Nurofen® express forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NUROFEN® EXPRESS FORTE (NUROFEN® EXPRESS FORTE)

Composition:

Active ingredient: ibuprofen.

1 soft capsule contains 400 mg of ibuprofen;

Excipients: macrogol 600, potassium hydroxide, purified water, gelatin, sorbitol solution partially dehydrated (E 420), Ponceau 4R (E 124), printing ink for capsule Opacode WB white NS-78-18011.

Pharmaceutical form. Soft capsules.

Main physicochemical characteristics: red, oval, transparent soft gelatin capsules with the identification mark "NUROFEN" printed in white ink.

Pharmacotherapeutic group.

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

ATC code M01AE01.

Pharmacological properties.

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

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when these drugs are used concomitantly. Some pharmacodynamic studies have shown that administration of single doses of 400 mg ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) resulted in reduced effects of acetylsalicylic acid (aspirin) on thromboxane production or platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to the clinical setting, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, non-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

Inside the capsules of Nurofen® Express Forte are ibuprofen dissolved in a hydrophilic solvent. After oral administration, the gelatin capsule disintegrates under the action of gastric juice, thereby releasing pre-dissolved ibuprofen.

Pharmacokinetics. After oral administration, ibuprofen is rapidly absorbed partially already in the stomach and completely in the small intestine.

Following hepatic metabolism (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are excreted predominantly in the urine (90%) and also in bile. The elimination half-life in healthy volunteers as well as in patients with hepatic or renal disease ranges from 1.8 to 3.5 hours. Plasma protein binding is approximately 99%. After oral administration of the conventional release dosage form, maximum plasma concentration is reached within 1–2 hours. In a pharmacokinetic study, the time to peak plasma concentration (Tmax) on an empty stomach was 90 minutes for the tablet formulation, whereas for Nurofen® Express Forte soft capsules it was 40 minutes. Ibuprofen remains detectable in plasma for more than 8 hours after administration of Nurofen® Express Forte soft capsules.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origins (headache, toothache, dysmenorrhea), including pain associated with colds and influenza.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product.
• Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
• Active peptic ulcer disease/gastrointestinal bleeding or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation related to previous use of NSAIDs.
• Severe impairment of liver function, severe impairment of kidney function, severe heart failure (NYHA Class IV).
• Third trimester of pregnancy.
• Active cerebrovascular or other bleeding.
• Hemorrhagic diathesis or coagulation disorders.
• Unexplained disturbances in blood formation.
• Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
• Patient weight less than 40 kg or patient age under 12 years.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, like other NSAIDs, should not be used in combination with:

• acetylsalicylic acid (aspirin), as this increases the risk of adverse reactions, except when aspirin (at a dose not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that concomitant administration of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. However, limitations regarding extrapolation of these data to clinical settings prevent definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant effects are considered unlikely with occasional use of ibuprofen.

• other NSAIDs, including selective cyclooxygenase-2 inhibitors:

Concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to synergistic effects. Therefore, concomitant use of ibuprofen with other NSAIDs should be avoided.

Ibuprofen should be used with caution in combination with the following medicinal products:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin.

Antihypertensive agents (ACE inhibitors (angiotensin-converting enzyme inhibitors) and angiotensin II antagonists) and diuretics: NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised kidney function), concomitant use 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 prescribed cautiously, especially in elderly patients. If long-term treatment is necessary, adequate hydration of the patient should be ensured, and monitoring of renal function should be considered at the initiation of combined therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Concomitant use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia (serum potassium levels should be checked).

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): may increase the risk of gastrointestinal bleeding.

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

Lithium: evidence suggests a potential increase in plasma lithium levels.

Phenytoin: concomitant use with phenytoin preparations may increase its serum levels.

MTX (methotrexate): administration of ibuprofen within 24 hours before or after methotrexate may lead to increased methotrexate concentrations and enhanced toxicity.

Cyclosporine: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used earlier than 8–12 days after administration of mifepristone, as they may reduce its efficacy.

Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

Zidovudine: increased risk of hematological toxicity is known with concomitant use of zidovudine and NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: concomitant use with ibuprofen may increase the risk of seizures.

Sulfonylureas: blood glucose levels should be monitored as a precautionary measure during concomitant use.

Probenecid and sulfinpyrazone: may delay excretion of ibuprofen.

