INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BOFEN 400 (BOFEN 400)

Composition:

Active substance: ibuprofen;

One tablet contains 400 mg of ibuprofen;

Excipients: lactose monohydrate; sodium lauryl sulfate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate;

Film coating: graft copolymer of polyethylene glycol with polyvinyl alcohol, talc, titanium dioxide (E 171), glycerol monocaprylocaprate, polyvinyl alcohol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, biconvex film-coated tablets of white color.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen is a propionic acid derivative and a non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, and antipyretic activity. The therapeutic effects of the drug are believed to be due to its inhibitory action on the enzyme cyclooxygenase, resulting in a pronounced reduction in prostaglandin synthesis. These properties provide relief from symptoms of inflammation, pain, and fever.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when both drugs are administered simultaneously.

Some pharmacodynamic studies have shown that single doses of ibuprofen 400 mg administered 8 hours before or 30 minutes after immediate-release acetylsalicylic acid (81 mg) reduced the effect of acetylsalicylic acid on thromboxane formation or platelet aggregation.

Although there are uncertainties regarding extrapolation of these data to clinical settings, the possibility cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically relevant interactions are unlikely with occasional, non-regular use of ibuprofen (see section "Interaction with other medicinal products and other forms of interactions").

Pharmacokinetics.

Ibuprofen is rapidly absorbed from the gastrointestinal tract (GI tract). Maximum serum concentration is reached within 1–2 hours after administration. The elimination half-life is approximately 2 hours.

Ibuprofen is metabolized in the liver into two inactive metabolites, which are excreted by the kidneys along with unchanged ibuprofen, either in free form or as conjugates. Renal excretion is rapid and complete. Ibuprofen is highly bound to plasma proteins.

Clinical characteristics.

Indications.

For relief of mild to moderate pain, such as pain associated with dysmenorrhea, dental pain, and postoperative pain, as well as for symptomatic relief of headache, including migraine.

Contraindications.

Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.
Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after taking ibuprofen, acetylsalicylic acid, or other NSAIDs.
Active or a history of ulcerative colitis, Crohn’s disease, recurrent peptic ulcer, or gastrointestinal bleeding (two or more distinct episodes of confirmed ulceration or bleeding).
Gastrointestinal bleeding or perforation related to previous NSAID therapy.
Severe hepatic impairment, severe renal impairment, or severe heart failure (NYHA Class IV).
Active cerebrovascular or other bleeding conditions.
Disorders of blood coagulation or haemostasis.
Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Caution is advised when co-administering Bofen 400 with the following medicinal products due to potential drug interactions reported in some patients.

Antihypertensive agents, β-blockers, and diuretics. NSAIDs may reduce the antihypertensive effect of agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, and diuretics. Diuretics may also increase the risk of NSAID-induced nephrotoxicity.

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

Cholestyramine. Concomitant administration of ibuprofen and cholestyramine may reduce gastrointestinal absorption of ibuprofen; however, the clinical significance of this interaction is unknown.

Lithium. NSAIDs may reduce renal clearance of lithium.

Methotrexate. NSAIDs may inhibit tubular secretion of methotrexate and reduce methotrexate clearance.

Cyclosporine. Increased risk of nephrotoxicity has been observed when cyclosporine is used concomitantly with ibuprofen.

Mifepristone. A reduction in efficacy is theoretically possible due to the anti-prostaglandin properties of NSAIDs. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not alter the effect of mifepristone or prostaglandin on cervical ripening or uterine contractility, nor does it reduce the clinical efficacy of medical termination of pregnancy.

Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors. Concomitant use of ibuprofen with other NSAIDs, including COX-2 inhibitors, should be avoided due to the risk of increased adverse reactions (see section "Special precautions for use").

Acetylsalicylic acid. As with other NSAID-containing medicinal products, concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the increased risk of adverse effects.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly.

However, although the clinical relevance of these data has not been definitively established, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. A clinically significant interaction is unlikely with occasional ibuprofen use (see section "Pharmacodynamics").

