Ketonal® rapid

INSTRUCTIONS for medical use of the medicinal product ketonal® Rapid (ketonal® Rapid)

Composition:

Active substance: ketoprofen lysine salt;

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

Excipients: mannite, povidone K30, peppermint flavor, sodium chloride, sodium saccharin, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: granules from white to yellowish, free from lumps and aggregates.

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

ATC code M01AE03.

Pharmacological properties.

Pharmacodynamics.

Ketoprofen lysinate is the lysine salt of 2-(3-benzoylphenyl) propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects, belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Ketoprofen lysinate is more soluble than ketoprofen acid.

Ketoprofen lysinate has pronounced analgesic activity, which correlates with both anti-inflammatory and central effects. Ketoprofen lysinate 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 related to the reduction of prostaglandin synthesis due to inhibition of cyclooxygenase activity.

In particular, 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.

Ketoprofen lysinate has high solubility compared to ketoprofen acid.

Absorption

The granules for oral solution dosage form allows administration of the active ingredient already in aqueous solution. This promotes rapid increase in plasma concentrations and rapid achievement of peak plasma concentration. Clinically, this is manifested by 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 bound to plasma proteins by 95–99%.

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 short-term symptomatic treatment of the following types of mild to moderate acute pain:

• Headache
• Toothache
• Menstrual pain (dysmenorrhea)
• Pain following minor strains and sprains

Indicated for adults and children aged 16 years and older.

Contraindications.

• Hypersensitivity to the active substance, acetylsalicylic acid, or other NSAIDs, or to any of the excipients.
• Hypersensitivity reactions such as bronchospasm, asthmatic attacks, acute rhinitis, urticaria, nasal polyps, or other allergic reactions to ketoprofen, acetylsalicylic acid, or other NSAIDs in medical history.

Severe, and sometimes fatal, hypersensitivity reactions have been reported in some patients (see section "Adverse reactions").

• History of bronchial asthma.
• Acute peptic ulcer or gastrointestinal bleeding, history of ulcers, perforations.
• Active phase or recurrence of gastric and/or duodenal ulcer (two or more confirmed episodes).
• Gastrointestinal bleeding or perforations resulting from NSAID therapy.
• Leukopenia or thrombocytopenia.
• Chronic dyspepsia.
• Crohn’s disease or ulcerative colitis.
• Gastritis.
• Severe heart failure.
• Severe hepatic insufficiency (liver cirrhosis, severe hepatitis).
• Severe renal insufficiency.
• Hemorrhagic diathesis and other coagulation disorders, hemostatic disorders.
• Intensive diuretic therapy.
• Third trimester of pregnancy.
• Age under 16 years.

Interaction with other medicinal products and other forms of interaction.

Medicinal product combinations not recommended

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

Increased risk of gastrointestinal ulcers and bleeding.

Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (such as 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 excretion of lithium. If combination therapy is necessary, plasma lithium levels should be carefully monitored during and after NSAID therapy, and when adjusting the lithium dose.

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

Increased risk of hematological toxicity of methotrexate, especially 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 ketoprofen and methotrexate administration is required.

Hydantoins (e.g., phenytoin) and sulfonamides

Toxic effects of these substances may be enhanced.

Medicinal product combinations requiring caution

Medicinal products that may cause hyperkalemia

Some medicinal products may cause hyperkalemia, for example: 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 ACE inhibitors or angiotensin II receptor antagonists and medicinal products that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure. Such patients should receive adequate fluid intake 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 taking diuretics, especially dehydrated patients, are at increased risk of developing renal failure due to reduced renal blood flow resulting from inhibition of prostaglandin synthesis. Such patients should receive adequate fluid intake before starting combination therapy, and renal function should be monitored after initiation of therapy (see section "Special precautions for use"). NSAIDs may reduce the effect 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 testing of bleeding time are required.

Zidovudine

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

Sulfonylurea preparations

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

Cardiac glycosides

NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase levels of cardiac glycosides; 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 activity (due to inhibition of vasodilatory prostaglandin synthesis by NSAIDs).

Mifepristone

The effectiveness of the contraceptive method may theoretically decrease due to the anti-prostaglandin properties of NSAIDs, including aspirin (acetylsalicylic acid). Evidence indicates that the use of NSAIDs 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

Effectiveness of the device may be reduced, thus there is a risk of pregnancy.

Cyclosporine, tacrolimus

Risk of additive nephrotoxic effects, especially in elderly patients.

Probenecid

Concomitant use of probenecid may significantly reduce the plasma clearance of ketoprofen, thus plasma concentrations of ketoprofen may be increased; such 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 platelet aggregation inhibitors (such as 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 may have an increased risk of convulsions.

Phenytoin and sulfonamides

Since ketoprofen protein binding is high, 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.

Warning

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

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

Masking of symptoms of underlying infections

The medicinal product may mask symptoms of infection, potentially delaying the initiation of appropriate treatment and thereby worsening the course of the disease. This has been observed in cases of community-acquired bacterial pneumonia and bacterial complications of varicella. When using this medicinal product for elevated body temperature 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, ulceration, and perforation, including fatal outcomes, have been reported with NSAID use at any stage of treatment, regardless of the presence of warning symptoms or history of severe gastrointestinal disorders.

