Ketolizin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOLYSINE® (KETOLYSINE®)

Composition:

Active substance: ketoprofen lysine salt;

1 sachet contains 80 mg of ketoprofen lysine salt, equivalent to 50 mg of ketoprofen;

Excipients: sorbitol, sodium chloride, colloidal anhydrous silicon dioxide, sodium saccharin, peppermint flavor.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white or yellowish granular powder with a smell of mint and anise.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives.

ATC code M01AE03.

Pharmacological Properties

Pharmacodynamics

Lysine salt of ketoprofen is the lysine salt of 2-(3-benzoylphenyl)-propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects; it belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). The lysine salt of ketoprofen is more soluble than ketoprofen acid.

The lysine salt of ketoprofen has pronounced analgesic activity, which correlates with both anti-inflammatory and central effects. The lysine salt of ketoprofen exerts antipyretic action without affecting normal thermoregulatory processes. Painful inflammatory symptoms are eliminated or alleviated, promoting joint mobility.

The mechanism of action of NSAIDs is associated with reduced synthesis of prostaglandins due to inhibition of cyclooxygenase activity.

Specifically, NSAIDs inhibit the conversion of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which form prostaglandins PGEb, PGE2, PGF2, and PGD2, as well as prostacyclin PGI2 and thromboxanes (TxA2 and TxB2). In addition, inhibition of prostaglandin synthesis may affect other mediators of inflammation, such as kinins, providing not only direct but also indirect action.

Pharmacokinetics

The lysine salt of ketoprofen has high solubility compared to ketoprofen acid.

Absorption

The granules for oral solution formulation allows administration of the active ingredient already in aqueous solution. This promotes rapid increase in plasma concentrations and fast achievement of peak plasma concentration. Clinically, this is manifested as a faster onset and enhanced intensity of analgesic and anti-inflammatory effects.

Distribution

Repeated administration does not alter the drug's kinetics and does not lead to accumulation.

Ketoprofen is 95–99% bound to plasma proteins.

After systemic administration, significant levels of ketoprofen have been detected in tonsillar tissues and synovial fluid.

Metabolism

Ketoprofen is extensively metabolized: 60–80% of the active substance administered systemically is excreted from the body in the form of metabolites in urine.

Excretion

Excretion is rapid and occurs primarily via the kidneys: 50% of the active substance administered systemically is excreted from the body in urine within 6 hours.

Children

The kinetic profile in children does not differ from that in adults.

Clinical characteristics.

Indications.

For symptomatic treatment of inflammation associated with pain, including: rheumatoid arthritis, ankylosing spondylitis, pain in osteoarthritis, periarticular rheumatism, post-traumatic inflammation, pain in inflammatory conditions in dentistry, otolaryngology, urology, and pulmonology.

Contraindications.

KETOLIZIN**®** should not be prescribed in the following cases:

• Hypersensitivity to the active substance, to other nonsteroidal anti-inflammatory drugs (NSAIDs), or to any of the excipients.
• History of hypersensitivity reactions such as bronchospasm, asthma attacks, acute rhinitis, urticaria, nasal polyps, angioneurotic edema, or other allergic-type reactions to ketoprofen or substances with a similar mechanism of action (e.g., acetylsalicylic acid or other NSAIDs).
• Bronchial asthma.
• Severe heart failure.
• Active peptic ulcer/bleeding or history of bleeding/recurrent gastric ulcer (two or more separate episodes, signs of bleeding or ulcers).
• Gastrointestinal bleeding, ulcer, or perforation, or chronic dyspepsia in medical history.
• History of gastrointestinal bleeding or perforation due to previous NSAID therapy.
• Leukopenia and thrombocytopenia.
• Coagulation disorders.
• Crohn’s disease or ulcerative colitis.
• Gastritis.
• Severe hepatic insufficiency (liver cirrhosis, severe hepatitis).
• Severe hemorrhagic diathesis, renal insufficiency, and other blood coagulation disorders during intensive diuretic therapy.
• Third trimester of pregnancy.
• Patient age under 18 years.

Interaction with other medicinal products and other forms of interaction.

Medicinal product combinations not recommended

Other NSAIDs (including selective cyclooxygenase-2 inhibitors) and high-dose salicylates (> 3 g/day)

Increased risk of gastrointestinal ulcers and bleeding.

Anticoagulants (heparin and warfarin) and antiplatelet agents (e.g., ticlopidine, clopidogrel)

NSAIDs may potentiate the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Increased risk of gastrointestinal bleeding due to inhibition of platelet function and damage to the gastrointestinal mucosa (see section "Special precautions for use"). If concomitant use cannot be avoided, regular monitoring of the patient's condition is required.