Corticosteroids. Increased risk of gastrointestinal ulceration or bleeding when used concomitantly with ibuprofen (see section "Special precautions for use").

Anticoagulants. Ibuprofen may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use").

Quinolone antibiotics. Animal studies indicate that NSAIDs may increase the risk of convulsions associated with quinolone antibiotics. Patients receiving concomitant NSAIDs and quinolones have an increased risk of developing convulsions.

Sulfonylureas. NSAIDs may potentiate the effects of sulfonylurea agents. Rare cases of hypoglycemia have been reported in patients receiving sulfonylureas during ibuprofen therapy.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding when taken concomitantly with ibuprofen (see section "Special precautions for use").

Tacrolimus. Potential increase in the risk of nephrotoxicity when used in patients receiving tacrolimus.

Zidovudine. NSAIDs increase the risk of haematological toxicity when administered concomitantly with zidovudine. Evidence suggests an increased risk of haemarthroses and haematoma in HIV-positive patients with haemophilia who are treated with ibuprofen while taking zidovudine.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Herbal extracts. Ginkgo biloba may potentiate the risk of bleeding associated with NSAIDs.

CYP2C9 inhibitors. Concomitant use of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). One study demonstrated that voriconazole and fluconazole (CYP2C9 inhibitors) increased S(+)-ibuprofen exposure by approximately 80–100%. Dose reduction of ibuprofen should be considered when co-administered with CYP2C9 inhibitors, particularly when high doses of ibuprofen are prescribed to patients receiving voriconazole or fluconazole.

Special precautions for use.

General warnings

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

With prolonged use of any analgesic medication, headache may occur, which should not be treated with increased doses of the medicinal product.

Concomitant use of the medicinal product with alcohol may increase the risk of adverse reactions associated with the active substance, particularly gastrointestinal or central nervous system (CNS) effects, possibly due to additive action.

Elderly patients

In elderly patients, the frequency of adverse reactions during NSAID use is higher, especially gastrointestinal bleeding and perforations, which may be fatal (see section "Dosage and administration").

Paediatric population

There is a risk of impaired renal function in dehydrated children and adolescents.

Gastrointestinal bleeding, ulceration and perforation

The medicinal product Bofen 400 should be used with caution in patients with a history of peptic ulcer or other gastrointestinal disorders, as their condition may worsen (see section "Contraindications").

Gastrointestinal bleeding, ulceration or perforation have been reported during treatment with all NSAIDs, at any time during therapy. These adverse reactions may be fatal and may occur with or without warning symptoms, regardless of prior history of serious gastrointestinal pathology.

The risk of gastrointestinal bleeding, ulceration or perforation increases with higher doses of ibuprofen, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should initiate treatment with the lowest effective dose.

For these patients, as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products that may increase gastrointestinal risk, consideration should be given to concomitant use of protective agents such as misoprostol or proton pump inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ibuprofen with other NSAIDs, including selective COX-2 inhibitors, should be avoided due to increased risk of ulceration or bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal disorders, particularly elderly patients, should be advised to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly in the initial stages of treatment.

Ibuprofen should be prescribed with caution to patients receiving concomitant therapy with medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g. warfarin), SSRIs, or antiplatelet agents, including acetylsalicylic acid (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in a patient taking ibuprofen, the drug should be discontinued.

The medicinal product Bofen 400 should be prescribed with caution to patients with a history of ulcerative colitis or Crohn’s disease due to possible exacerbation (see section "Adverse reactions").

Respiratory disorders and hypersensitivity reactions

Ibuprofen should be prescribed with caution to patients suffering from bronchial asthma, chronic rhinitis, allergic conditions, or with a history of such conditions, as NSAIDs have been reported to induce bronchospasm, urticaria, or angioneurotic oedema in such patients.

Impairment of heart, kidney and liver function

Bofen 400 should be used with caution in patients with impaired renal, hepatic or cardiac function, as this may lead to worsening renal function.

The habitual concomitant use of various analgesics further increases this risk.

Systematic use of analgesics, especially combinations of different analgesic agents, further increases this risk.

