDs may also potentially worsen the course of such infectious conditions. Use of the medicinal product should be avoided in patients with active chickenpox.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product 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 and during labor; therefore, the medicinal product is not recommended for use 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 indicate an increased risk of pregnancy loss and congenital heart defects with the use of prostaglandin synthesis inhibitors during early pregnancy. The risk increases with higher doses and longer duration of treatment. In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation embryo loss and embryofetal mortality. Prostaglandin synthesis inhibitors should not be used during the first and second trimesters of pregnancy. Use should be limited to cases of extreme necessity.

Starting from the 20th week of pregnancy, lornoxicam use may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following second-trimester treatment, most of which resolved after stopping treatment. Therefore, lornoxicam should not be used during the first and second trimesters of pregnancy unless absolutely necessary.

If lornoxicam is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of lornoxicam exposure starting from the 20th gestational week. The medicinal product should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

• Cardio-pulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• Renal dysfunction, which may progress to renal failure with development of oligohydramnios (see above).

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

• Possible prolongation of bleeding time, antiplatelet 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 the medicinal product 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 in the milk of lactating rats. The medicinal product 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 affect reaction speed when driving or operating machinery

If dizziness and/or somnolence occur during treatment with the medicinal product, driving or operating machinery should be avoided.

Method of Administration and Dosage

The medicinal product should be used for initial therapy and when rapid onset of analgesic effect is required or when oral administration is not feasible. In general, treatment should include only one injection to initiate therapy.

Adverse reactions can be minimized by using the lowest effective dose of lornoxicam for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Reconstitution of the lyophilisate with solvent must be performed under appropriate conditions ensuring microbiological purity.

After reconstitution, the ready-to-use (reconstituted) solution should be used immediately.

Dosage

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

The recommended dose of the medicinal product is 8 mg administered intravenously or intramuscularly. The maximum daily dose is 16 mg. Some patients may require an additional 8 mg dose within the first 24 hours.

Elderly patients (aged 65 years and older)

Elderly patients without hepatic or renal impairment do not require dose adjustment; however, lornoxicam should be used with caution in this patient group, as gastrointestinal adverse reactions are less well tolerated.

Patients with renal impairment

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

Patients with hepatic impairment

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

Method of Administration

The medicinal product is intended for intravenous or intramuscular administration. The intravenous injection should last at least 15 seconds, and the intramuscular injection should last at least 5 seconds.

After reconstitution, the needle should be replaced.

For intramuscular injection, a long needle is required to ensure deep injection.

The reconstituted medicinal product is intended for single use only.

The injection solution should be prepared immediately before use (the contents of one vial (8 mg lyophilisate) should be dissolved in 2 ml of water for injections).

Children

The medicinal product is not recommended for use in children under 18 years of age due to insufficient clinical data on the efficacy and safety of lornoxicam.

Overdose

Currently, there are no data on overdose that would allow determination of its consequences or suggest specific treatment. However, symptoms of lornoxicam overdose may include: nausea, vomiting, central nervous system symptoms (dizziness, visual disturbances); in severe cases – ataxia progressing to coma and seizures; hepatic and renal damage, and possible impairment of blood coagulation.

In the case of actual or suspected overdose, administration of the medicinal product 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. For the treatment of gastrointestinal disturbances, for example, a prostaglandin analogue or ranitidine may be used.

Adverse Reactions

The most common adverse reactions associated with NSAIDs involve 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 reactions. The most commonly reported adverse reactions 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 treatment with NSAIDs.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and during long-term 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").

Rarely, severe skin and soft tissue infections have been reported during varicella (chickenpox) infection.

Adverse reactions are classified by frequency 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); frequency 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 class-specific, potentially serious hematological disorders such as neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia.

Immune system disorders:

rare – hypersensitivity reactions, anaphylactoid reactions, and anaphylaxis.

Metabolism and nutrition disorders:

uncommon – loss of appetite, weight changes.

Psychiatric disorders:

uncommon – insomnia, depression; rare – confusion, nervousness, agitation.

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) and mixed connective tissue disease (see section "Special Warnings and Precautions for Use").

Eye disorders:

uncommon – conjunctivitis; rare – visual disturbances.

Ear and labyrinth disorders:

uncommon – vertigo, tinnitus.

Cardiac disorders:

uncommon – palpitations, tachycardia, edema, heart failure, facial flushing; rare – hypertension, hot flushes, hemorrhage, hematomas.

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 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, angioedema, alopecia; rare – dermatitis, eczema, purpura; very rare – swelling and bullous reactions such as Stevens-Johnson syndrome and 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.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

Lyophilisate for injection solution in vial – 3 years.

Solvent in ampoule – 5 years.

The reconstituted solution should be used immediately after preparation.

Storage conditions

Store at temperatures not exceeding 25°C, in the original packaging, and in a place inaccessible to children.

Incompatibilities

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

Packaging

Each pack contains 8 mg lyophilisate for injection solution in a vial and 2 ml solvent (water for injection) in an ampoule;

1 vial of lyophilisate for injection solution and 1 ampoule of solvent in a cardboard box;

3 vials of lyophilisate for injection solution and 3 ampoules of solvent in a blister pack, 1 blister pack in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mefar Ilac San. A.S.

Manufacturer's address and place of business

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.