Lithium preparations

Risk of increased plasma lithium concentration, sometimes to toxic levels, due to reduced renal lithium excretion. If combination therapy is necessary, plasma lithium levels should be closely monitored during and after NSAID therapy, and lithium dosage adjustments may be needed.

Combination with methotrexate at doses of 15 mg/week or higher

Increased risk of methotrexate hematological toxicity, particularly with high doses (> 15 mg/week), possibly due to displacement of methotrexate from plasma protein binding and reduced renal clearance. A 12-hour interval between administration of ketoprofen and methotrexate is required.

Hydantoins (e.g., phenytoin) and sulfonamides

Toxic effects of these substances may be increased.

Medicinal product combinations requiring caution

Medicinal products that may cause hyperkalemia

Some medicinal products may cause hyperkalemia, e.g.: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins (low molecular weight or unfractionated), cyclosporine, tacrolimus, and trimethoprim. The occurrence of hyperkalemia may depend on additional factors. The risk increases when the above-mentioned medicinal products are used concomitantly.

Tenofovir

Concomitant use of tenofovir disoproxil fumarate and NSAIDs increases the risk of renal failure.

ACE inhibitors and angiotensin II receptor antagonists

In patients with impaired renal function (e.g., dehydrated patients or elderly patients), concomitant use of an ACE inhibitor or angiotensin II receptor antagonists with medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure. Such patients should receive adequate hydration before starting combination therapy, and renal function should be monitored after initiation of therapy.

Corticosteroids

Increased risk of gastrointestinal bleeding or ulcers (see section "Special precautions for use").

Diuretics

Patients receiving diuretics, especially dehydrated patients, are at increased risk of developing renal failure due to reduced renal blood flow caused by inhibition of prostaglandin synthesis. Such patients should receive adequate hydration before starting combination therapy, and renal function should be monitored after therapy initiation (see section "Special precautions for use"). NSAIDs may reduce the efficacy of diuretics.

Combination with methotrexate at doses below 15 mg/week

Increased hematological toxicity of methotrexate due to reduced renal clearance caused by anti-inflammatory agents in general. Blood tests should be performed weekly during the first weeks of combination therapy. Monitoring should be more frequent in patients with changing renal function and in elderly patients.

Pentoxifylline

Increased risk of bleeding. Intensive clinical monitoring and frequent assessment of bleeding time are required.

Zidovudine

Risk of increased toxic effects on erythrocytes due to effects on reticulocytes, potentially leading to severe anemia within a week of NSAID administration. Blood parameters, including reticulocyte count, should be monitored during the first 1–2 weeks after initiation of lysine salt of ketoprofen therapy.

Sulfonylurea preparations

NSAIDs may enhance the hypoglycemic effect of sulfonylurea drugs by displacing them from plasma protein binding sites.

Cardiac glycosides

NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase cardiac glycoside levels; however, pharmacokinetic interaction between ketoprofen and active glycosides has not been proven.

Medicinal product combinations with warnings

Antihypertensive agents (beta-blockers, ACE inhibitors, diuretics)

Risk of reduced antihypertensive efficacy (due to inhibition of vasodilatory prostaglandin synthesis by NSAIDs).

Mifepristone

The contraceptive efficacy may theoretically be reduced due to the anti-prostaglandin properties of NSAIDs, including aspirin (acetylsalicylic acid). Evidence indicates that NSAID use on the day of prostaglandin administration does not negatively affect the effect of mifepristone or prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

Intrauterine contraceptive devices

The efficacy of the device may be reduced, thus increasing the risk of pregnancy.

Cyclosporine, tacrolimus

Risk of additive nephrotoxic effects, particularly in elderly patients.

Probenecid

Concomitant use of probenecid may significantly reduce the plasma clearance of ketoprofen, thus increasing plasma concentrations of ketoprofen; this interaction may result from an inhibitory mechanism at the site of renal tubular secretion and glucuronidation, and requires dose adjustment of ketoprofen.

Selective serotonin reuptake inhibitors (SSRIs) and antiplatelet agents (e.g., ticlopidine, clopidogrel)

Increased risk of gastrointestinal bleeding (see section "Special precautions for use").

Thrombolytic agents

Increased risk of bleeding.

Quinolone antibiotics

Animal studies indicate that NSAIDs increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones have an increased risk of convulsions.

Phenytoin and sulfonamides

Since ketoprofen is highly protein-bound, dose reduction of phenytoin or sulfonamides may be necessary when used concomitantly.