Cases of Kounis syndrome have been reported in patients receiving treatment with ibuprofen. 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.

Patients with impaired renal, hepatic or cardiac function should be prescribed the lowest effective dose for the shortest possible duration, and renal function should be monitored, especially during prolonged treatment (see section "Contraindications").

Cardiovascular and cerebrovascular effects

Ibuprofen should be prescribed with caution to patients with a history of arterial hypertension and/or heart failure, as fluid retention and oedema associated with NSAID therapy have been reported.

Clinical studies indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may be associated with a small increase in the risk of arterial thrombotic events such as myocardial infarction or stroke. Overall, epidemiological data do not suggest an association between low-dose ibuprofen (≤ 1200 mg per day) and increased risk of arterial thrombotic events.

Ibuprofen should be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure (NYHA functional class II-III), diagnosed ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease only after careful consideration, and high doses of ibuprofen (2400 mg per day) should be avoided.

Careful consideration is also required before initiating long-term ibuprofen therapy in patients with risk factors for cardiovascular disease (such as arterial hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high-dose ibuprofen (2400 mg per day) is required.

Renal effects

Treatment with ibuprofen should be initiated with caution in patients with significant dehydration. There is a risk of impaired renal function, particularly in dehydrated children, adolescents and elderly patients.

As with other NSAIDs, prolonged use of ibuprofen may lead to renal papillary necrosis and other pathological changes in the kidneys. Renal toxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. Use of the medicinal product in such patients may cause dose-dependent reduction in prostaglandin synthesis and, secondarily, reduced renal blood flow, which may lead to renal failure.

Patients at high risk of such reactions include those with impaired renal function, heart failure, hepatic dysfunction, patients taking diuretics and ACE inhibitors, and elderly patients. Discontinuation of the medicinal product is usually followed by recovery to the pre-treatment state.

Systemic lupus erythematosus and mixed connective tissue disease

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue disease due to an increased risk of aseptic meningitis (see section "Adverse reactions" and aseptic meningitis below).

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), 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, have been reported during treatment with ibuprofen (see section "Adverse reactions"). Most of these reactions occur during the first month of treatment.

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

In rare cases, serious skin and soft tissue infections may occur during chickenpox. The role of NSAIDs in worsening such infections cannot currently be excluded; therefore, use of the medicinal product is not recommended during chickenpox.

Like other NSAIDs, ibuprofen may mask symptoms of infection, potentially delaying initiation of appropriate treatment and thereby complicating the course of the disease. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. If ibuprofen is used for fever or pain relief during infection, monitoring of the infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Haematological effects

Ibuprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time.

Aseptic meningitis

Rarely, aseptic meningitis has been observed in patients during treatment with ibuprofen. Although aseptic meningitis is more commonly observed in patients with systemic lupus erythematosus and related connective tissue diseases, cases have also been reported in patients without these chronic conditions.

Masking symptoms of underlying infections

Like other NSAIDs, ibuprofen may mask symptoms of infectious disease, potentially delaying initiation of appropriate treatment and thereby complicating the course of the infection. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When ibuprofen is used for fever or pain relief during infection, monitoring of the disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Excipients

Patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The medicinal product contains < 1 mmol sodium per dose, i.e. essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or embryonic/foetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with higher doses and longer duration of therapy. Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre- and post-implantation loss and embryo/foetal death. In addition, increased incidence of various malformations, including cardiovascular, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Use of ibuprofen from week 20 of pregnancy may cause oligohydramnios due to foetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of the drug. Furthermore, cases of foetal ductus arteriosus constriction have been reported after treatment during the second trimester of pregnancy, most of which resolved after discontinuation of therapy. Therefore, during the first and second trimesters of pregnancy, ibuprofen should not be used except when clearly necessary. When ibuprofen is used in women planning pregnancy or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered if exposure to ibuprofen occurs for several days starting from week 20 of gestation. Use of the medicinal product Bofen 400 should be discontinued if oligohydramnios or ductus arteriosus constriction in the foetus is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the foetus by causing:

− cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

− impaired renal function, which may progress to renal failure with oligohydramnios.

