Ibutard 300

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IBUTARD 300

Composition:

Active substance: ibuprofen;

1 capsule contains ibuprofen (pellets with prolonged release) 300 mg;

Excipients: in the composition of pellets − spherical sugar, povidone, talc, ethylcellulose, shellac; in the composition of capsule − azorubine (E 122), gelatin.

Pharmaceutical form. Prolonged-release capsules.

Main physicochemical properties: hard capsules with a transparent red cap and a transparent colorless body, containing white pellets with a yellowish or cream tint.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs. Propionic acid derivatives. Ibuprofen. ATC Code M01AE01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which effectively inhibits the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen exerts antipyretic, anti-inflammatory, and analgesic effects. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental ex vivo data indicate that when used concomitantly, ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to the clinical setting, the possibility that regular and long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. The occurrence of such clinically significant effects with occasional use of ibuprofen is considered unlikely.

Pharmacokinetics

Ibuprofen is well absorbed from the gastrointestinal tract and actively binds to plasma proteins (approximately 99%). After oral administration of the immediate-release dosage form, peak plasma concentration is reached within 1–2 hours.

Ibuprofen is metabolized in the liver (via hydroxylation and carboxylation).

Pharmacologically inactive metabolites are completely eliminated from the body, primarily via urine (90%) and also through bile. The elimination half-life in healthy individuals and in patients with hepatic or renal disease ranges from 1.8 to 3.5 hours. The half-life (T_1/2) of ibuprofen from sustained-release formulations is approximately 8 hours. Sustained-release capsules Ibutard 300 provide 12-hour duration of action (ibuprofen is slowly released, thereby maintaining a constant drug concentration in the blood).

Linear kinetics of ibuprofen were observed at doses from 200 to 400 mg. Non-linear kinetics were observed at higher doses.

In elderly patients, no significant differences in pharmacokinetic profile have been observed.

Clinical characteristics.

Indications.

Symptomatic treatment of headache, including migraine, toothache, dysmenorrhea, neuralgia, back pain, joint and muscle pain, rheumatic pain, as well as symptoms of cold and flu.

Contraindications.

• Known or suspected hypersensitivity to ibuprofen or to any of the excipients of the medicinal product;
• Hypersensitivity reactions (acute asthmatic attacks or asthma symptoms, urticaria, nasal polyps, anaphylaxis, rhinitis, angioedema) following administration of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) — risk of fatal anaphylactic reactions due to possible cross-sensitivity;
• History of gastrointestinal bleeding/perforation associated with previous NSAID therapy;
• Active peptic ulceration/bleeding or perforation, or two or more episodes of ulcer complications/bleeding or perforation in history;
• Active inflammatory bowel disease (Crohn’s disease or ulcerative colitis);
• Recent cerebrovascular bleeding or other bleeding disorders;
• Disorders of hematopoiesis or blood coagulation;
• Optic nerve disorders (optic neuritis);
• Severe impairment of liver or kidney function;
• Severe uncontrolled heart failure (NYHA IV);
• Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations of ibuprofen and other NSAIDs

• Aspirin (since it may increase the risk of adverse reactions), except when low-dose aspirin (not exceeding 75 mg/day) is prescribed by a physician.

Ex vivo experimental data indicate that concomitant use of ibuprofen may competitively inhibit the antiplatelet effect of low-dose acetylsalicylic acid. Although uncertainty exists regarding extrapolation of these data to clinical settings, the possibility that regular and prolonged use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. Occasional use of ibuprofen is considered unlikely to cause clinically significant effects.

• Other NSAIDs (including selective COX-2 inhibitors).

Increased likelihood of additive adverse effects such as bleeding, gastrointestinal ulcers, without synergistic positive effect.

Combinations to be used with caution

Glucocorticoids (including corticosteroids), alcohol: increased risk of gastrointestinal adverse effects, particularly gastrointestinal ulcers and bleeding.

Antihypertensive agents (including ACE inhibitors, angiotensin II receptor antagonists, ß-blockers), diuretics: reduced antihypertensive and diuretic effects; diuretics may increase NSAID nephrotoxicity. Concomitant use with potassium-sparing diuretics may lead to hyperkalemia.

In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced kidney function), concomitant administration of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be used with caution, particularly in elderly patients. Patients should be advised to maintain adequate fluid intake; monitoring of renal function at the start of combined therapy and periodically thereafter should be considered.