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

Extreme caution is required when prescribing the drug to patients receiving concomitant medications that increase the risk of ulcers or perforations, such as oral corticosteroids or anticoagulants (e.g., 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 for those requiring concomitant use of 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 have an increased frequency of adverse reactions during NSAID therapy, particularly gastrointestinal bleeding and perforation, which may be fatal.

Patients with gastrointestinal diseases, including those in the past medical history, require careful monitoring for the development of digestive disorders, especially gastrointestinal bleeding.

If gastrointestinal bleeding or ulceration occurs in patients taking ketoprofen, 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 these conditions may worsen (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 therapy should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Clinical and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and for 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 induce 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 reported in some children receiving lysine salt of ketoprofen (see section "Undesirable effects"). Therefore, the medicinal product should be used under strict medical supervision. The treating physician must evaluate the treatment regimen in each individual case.

The medicinal product does not require modifications in low-calorie or controlled diets and can be used even 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.

Precautions

Ketoprofen should be administered with particular caution in patients with impaired renal function, as the drug is primarily excreted via the kidneys.

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 elderly patients. In these patients, ketoprofen use may reduce renal blood flow due to inhibition of prostaglandin biosynthesis, potentially leading 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 observed during NSAID therapy.

In infectious diseases, it should be considered that the anti-inflammatory, analgesic, and antipyretic effects of ketoprofen may mask typical signs of infection progression, such as elevated body temperature.

Caution is also required in patients undergoing treatment with 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 the renal system, 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 prolonged therapy.

As with other NSAIDs, the drug may cause mild, transient increases in certain 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 after ketoprofen intake have been reported.

During prolonged treatment, liver and kidney function tests and complete blood count should be performed regularly.

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 allergy to aspirin and/or NSAIDs. Use of this medicinal product may trigger asthma attacks or bronchospasm, particularly in patients with known aspirin or NSAID allergy (see section "Contraindications"). Due to drug-induced disturbances in arachidonic acid metabolism, bronchospasm, shock, and other allergic reactions may occur in asthmatics and susceptible individuals.

Ketoprofen therapy should be initiated only after careful consideration in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar risk 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, such as blurred vision, occur.

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

The 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 progression and/or fetal/embryonic development. Epidemiological data suggest an increased risk of miscarriage, congenital heart defects, and gastroschisis when prostaglandin synthesis inhibitors are used 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 treatment duration. 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, an increased incidence of various developmental abnormalities, including cardiovascular defects, was observed. Starting from the 20th week of pregnancy, use of Ketonāl Rapid may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting 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 treatment cessation. Therefore, 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 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 exposure to Ketonāl Rapid for several days, starting from the 20th gestational week. Ketonāl Rapid should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose the following risks:

Risks for the fetus:

• Cardio-pulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• Renal dysfunction (see above);

Risks for the mother at the end of pregnancy and for the newborn:

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

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

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 is therefore not recommended for women attempting to conceive. If a woman experiences difficulties in conception or is undergoing infertility evaluation, 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 the possible occurrence of adverse reactions such as drowsiness, 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 Instructions").

Adults and children aged 16 years and older

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

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

If adults or children aged 16 years and older require treatment for more than 3 days due to 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 reduce the dose indicated above if necessary (see section "Special Instructions").

Patients with hepatic impairment

Patients with mild to moderate hepatic impairment should start treatment with the lowest daily dose (see section "Special Instructions").

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

Patients with renal impairment

Patients with mild to moderate renal impairment should be started on a reduced dose and maintained on the lowest effective dose. After establishing good tolerance to the medicinal product, individual dose adjustment may be considered.

Monitoring of urine output and renal function is required (see section "Special Instructions").

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

Method of Administration

For oral use.

One sachet up to the line marked "half dose" contains 25 mg of ketoprofen (equivalent to 40 mg of ketoprofen lysine salt).

One sachet up to the line marked "full dose" contains 50 mg of ketoprofen (equivalent to 80 mg of ketoprofen lysine salt).

Oral solution preparation

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

The solution should be taken during meals.

Children

The medicinal product is not recommended for use in children under 16 years of age.

Overdose

Symptoms

Cases of overdose have been reported with 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 case of severe overdose, the patient should be immediately transferred to hospital. 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 functions should be closely monitored. In case of renal failure, hemodialysis should be performed to remove circulating active substance.

Adverse reactions

The most commonly observed adverse reactions were gastrointestinal in nature. The development of peptic ulceration, 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 trials, vomiting, diarrhea, and hypersensitivity reactions were observed in infants and children.

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

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

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 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, stomach pain, erosive gastritis, tongue edema.

Hepatobiliary disorders

Rare: hepatitis, increased transaminase levels, increased serum bilirubin levels 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 suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

The reconstituted solution should be used immediately after preparation.

Storage conditions. No special storage conditions required. Keep out of the reach of children.

Packaging. 2 g granules per sachet; 6, 12, or 18 sachets per cardboard box.

Prescription status. Over-the-counter (without prescription).

Manufacturer.

1. Lek Pharmaceuticals d.d.
2. Fine Foods & Pharmaceuticals N.T.M. S.p.A.

Manufacturer's address and place of business.

1. Verovskova 57, 1526 Ljubljana, Slovenia.
2. Via Grignano, 43, Brembate, 24041, Italy.