Hemeprost

Reduced efficacy of hemeprost.

Alcohol consumption should be avoided.

Special precautions for use

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Dosage and administration"; for risks of gastrointestinal and cardiovascular disorders, see below).

Ketoprofen should not be used concomitantly with other NSAIDs, including selective cyclooxygenase-2 inhibitors.

Masking symptoms of underlying infections. The medicinal product may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thereby complicating the course of the disease. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When this medicinal product is used for fever or pain relief during infection, monitoring of the infectious condition is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Cases of gastrointestinal bleeding, ulcers, and perforation, including fatal outcomes, have been reported with NSAID use at any stage of treatment, regardless of prior warning signs or history of severe gastrointestinal disorders.

Results of some epidemiological studies indicate that concomitant use of ketoprofen with certain other NSAIDs, especially at high doses, is associated with an increased risk of serious gastrointestinal toxicity (see also section "Contraindications").

The drug should be prescribed with caution to patients receiving concomitant medications that increase the risk of ulceration or gastrointestinal perforation, such as oral corticosteroids or anticoagulants like warfarin, selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as aspirin (see section "Interaction with other medicinal products and other forms of interaction").

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. These patients should start treatment with the lowest possible dose. For such patients, as well as those requiring concomitant low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, combined therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) may be necessary (see below and section "Interaction with other medicinal products and other forms of interaction").

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

Elderly patients are at increased risk of adverse reactions during NSAID therapy, particularly gastrointestinal bleeding and perforation, which may be fatal.

Patients with gastrointestinal diseases, including those with a history of such conditions, require careful monitoring for gastrointestinal disturbances, especially gastrointestinal bleeding.

If gastrointestinal bleeding or ulcers develop in patients taking ketoprofen, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease), as such conditions may be exacerbated (see section "Undesirable effects").

Very rarely, severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur during NSAID therapy (see section "Undesirable effects"). The highest risk of such reactions occurs early in treatment, usually within the first month. Ketoprofen should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Clinical and epidemiological data suggest that use of certain NSAIDs (particularly at high doses and over prolonged periods) is associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data are insufficient to exclude such risk with ketoprofen use.

An increased risk of atrial fibrillation associated with NSAID use has been reported.

Hyperkalemia may occur, particularly in patients with diabetes, renal impairment, and/or concomitant use of drugs that cause hyperkalemia (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, potassium levels should be monitored.

Children. Gastrointestinal bleeding, sometimes severe, and ulcers have been observed in some children receiving ketoprofen lysine salt (see section "Undesirable effects"). Use in children is contraindicated (see section "Children").

The medicinal product does not require modifications to low-calorie or controlled diets and may be used by diabetic patients. It is gluten-free and therefore not contraindicated in patients with celiac disease. It does not contain aspartame and can be used by patients with phenylketonuria.

Precautionary measures

Ketoprofen should be used with particular caution in patients with impaired renal function due to its predominant renal elimination.

Renal function should be monitored at the beginning of treatment in patients with heart failure, liver cirrhosis, nephrotic syndrome, those taking diuretics, patients with chronic renal impairment, especially if elderly. In these patients, ketoprofen use may reduce renal blood flow due to inhibition of prostaglandin synthesis and may lead to renal failure.

Close monitoring is required in patients with hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been reported during NSAID therapy.

In patients with infectious diseases, it should be noted that the anti-inflammatory, analgesic, and antipyretic effects of ketoprofen may mask typical signs of infection progression, such as fever.

Caution is also required when administering to patients receiving diuretics or hypovolemic agents, as the risk of nephrotoxicity is increased.

Like other NSAIDs, this medicinal product may increase blood urea nitrogen and serum creatinine levels.

Like other prostaglandin synthesis inhibitors, ketoprofen may adversely affect renal function, potentially leading to glomerulonephritis, necrotizing papillitis, nephrotic syndrome, and acute renal failure.

In patients with impaired liver function tests or a history of liver disease, transaminase levels should be monitored periodically, especially during long-term therapy.

Like other NSAIDs, the drug may cause mild, transient increases in some liver parameters, as well as significant increases in glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase. Treatment should be discontinued if these parameters increase markedly.

Rare cases of jaundice and hepatitis have been reported after ketoprofen administration.

Liver and kidney function tests and complete blood counts should be performed periodically during prolonged treatment.

Elderly patients are more prone to reduced renal, cardiovascular, and hepatic function.

NSAID use may impair female fertility (see section "Use during pregnancy or breastfeeding").