Oral anticoagulants, antiplatelet agents, systemic heparin, thrombolytic agents, and selective serotonin reuptake inhibitors (SSRIs): possible potentiation of anticoagulant effects, such as with warfarin, and increased risk of bleeding, including gastrointestinal bleeding, due to inhibition of platelet function. If such combination is necessary, careful monitoring of the coagulation system is recommended.

Calcineurin inhibitors (cyclosporine, tacrolimus): NSAIDs enhance the nephrotoxicity of these agents via effects on renal prostaglandins, requiring close monitoring of renal function during concomitant use, especially in elderly patients.

Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.

Lithium, phenytoin: reduced renal excretion of these drugs may lead to increased plasma concentrations and enhanced effects.

Short-term use of ibuprofen (up to a maximum of 4 days) generally does not require monitoring of plasma concentrations of digoxin, phenytoin, or lithium.

Methotrexate: possible reduction in tubular secretion of methotrexate, thereby increasing its blood concentration and hematotoxicity. Therefore, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (over 15 mg/week) or in patients with impaired renal function. In cases of combination therapy, blood counts and renal function should be monitored.

Mifepristone: NSAIDs should not be used within 8–12 days after mifepristone administration, as this may reduce the efficacy of the latter.

Zidovudine: increased risk of hematological toxicity; data exist on increased risk of hemarthrosis and hematomas in HIV-infected individuals with hemophilia receiving zidovudine and ibuprofen concurrently.

Baclofen: increased baclofen toxicity.

Quinolone antibiotics: possible increased risk of seizures.

Aminoglycosides: since ibuprofen may reduce aminoglycoside clearance, concomitant use may increase the risk of nephrotoxicity and ototoxicity.

Cholestyramine: concomitant administration may reduce gastrointestinal absorption of ibuprofen. Clinical significance is unknown.

Oral antidiabetic agents (sulfonylureas): NSAIDs may enhance the hypoglycemic effect of these agents. Isolated reports exist of hypoglycemia in patients receiving sulfonylureas and ibuprofen. Blood glucose monitoring is recommended during concomitant use.

Probenecid, sulfinpyrazone: concomitant use with ibuprofen may delay elimination of the latter and reduce the uricosuric effect of probenecid and sulfinpyrazone.

CYP2C9 inhibitors: possibility of pharmacokinetic interaction — increased exposure (plasma concentration over time) of ibuprofen (a CYP2C9 substrate). Consideration should be given to reducing the dose of ibuprofen when used concomitantly with potent CYP2C9 inhibitors (such as voriconazole, fluconazole), especially at high ibuprofen doses.

Ginkgo biloba extracts: possible increased risk of bleeding when used with NSAIDs, including ibuprofen.

Special precautions for use.

Before starting treatment with the medicine, consult your doctor!

To minimize the risk of adverse effects, the lowest effective dose should be used for the shortest duration necessary to relieve disease symptoms.

Prolonged use of NSAIDs, especially at high doses, may cause headache that cannot be treated by increasing the dose of the drug. Patients should consult their doctor if headache becomes persistent.

Also, its use is not recommended for postoperative pain following coronary artery bypass grafting.

Masking symptoms of underlying infections

Ibuprofen may mask signs of infectious disease, potentially leading to delayed initiation of appropriate treatment and thereby complicating the course of the disease. This has been observed in cases of community-acquired bacterial pneumonia and bacterial complications of varicella (chickenpox). When ibuprofen is used for fever or pain relief during infection, monitoring of the infectious disease course is recommended. The use of ibuprofen should be avoided in patients with active varicella due to the risk of severe skin infections and soft tissue complications. In outpatient settings, patients should seek medical advice if symptoms persist or worsen.

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective COX-2 inhibitors, should be avoided, as this increases the risk of adverse reactions without providing synergistic therapeutic benefit.

Elderly patients

Use of NSAIDs, including ibuprofen, in elderly patients may lead to an increased frequency of adverse reactions, particularly gastrointestinal bleeding and perforation, which may be fatal.

Cardiovascular and cerebrovascular effects

Patients with elevated blood pressure and/or heart failure should start treatment with ibuprofen cautiously, especially long-term therapy (medical consultation required), as fluid retention, edema, and arterial hypertension have been reported with NSAID therapy, including ibuprofen.

Clinical studies and epidemiological data suggest that the use of ibuprofen, particularly at high doses (2400 mg/day) over prolonged periods, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke. Overall, available epidemiological studies do not indicate that low-dose ibuprofen (less than 1200 mg daily) is associated with an increased risk of arterial thrombotic events.