At the end of pregnancy, prostaglandin synthesis inhibitors expose both mother and newborn to the following risks:

− possible prolongation of bleeding time, antiplatelet effect, which may develop even at very low doses;

− inhibition of uterine contractions, which may lead to delayed or prolonged labour.

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

Labour and delivery

Use of ibuprofen during labour and delivery is not recommended.

Onset of labour may be delayed, duration prolonged, and susceptibility to bleeding in both mother and child increased.

Lactation

Limited available data show that NSAIDs, including ibuprofen, pass into breast milk in very low concentrations. Ibuprofen is not recommended for use in women during lactation.

Fertility

Use of ibuprofen may impair female fertility and is therefore not recommended for women attempting to conceive. For women experiencing infertility or undergoing fertility investigations, discontinuation of ibuprofen should be considered.

Ability to affect reaction speed when driving or operating machinery.

Ibuprofen may affect patients' reaction speed, which should be considered when engaging in activities requiring heightened attention, such as driving or operating machinery. This effect is significantly enhanced when combined with alcohol.

After taking NSAIDs, adverse effects such as dizziness, somnolence, fatigue and visual disturbances may occur. If such effects occur during NSAID use, patients should not drive or operate machinery.

Method of administration and dosage.

Doses

For short-term use only.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control disease symptoms (see section "Special precautions for use***"*** ).

During short-term use, if symptoms persist or worsen, the patient should consult a physician.

Adults and children aged 12 years and older

The recommended daily dose is 1200 mg, divided into several doses. Some patients may require only 600–1200 mg per day.

Elderly patients

There is an increased risk of serious adverse reactions when using the drug in elderly patients. If treatment is necessary, the lowest effective dose should be prescribed for the shortest possible duration. Regular monitoring for gastrointestinal bleeding should be performed during NSAID therapy. In cases of impaired liver and/or kidney function, dosage must be individually adjusted.

Patients with renal impairment

Patients with mild to moderate renal impairment do not require dose reduction (for patients with severe renal impairment, see section "Contraindications").

Patients with hepatic impairment

Patients with mild to moderate hepatic impairment do not require dose reduction (for patients with severe hepatic impairment, see section "Contraindications").

Method of administration

For oral use.

The drug should preferably be taken during or after meals, with a large amount of liquid. Tablets should be swallowed whole, without chewing, dividing, crushing, or dissolving, to avoid oral discomfort and throat irritation.

Children

Do not use in children under 12 years of age.

More convenient dosage forms are available for young children.

Overdose

Toxicity

Toxicity symptoms are generally not observed with doses below 100 mg/kg in children and adults. However, supportive measures may be required in some cases. In children, toxicity symptoms have been reported after ibuprofen ingestion at doses of 400 mg/kg or higher.

Symptoms

In most patients, overdose symptoms develop within 4–6 hours after ingestion of a significant amount of ibuprofen.

The most common symptoms of overdose include nausea, vomiting, abdominal pain, lethargy, and drowsiness. Central nervous system (CNS) effects: headache, tinnitus, dizziness, seizures, and loss of consciousness. Rarely reported: nystagmus, metabolic acidosis, hypothermia, renal symptoms, gastrointestinal bleeding, diarrhea, coma, apnea, CNS depression, and respiratory depression.

Metabolic acidosis may occur in severe poisoning. Disorientation, agitation, unconsciousness, and cardiovascular toxicity, including arterial hypotension, bradycardia, and tachycardia, have been reported. With significant overdose, renal failure and liver damage may develop. Overdose with large doses of the drug is usually well tolerated, provided no other drugs are taken concomitantly.

Treatment

There is no specific antidote for ibuprofen overdose. If the ingested amount exceeds 400 mg/kg, gastric lavage/emptying is recommended within 1 hour of ingestion, followed by symptomatic treatment. Activated charcoal should be administered within 1 hour after ingestion of a potentially toxic amount. Treatment should include ensuring airway patency and monitoring cardiac function and vital signs until the patient's condition normalizes.

Adequate diuresis should be maintained.