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps have an increased risk of aspirin and/or NSAID allergy. This medicinal product may trigger asthma attacks or bronchospasm, particularly in patients allergic to aspirin or NSAIDs (see section "Contraindications"). Due to drug-induced disturbances in arachidonic acid metabolism, bronchospasm, shock, and other allergic reactions may occur in asthmatic and susceptible individuals.

Ketoprofen therapy should be initiated only after careful assessment in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar assessment is required before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes, smoking).

Treatment should be discontinued if visual disturbances, particularly blurred vision, occur.

This medicinal product should be used with caution in patients with a history of allergic reactions or allergies, as well as in patients with hematopoietic disorders (blood formation), systemic lupus erythematosus, or mixed connective tissue disease.

The medicinal product contains less than 1 mmol of sodium (23 mg) per sachet and is therefore considered sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal/embryonic development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis with use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from 1% to approximately 1.5%. It is believed that the risk of such events increases with higher drug doses and longer duration of therapy. In animal studies, administration of prostaglandin synthesis inhibitors increased pre- and post-implantation fetal loss and embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of various developmental abnormalities, including cardiovascular defects, increased. Ketoprofen should not be used during the first and second trimesters of pregnancy unless clearly indicated. If ketoprofen is used in women planning pregnancy or during the first and second trimesters, the dose should be as low as possible and the duration of treatment as short as possible.

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

• Cardio-pulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• Renal dysfunction, which may progress to renal failure with oligohydramnios.

Near the end of pregnancy, prostaglandin synthesis inhibitors may affect the mother and the newborn as follows:

• Prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• Inhibition of uterine contractions, leading to delayed or prolonged labor.

Use of the drug near term may lead to hemodynamic disturbances in the neonatal pulmonary circulation with serious consequences for respiration.

Therefore, ketoprofen is contraindicated during the third trimester of pregnancy.

Breastfeeding

Data on the excretion of ketoprofen into breast milk are lacking. Women who are breastfeeding should not take ketoprofen.

Reproductive function

NSAID use may impair female fertility and therefore is not recommended for women attempting to conceive. If a woman experiences difficulty conceiving or is undergoing infertility investigations, discontinuation of NSAID therapy should be considered.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product has negligible or no influence on the ability to drive or operate machinery.

However, patients should be warned about possible adverse reactions such as somnolence, dizziness, seizures, or blurred vision. If such symptoms occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Dosage

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Warnings and Precautions for Use").

Adults

50 mg of ketoprofen (equivalent to 80 mg of ketoprofen lysinate) three times daily.

Maximum daily dose — 200 mg of ketoprofen, equivalent to 320 mg of ketoprofen lysinate. The risk-benefit balance should be carefully considered before initiating treatment with a daily dose of 200 mg of ketoprofen. Higher doses are not recommended (see also section "Special Warnings and Precautions for Use").

If the patient's condition does not improve despite taking the medicinal product for more than 3 days in the case of fever or more than 5 days without fever, or if symptoms worsen, medical advice should be sought.

Elderly Patients

Dosage should be prescribed by a physician, who may, if necessary, reduce the recommended dose above (see section "Special Warnings and Precautions for Use").

Patients with Hepatic Impairment

For patients with mild to moderate hepatic impairment, treatment should be initiated with the lowest daily dose (see section "Special Warnings and Precautions for Use").

The medicinal product should not be used in patients with severe hepatic impairment (see section "Contraindications").

Patients with Renal Impairment

For patients with mild to moderate renal impairment, it is recommended to reduce the initial dose and continue treatment with the lowest effective dose. After establishing good tolerance to the medicinal product in the patient, individual dose adjustment may be considered.

Monitoring of urine output and renal function is required (see section "Special Warnings and Precautions for Use").

The medicinal product should not be used in patients with severe renal impairment (see section "Contraindications").

Method of Administration

For oral use.

Preparation of the Oral Solution

Before use, dissolve the contents of one sachet in a glass of water (200 mL) and mix thoroughly for approximately 30 seconds until all granules are completely dissolved.

The solution should be taken during a meal.

Children

The medicinal product KETOLIZIN**®** is contraindicated in children under 18 years of age (see section "Contraindications").

Overdose

Symptoms

Cases of overdose have been reported following ingestion of doses up to 2.5 g of ketoprofen. In most cases, symptoms were mild and limited to lethargy, drowsiness, nausea, vomiting, epigastric pain, headache, dizziness, and diarrhea.

In cases of severe overdose, arterial hypotension, respiratory depression, and gastrointestinal bleeding have been observed.