Inhibitors of CYP2C9: concomitant use of ibuprofen with CYP2C9 inhibitors may increase the effect of ibuprofen (a CYP2C9 substrate). Studies with voriconazole and fluconazole (CYP2C9 inhibitors) have shown an approximately 80–100% increase in the effect of S(+)-ibuprofen. Dose reduction of ibuprofen should be considered when potent CYP2C9 inhibitors are used concomitantly, especially when high doses of ibuprofen are administered with voriconazole or fluconazole.

Special precautions for use.

Adverse effects associated with the use of ibuprofen and NSAIDs in general can be minimized by using the lowest effective dose required to treat symptoms, for the shortest possible duration.

Caution is necessary when treating patients:

• with systemic lupus erythematosus or mixed connective tissue disease – increased risk of aseptic meningitis (see section "Adverse reactions");
• with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria) (see section "Adverse reactions");
• with gastrointestinal disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) (see section "Adverse reactions");
• with arterial hypertension and/or heart failure (see sections "Contraindications" and "Adverse reactions");
• with impaired renal function, as kidney function may deteriorate (see sections "Contraindications" and "Adverse reactions");
• with impaired liver function (see sections "Contraindications" and "Adverse reactions");
• following major surgical procedures;
• with allergic reactions to other substances, as they may have an increased risk of hypersensitivity reactions when using the drug;
• who suffer from hay fever, nasal polyps, chronic obstructive respiratory diseases, or have a history of allergic diseases, as they are at increased risk of allergic reactions. Such patients may experience asthma attacks (so-called analgesic-induced asthma), Quincke's edema (angioedema), or urticaria.

Elderly patients are at increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be fatal.

Respiratory effects

Bronchospasm may occur in patients suffering from bronchial asthma or allergic diseases, or with a history of such conditions.

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, increases the risk of adverse reactions and should therefore be avoided.

Systemic lupus erythematosus and mixed connective tissue diseases

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue diseases due to an increased risk of aseptic meningitis.

Porphyrin metabolism

Caution should be exercised in patients with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Effects on the cardiovascular and cerebrovascular systems

Patients with a history of arterial hypertension and/or heart failure should begin treatment cautiously (medical consultation is required), as fluid retention, arterial hypertension, and edema have been reported during ibuprofen therapy, as with other NSAIDs.

Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses (2400 mg per day), may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g., ≤1200 mg per day) increases the risk of arterial thrombotic complications.

Patients with uncontrolled arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful assessment of the clinical condition. High doses (2400 mg per day) should be avoided.

The clinical condition should also be carefully evaluated before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg per day) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen. Kounis syndrome presents with cardiovascular symptoms related to coronary artery spasm due to an allergic or hypersensitivity reaction, which may lead to myocardial infarction.

Effects on the kidneys

Ibuprofen should be used with caution in patients with impaired renal function, as kidney function may deteriorate.

Effects on the liver

Liver function impairment is possible.

Surgical procedures

Caution is required immediately after major surgical procedures.

Effects on female fertility

Limited data suggest that drugs which inhibit cyclooxygenase/prostaglandin synthesis, when used long-term (doses of 2400 mg per day and treatment duration exceeding 10 days), may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Effects on the gastrointestinal system

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as these conditions may worsen. Cases of gastrointestinal bleeding, perforation, and ulcers, possibly fatal, have been reported during NSAID therapy at any stage, regardless of prior warning symptoms or history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer (especially complicated by bleeding or perforation), and in elderly patients. Such patients should start treatment with the lowest possible doses. For these patients, as well as for individuals requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, consideration should be given to combining therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

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

Caution is required when treating patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., aspirin).

In case of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Severe skin adverse reactions

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

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

In rare cases, varicella (chickenpox) may lead to severe skin and soft tissue infections. At present, a potential negative influence of NSAIDs on such infections cannot be excluded; therefore, the use of ibuprofen in cases of varicella is not recommended.

Masking symptoms of underlying infections

Nurofen® Express Forte may mask symptoms of bacterial infection, potentially delaying appropriate treatment and worsening disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Nurofen® Express Forte is used to reduce fever or relieve pain associated with infection, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Allergy

Caution is required in patients with allergic reactions to other substances, as they may have an increased risk of hypersensitivity reactions when using ibuprofen.

Patients with hay fever, nasal polyps, chronic obstructive respiratory diseases, or a history of allergic diseases are at increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic-induced asthma), Quincke's edema (angioedema), or urticaria.