Renal and hepatic function should be closely monitored.

Patients should be observed for at least 4 hours after ingestion of a potentially toxic amount.

Frequent or prolonged seizures should be treated with intravenous diazepam. Other interventions may be indicated depending on the patient's clinical condition.

For the most up-to-date information, contact the local poison control center.

Adverse reactions.

The adverse reactions of ibuprofen are similar to those observed with other NSAIDs.

Gastrointestinal system. Adverse reactions affecting the gastrointestinal system are the most commonly observed. Peptic ulcers, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special precautions").

Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, gastrointestinal bleeding, and exacerbation of colitis and Crohn's disease have been reported during ibuprofen use (see section "Special precautions"). Gastritis, gastric ulcer, duodenal ulcer, gastrointestinal perforation, and pancreatitis have been observed less frequently.

Immune system. Hypersensitivity reactions have been reported with NSAIDs, including ibuprofen. These include nonspecific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, worsening of asthma, bronchospasm, or dyspnea; and various skin manifestations, including rashes of different types, pruritus, urticaria, purpura, angioedema, and very rarely—multiform erythema, bullous dermatoses (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

Cardiovascular system. Edema, arterial hypertension, and heart failure have been reported in association with NSAID therapy.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg per day), may slightly increase the risk of arterial thrombotic events, such as myocardial infarction or stroke (see section "Special precautions").

Infections and infestations. Rhinitis and aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus and mixed connective tissue diseases) with symptoms such as neck rigidity, headache, nausea, vomiting, fever, or disorientation have been reported (see section "Special precautions").

Cases of exacerbation of infectious diseases coinciding with NSAID use have been described. If signs of infection appear or worsen during treatment, patients should seek immediate medical advice.

Skin and subcutaneous tissue disorders. In rare cases, severe skin infections and soft tissue complications may occur during chickenpox (see also "Infections and infestations").

Adverse reactions reported with ibuprofen use are classified by organ systems and frequency of occurrence according to MedDRA.

Frequency of adverse reactions is defined as follows: 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), and frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – rhinitis; rare – aseptic meningitis (see section "Special precautions").

Blood and lymphatic system disorders: rare – leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Immune system disorders: uncommon – hypersensitivity reactions; rare – anaphylactic reaction.

Psychiatric disorders: uncommon – insomnia, anxiety disorders; rare – depression, confusion.

Nervous system disorders: common – headache, dizziness; uncommon – paresthesia, somnolence; rare – optic neuritis.

Eye disorders: uncommon – visual disturbances; rare – toxic optic neuropathy.

Ear and labyrinth disorders: uncommon – hearing impairment, tinnitus, vertigo.

Respiratory system disorders: uncommon – bronchial asthma, bronchospasm, dyspnea.

Gastrointestinal disorders: common – dyspepsia, diarrhea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, hematemesis, gastrointestinal bleeding; uncommon – gastritis, duodenal ulcer, gastric ulcer, ulcerative stomatitis, gastrointestinal perforation; very rare – pancreatitis; frequency not known – exacerbation of colitis and Crohn's disease.

Hepatobiliary disorders: uncommon – hepatitis, jaundice, liver function abnormalities; very rare – liver failure.

Skin and subcutaneous tissue disorders: common – rash; uncommon – urticaria, pruritus, purpura, angioedema, photosensitivity reactions; very rare – serious skin adverse reactions (SSARs) (including multiform erythema, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis); frequency not known – drug-induced eosinophilia with systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP).

Renal and urinary disorders: uncommon – toxic nephropathy in various forms, including tubulointerstitial nephritis, nephrotic syndrome, and renal failure.

General disorders and administration site conditions: common – fatigue; rare – edema.

Cardiac disorders: very rare – heart failure, myocardial infarction (see section "Special precautions"); frequency not known – Kounis syndrome.

Vascular disorders: very rare – arterial hypertension.

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life.

4 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 2 blisters per carton.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

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

Manufacturer's address and location of business activity.

17 Miru Street, Kyiv, 03134, Ukraine.

Bophen 400