Long-term treatment with ibuprofen in patients with uncontrolled arterial hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be initiated after careful benefit-risk assessment, and high doses (2400 mg/day) should be avoided.

Particular caution should also be exercised before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high-dose ibuprofen (2400 mg/day) is required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen treatment. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Gastrointestinal effects

NSAIDs should be used with caution in patients with gastrointestinal disorders and a history of chronic inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease, due to the potential for disease exacerbation.

Gastrointestinal ulcers, bleeding, and perforations, including fatal cases, have been reported with all NSAIDs. These events may occur at any time during treatment, with or without prior warning symptoms, and may occur in individuals without a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulcers, and perforations increases with higher NSAID doses, particularly in patients with a history of erosive or ulcerative gastrointestinal disorders, especially those complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Treatment of such patients should begin with the lowest effective dose, and concomitant use of gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered, as well as in patients requiring concomitant low-dose acetylsalicylic acid or other drugs that increase gastrointestinal risk.

Patients with a history of gastrointestinal disorders, especially elderly patients, should inform their doctor about any unusual symptoms (particularly severe upper abdominal pain, black stools (melena), or vomiting blood), especially during the initial stages of treatment.

Caution is advised when treating patients taking medications such as corticosteroids, anticoagulants (warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., aspirin), which increase the risk of gastrointestinal toxicity, including gastrointestinal ulcers or bleeding.

If gastrointestinal toxicity occurs, the drug should be discontinued immediately.

Serious skin adverse reactions (SSARs)

During ibuprofen use, serious skin adverse reactions (SSARs) have been reported, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal (see section "Adverse reactions"). Most such reactions occurred within the first month of treatment.

If signs or symptoms suggestive of these reactions occur, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary).

Hypersensitivity

Caution should be exercised when using NSAIDs, including ibuprofen, in patients with a history of allergic conditions due to an increased risk of hypersensitivity reactions. Severe acute hypersensitivity reactions, including anaphylactic shock, have been rarely observed. If any signs of hypersensitivity occur, the drug should be discontinued immediately. Appropriate medical measures should be taken by qualified professionals according to symptom severity.

Respiratory effects

The use of NSAIDs, including ibuprofen, may trigger bronchospasm, asthma attacks, nasal mucosal edema, and other respiratory symptoms in patients with bronchial asthma, chronic obstructive pulmonary disease, allergic conditions, or a history of such diseases.

Nephrological effects

Long-term use of NSAIDs may lead to nephrotoxicity due to dose-dependent reduction in prostaglandin synthesis, potentially causing renal impairment via disturbances in renal blood flow. High-risk groups include patients with impaired renal function, cardiac disorders, hepatic dysfunction, those taking diuretics, ACE inhibitors/angiotensin II receptor antagonists, and elderly patients. Renal function should be monitored in these patients. Renal function usually returns to normal after discontinuation of NSAID therapy.

Prolonged and uncontrolled use of analgesics, especially combinations of different painkillers, may lead to persistent kidney damage with a risk of renal failure (analgesic nephropathy).

Hepatic effects

Very rarely, liver function disturbances have been reported with NSAIDs, including ibuprofen.

NSAIDs should be used with caution in patients with hepatic dysfunction, as elevated blood pressure and/or heart failure may worsen and/or fluid retention may occur.

Hematological effects

Ibuprofen, like other NSAIDs, may affect platelet aggregation and prolong bleeding time in healthy individuals.

Systemic lupus erythematosus and connective tissue diseases

Ibuprofen should be used cautiously in patients with systemic lupus erythematosus and other diffuse connective tissue diseases due to an increased risk of aseptic meningitis as a manifestation of hypersensitivity reactions. Aseptic meningitis has also been observed in patients without these chronic conditions.

Female fertility impairment

There is evidence that drugs inhibiting cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Long-term use of ibuprofen (referring to a dose of 2400 mg per day and treatment duration exceeding 10 days) may impair female fertility and is not recommended for women attempting to conceive. Women experiencing difficulties in conception or undergoing infertility evaluation should discontinue ibuprofen.

Alcohol consumption during NSAID treatment may increase the risk of adverse reactions related to the active substance, particularly gastrointestinal or central nervous system effects.

If a dose is missed, the patient should take the usual dose as soon as remembered, and subsequent doses should be taken 12 hours apart. Do not take a double dose.