This medicinal product contains sorbitol. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

This medicinal product contains Ponceau 4R (E124), which may cause allergic reactions.

NSAIDs may mask symptoms of infection and fever.

Other

Very rarely, severe acute hypersensitivity reactions (e.g., anaphylactic shock) may occur. At the first signs of a hypersensitivity reaction after taking Nurofen® Express Forte, treatment must be discontinued. Symptomatic and specialized therapy should be initiated in such cases.

Ibuprofen may temporarily inhibit platelet function (affect platelet aggregation). Therefore, careful monitoring of patients with coagulation disorders is recommended.

During prolonged treatment with Nurofen® Express Forte, liver and kidney function tests, as well as blood counts, should be monitored regularly.

Long-term use of any analgesic for headache treatment may worsen the condition. If this is suspected or confirmed, medical advice should be sought and treatment discontinued. Medication-overuse headache should be considered in patients with frequent or daily headaches despite (or because of) regular use of headache medications.

Regular use of analgesics, particularly combinations of multiple analgesics, may lead to persistent kidney dysfunction with a risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration.

Concomitant use of alcohol with NSAIDs may increase the risk of adverse effects related to the active substance, particularly gastrointestinal or central nervous system (CNS) effects.

There is a risk of impaired kidney function in dehydrated adolescents.

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 heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

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, there have been reports of arterial duct constriction after second-trimester treatment, most of which resolved after stopping treatment. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless necessary. If ibuprofen is used by women trying to conceive 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 several days of ibuprofen exposure from the 20th gestational week onward. Ibuprofen use 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 to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above);

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

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

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

In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to adversely affect a breastfed infant. However, NSAIDs are not recommended during breastfeeding.

Fertility

Ibuprofen use may affect female fertility. This effect is reversible upon discontinuation of treatment. Therefore, ibuprofen is not recommended for women experiencing difficulty conceiving.

Ability to affect reaction speed when driving or operating machinery

Patients who experience dizziness, drowsiness, or visual disturbances while taking ibuprofen should avoid driving or operating machinery. Single-dose administration or short-term use of ibuprofen generally does not require special precautions. This primarily applies to concomitant use of the drug with alcohol.

When used according to recommended doses and treatment duration, the drug does not affect reaction speed during driving or operating machinery.

Dosage and Administration

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

Administered orally to adults and children aged 12 years and older with body weight > 40 kg. For short-term use only. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Capsules should preferably be taken during or after meals, without chewing, and swallowed with water.

The single dose for children aged 12 years and older with body weight > 40 kg and for adults is 1 capsule (400 mg of ibuprofen). If necessary, 1 capsule may be administered every 6 hours. The maximum daily dose is 1200 mg (3 capsules per day). The minimum effective dose required to treat symptoms should be used for the shortest possible duration.

If symptoms worsen or persist for more than 3 days in adolescents, a physician should be consulted for diagnosis clarification and treatment adjustment.

If elevated body temperature persists for more than 3 days in adults, or if pain persists for more than 4 days, or if disease symptoms worsen, a physician should be consulted for diagnosis clarification and treatment adjustment.

The duration of treatment is determined individually by a physician, depending on the course of the disease and the patient's condition.

Elderly patients do not require special dose adjustment, except in cases of severe renal or hepatic impairment. Due to the possibility of adverse effects, elderly patients require careful monitoring.

Patients with mild to moderate renal impairment do not require dose reduction; for patients with severe renal impairment, see section "Special Warnings and Precautions for Use".

Dose reduction is not required for patients with mild or moderate hepatic impairment; for patients with severe renal impairment, see section "Special Warnings and Precautions for Use".

Children

Not recommended for children under 12 years of age or for children with body weight < 40 kg.

Overdose

Administration of doses exceeding 400 mg/kg of the drug to children may cause intoxication symptoms. In adults, the effect of overdose is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients who have ingested clinically significant amounts of NSAIDs, only nausea, vomiting, epigastric pain, or very rarely diarrhea, develop. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may occur, manifesting as vertigo, drowsiness, occasionally agitation, disorientation, or coma. Seizures may occasionally be observed in patients. Severe poisoning may lead to hyperkalemia and metabolic acidosis. Prolongation of prothrombin time/increased prothrombin index may be observed, possibly due to effects on circulating blood coagulation factors. Acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis may develop. In patients with bronchial asthma, exacerbation of the disease may occur.