Treatment

There is no specific antidote for ketoprofen overdose.

In cases of severe overdose, the patient should be immediately hospitalized. Gastric lavage should be promptly performed.

Symptomatic and supportive therapy should be initiated to correct dehydration, monitor diuresis, and correct acidosis if present.

Renal and hepatic function should be closely monitored. In the event of renal failure, hemodialysis should be performed to remove circulating active substance.

Side effects

The most commonly observed adverse reactions were gastrointestinal in nature. The development of peptic ulcer disease, gastrointestinal perforation, or gastrointestinal bleeding, sometimes fatal, is possible, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment (see section "Special precautions"). Gastritis has been observed less frequently.

During clinical studies, vomiting, diarrhea, and hypersensitivity reactions were reported in infants and children.

The adverse reactions listed below were observed during ketoprofen use in adult patients.

Classification of frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (≤1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations

Frequency not known: aseptic meningitis, lymphangitis.

Blood and lymphatic system disorders

Rare: hemorrhagic anemia.

Frequency not known: agranulocytosis, thrombocytopenia, bone marrow suppression, hemolytic anemia, leukopenia, neutropenia, aplastic anemia, leukocytosis, thrombocytopenic purpura.

Immune system disorders

Frequency not known: anaphylactic reactions (including anaphylactic shock), mucosal edema of the oral cavity, hypersensitivity.

Metabolism and nutrition disorders

Frequency not known: hyperkalemia, hyponatremia.

Psychiatric disorders

Frequency not known: mood swings, restlessness, insomnia, depression, hallucinations, confusion. In one pediatric patient who received a double dose compared to the recommended dose, anxiety and behavioral disturbances occurred.

Nervous system disorders

Uncommon: headache, dizziness, vertigo, somnolence.

Rare: paresthesia.

Very rare: dyskinesia, syncope.

Frequency not known: convulsions, dysgeusia, tremor, hyperkinesia.

Eye disorders

Rare: blurred vision (see section "Special precautions").

Frequency not known: periorbital edema.

Ear and labyrinth disorders

Rare: tinnitus.

Cardiac disorders

Frequency not known: heart failure, tachycardia, atrial fibrillation, palpitations.

Vascular disorders

Very rare: arterial hypotension.

Frequency not known: arterial hypertension, vasodilation, vasculitis (including leukocytoclastic vasculitis).

Respiratory, thoracic and mediastinal disorders

Rare: asthma.

Very rare: laryngeal edema.

Frequency not known: bronchospasm (particularly in patients with aspirin and other NSAID hypersensitivity), rhinitis, dyspnea, laryngospasm, acute respiratory failure (one fatal case was reported in a patient with asthma and aspirin sensitivity).

Gastrointestinal disorders

Common: dyspepsia, nausea, abdominal pain, vomiting.

Uncommon: gastric discomfort, constipation, diarrhea, flatulence, gastritis.

Rare: stomatitis, colitis, peptic ulcer.

Frequency not known: gastralgia, exacerbation of colitis and Crohn's disease, gastrointestinal hemorrhage and perforation (sometimes fatal, especially in elderly patients — see section "Special precautions"), fever, gastric ulcer, duodenal ulcer, gastric pyrosis, oral cavity edema, pancreatitis, melena, hematemesis, hyperchlorhydria, epigastric pain, erosive gastritis, tongue edema.

Hepatobiliary disorders

Rare: hepatitis, elevated transaminase levels, increased serum bilirubin due to worsening of hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus.

Frequency not known: photosensitivity reactions, alopecia, urticaria, angioneurotic edema, bullous eruptions including Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema, exanthema, maculopapular rash, purpura, acute generalized exanthematous pustulosis, dermatitis.

Renal and urinary disorders

Very rare: hematuria.

Frequency not known: acute renal failure, tubulointerstitial nephritis, nephritis or nephritic syndrome, nephrotic syndrome, worsening of renal function tests, fluid/sodium retention with possible edema, acute tubular syndrome, papillary necrosis, oliguria.

General disorders and administration site conditions

Uncommon: edema, fatigue.

Investigations

Rare: weight gain.

Clinical and epidemiological data indicate that use of certain NSAIDs (particularly at high doses and for prolonged periods) may increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 30 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

I.T.I. Production S.r.l.

Manufacturer's address and place of business.

Via Pontina Km 29, Pomezia, 00071, Italy.

Marketing authorization holder.

VIGAFARMA S.R.L.

Address of the marketing authorization holder.

Via della Costa, 16F, Manziana (Rome), Italy.