Do not exceed the recommended doses of Ibutard 300.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital malformations, including congenital heart defects and gastroschisis, with the use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with higher doses and longer duration of treatment.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction have been reported after second-trimester treatment, most of which resolved after stopping treatment. Therefore, the use of the drug during the first and second trimesters of pregnancy is only possible if the expected benefit to the mother clearly outweighs the potential risk to the fetus.

If ibuprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose should be used for the shortest possible duration. Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of ibuprofen exposure, starting from the 20th gestational week. Ibutard 300 treatment should be discontinued if oligohydramnios or arterial duct constriction is detected.

The use of any prostaglandin synthesis inhibitors during the third trimester of pregnancy may result in the following effects on the fetus:

• Cardio-pulmonary toxicity (premature closure/constriction of the arterial duct and pulmonary hypertension);
• Impaired renal function, potentially progressing to renal failure with oligohydramnios.

Additionally, ibuprofen use near the end of pregnancy may cause:

• Prolonged bleeding time and antiplatelet effects, which may occur even at very low doses, increasing the risk of bleeding in both mother and child;
• Inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

Therefore, the use of ibuprofen during the third trimester of pregnancy is contraindicated.

Limited studies have shown that a small amount of ibuprofen passes into breast milk. The drug is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

When used at recommended doses and treatment duration, the drug does not affect reaction speed during driving or operating machinery. Patients experiencing dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery.

Method of Administration and Dosage

For oral use.

For over-the-counter use, Ibutard 300 is intended only for short-term treatment not exceeding 3 days.

If symptoms persist for more than 3 days or worsen, it is essential to consult a physician for diagnosis clarification and treatment adjustment.

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

Adults and children aged 12 years and older: Take 1 or 2 capsules twice daily (every 12 hours), preferably during or after meals. The capsule should be swallowed whole, without chewing or crushing, with sufficient amount of water.

Do not exceed 4 capsules (1200 mg) per day. The interval between doses should be at least 8 hours.

Special Populations

Elderly patients: Dose adjustment is not required. However, careful monitoring is recommended due to increased risk of adverse effects.

Patients with mild or moderate renal or hepatic impairment: Dose reduction is not necessary.

Children: Ibutard 300 should not be used in children under 12 years of age.

Overdose

Administration of ibuprofen to children at doses exceeding 400 mg/kg may lead to symptoms of intoxication. In adults, dose-dependent effects are less pronounced. The elimination half-life of the drug in the prolonged-release capsule form is approximately 8 hours.

Symptoms: Depend on the amount ingested and the time elapsed since ingestion, but individual reactions cannot be excluded. In most cases – nausea, vomiting, epigastric pain, less frequently – diarrhea. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur.

In more severe poisoning, neurotoxicity symptoms may develop, such as drowsiness, nystagmus, visual disturbances, sometimes excitement and disorientation, loss of consciousness, or coma. Seizures may occur rarely.

In severe intoxication, hyperkalemia may develop, leading to cardiac rhythm disturbances (including bradycardia/tachycardia, atrial fibrillation), metabolic acidosis, and prolonged prothrombin time/INR, possibly due to effects on circulating coagulation factors. Subsequently, acute renal failure, liver damage, marked arterial hypotension, dyspnea, respiratory depression/apnea, respiratory failure, and cyanosis may occur. In patients with bronchial asthma, worsening of asthma symptoms is possible.

Treatment: Symptomatic and supportive; there is no specific antidote. Ensure airway patency and monitor vital signs until stabilization. Within one hour after ingestion of a potentially toxic dose of ibuprofen, gastric lavage, induction of emesis, or administration of activated charcoal is recommended. If ibuprofen has already been absorbed, alkalizing agents may be administered to enhance renal excretion of the acidic ibuprofen.

For seizures, intravenous diazepam or lorazepam should be administered. For bronchial asthma symptoms, bronchodilators are indicated. Therapeutic measures depend on the severity of the patient's condition and should be implemented according to general principles of intensive care. Monitoring of renal and hepatic function is required. Hemodialysis is not effective.

Side effects.

The adverse reactions listed below were observed during short-term use of ibuprofen at over-the-counter doses not exceeding 1200 mg per day. Additional adverse reactions may occur during treatment of chronic conditions or with long-term therapy.

Gastrointestinal adverse reactions are the most commonly observed and are dose-dependent; in particular, the risk of gastrointestinal bleeding depends on the dose range and duration of treatment.

Clinical studies indicate that the use of ibuprofen (especially at high doses of 2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions for use").

Blood and lymphatic system.

• Blood dyscrasias (anemia, including hemolytic anemia, aplastic anemia, decreased hematocrit and hemoglobin, leukopenia, thrombocytopenia with or without purpura, pancytopenia, agranulocytosis, eosinophilia). Initial signs include fever, sore throat, oral mucosal erosions, flu-like symptoms, increased fatigue, bleeding (including epistaxis), ecchymoses, menorrhagia. Blood counts should be monitored during long-term ibuprofen therapy.

Immune system.

• Hypersensitivity reactions with skin rash, urticaria, and pruritus;
• severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal edema, dyspnea, tachycardia, hypotension, anaphylaxis, angioedema, or severe anaphylactic shock;
• increased respiratory tract reactivity, including bronchial asthma, worsening of asthma symptoms, bronchospasm;
• aseptic meningitis (as a manifestation of hypersensitivity reaction) with nuchal rigidity, headache, nausea, vomiting, fever, disorientation – usually in patients with autoimmune diseases (such as systemic lupus erythematosus, diffuse connective tissue diseases).

Cases of serum sickness-like syndrome, lupus-like syndrome, and Henoch-Schönlein purpura have been reported during ibuprofen use.

Skin and subcutaneous tissue.

• Skin rashes (including maculopapular);
• severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis);
• DRESS syndrome (drug-induced eosinophilia with systemic symptoms), acute generalized exanthematous pustulosis.

Cases of photosensitivity reactions, alopecia, and increased sweating have been reported.

In rare cases, severe skin infections and soft tissue complications may occur during varicella infection.

Nervous system/psychiatric disorders.

• Headache;
• seizures, dizziness, emotional lability, irritability, nervousness; with long-term use only: psychotic reactions such as depression, hallucinations, confusion, coma;
• psychomotor agitation, anxiety, asthenia, sleep disturbances (including somnolence, insomnia), malaise, paresthesia, tremor.

Gastrointestinal tract.

• Epigastric discomfort, abdominal pain/cramps, dyspepsia, nausea;
• dry mouth, diarrhea, constipation, flatulence, vomiting, appetite changes (including anorexia);
• heartburn, glossitis, esophagitis, gastritis, duodenitis, erosive-ulcerative lesions of the gastrointestinal tract (including ulcerative stomatitis, gastric ulcer), perforations or gastrointestinal bleeding (including rectal bleeding), melena, hematemesis, sometimes fatal (especially in elderly patients), exacerbation of ulcerative colitis and Crohn's disease, pancreatitis, formation of diaphragm-like intestinal strictures.

Hepatobiliary system.

• Especially with long-term treatment: elevated serum transaminases, impaired liver function, hepatitis, jaundice, hepatorenal syndrome, liver necrosis, liver failure.

Urinary system.

• Cystitis, dysuria, possible renal function impairment leading to hyperkalemia, hyperuricemia, azotemia, decreased creatinine clearance, oliguria/polyuria, edema, acute renal failure (especially in patients with pre-existing significant renal impairment), tubular necrosis, papillary necrosis (especially with long-term use, associated with increased serum urea levels), various forms of toxic nephropathy, including interstitial nephritis, glomerulonephritis, nephritic syndrome, nephrotic syndrome, hematuria, proteinuria.

Sensory organs.

• With long-term treatment: tinnitus, hearing disturbances, hearing loss, vertigo, toxic optic neuritis, blurred vision, visual impairment, scotoma, toxic amblyopia, diplopia, color vision changes, conjunctivitis, "dry eye", cataract.

Cardiovascular system.

• Fluid retention, edema, hypotension/hypertension, palpitations, arrhythmias (including sinus tachycardia/bradycardia), heart failure, usually in patients with impaired cardiac function;
• Cozzarelli syndrome.

Respiratory system.

• Respiratory depression, apnea, non-cardiogenic pulmonary edema, pneumonia, alveolitis, rhinitis.

Metabolic disorders.

• Possible hyponatremia, hypoglycemia/hyperglycemia, acidosis, weight gain/loss, gynecomastia, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

If any adverse reactions occur, consult a physician regarding further use of the medication!

Reporting suspected adverse reactions.

Reporting of adverse reactions after drug registration is of great importance. It enables 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: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 capsules in a blister, 1 blister per pack; 10 capsules in a blister, 2 blisters per pack.

Prescription status. Over-the-counter.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical-Pharmaceutical Plant".

Manufacturer's address.

17 Myru Street, Kyiv, 03134, Ukraine.