Treatment. Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac and vital functions until condition stabilizes. Oral activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, alkalizing agents may be administered to enhance urinary excretion of the acidic ibuprofen. In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used to treat bronchial asthma exacerbation.

There is no specific antidote.

Adverse Reactions

The list of adverse reactions observed following ibuprofen treatment includes all side effects reported during short-term use as well as those observed during long-term, high-dose therapy in patients with rheumatic diseases. The frequency stated beyond very rare reports refers to short-term use of doses (maximum 1200 mg ibuprofen per day) for oral dosage forms and up to 1800 mg per day for suppositories.

The development of adverse drug reactions primarily depends on dosage and individual patient characteristics.

The most commonly observed adverse reactions are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation, or gastrointestinal hemorrhage, sometimes with fatal outcomes, particularly in elderly patients, may occur. During treatment, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn’s disease have been reported. Gastritis occurs less frequently. The risk of gastrointestinal bleeding is mainly dose- and duration-dependent. Reports have also documented edema, arterial hypertension, and heart failure associated with NSAID therapy.

Clinical studies indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Hypersensitivity reactions have been reported, which may manifest as:

• Non-specific allergic reactions and anaphylaxis;
• Respiratory tract reactivity, such as asthma, worsening of asthma, bronchospasm, dyspnea;
• Various skin reactions, for example, pruritus, urticaria, angioedema, and less frequently – exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

The patient should immediately discontinue the drug and inform their physician if any of the above symptoms occur.

Adverse reactions associated with ibuprofen use are listed by organ systems and frequency of occurrence. Frequency categories are 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 parasitic diseases.

Very rare: Exacerbation of infection-related inflammation.

If signs of infection occur or worsen during treatment, patients are advised to seek immediate medical attention. It is necessary to determine whether anti-infective/antibacterial therapy is indicated.

Symptoms of aseptic meningitis, including nuchal rigidity, headache, nausea, vomiting, fever, or altered consciousness, have been observed in patients with autoimmune diseases such as systemic lupus erythematosus and mixed connective tissue disease during ibuprofen use.

Blood and lymphatic system disorders.

Very rare: Blood dyscrasias (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms may include fever, sore throat, oral ulceration, influenza-like symptoms, severe fatigue, unexplained bleeding, or bruising.

In such cases, patients should be advised to discontinue the drug and consult a physician.

Regular blood monitoring is recommended during prolonged therapy.

Immune system disorders.

Uncommon: Hypersensitivity reactions including urticaria and pruritus;

Very rare: Severe hypersensitivity reactions, symptoms of which may include facial, tongue, or laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylactic reactions, angioedema, or severe shock; asthma exacerbation, bronchospasm.

Psychiatric disorders.

Very rare: Psychotic reactions, depression.

Nervous system disorders.

Uncommon: Headache, dizziness, insomnia, anxiety, irritability, or fatigue.

Eye disorders.

Uncommon: Visual disturbances.

Ear and labyrinth disorders.

Rare: Tinnitus, hearing loss.

Cardiac disorders.

Very rare: Palpitations, heart failure, myocardial infarction.

Frequency not known: Kounis syndrome.

Vascular disorders.

Very rare: Arterial hypertension, vasculitis;

Frequency not known: Edema.

Gastrointestinal disorders.

Common: Dyspepsia, heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, minor gastrointestinal bleeding, which may exceptionally lead to anemia;

Uncommon: Peptic ulcer, perforation or gastrointestinal hemorrhage, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis;

Very rare: Esophagitis, pancreatitis, intestinal diaphragm-like strictures.

Patients should immediately discontinue the drug and seek medical advice if upper abdominal pain, melena, or hematemesis occurs.

Hepatobiliary disorders.

Very rare: Liver function abnormalities, liver damage (especially with prolonged therapy), liver failure, acute hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: Various skin rashes;

Very rare: Severe skin adverse reactions (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), alopecia.

In some cases, varicella may be a source of serious skin and soft tissue infections;

Frequency not known: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis; photosensitivity reactions.

Renal and urinary disorders.

Rare: Acute renal impairment, papillary necrosis (especially with prolonged use), associated with increased serum urea levels;

Very rare: Edema, particularly in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis, which may be accompanied by acute renal failure. Therefore, regular monitoring of renal function is recommended.

Laboratory investigations.

Rare: Decreased hemoglobin levels.

Shelf life. 3 years.

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 pack, 1 or 2 blisters per cardboard box.

Availability.

Over-the-counter.

Manufacturer.

Reckitt Benckiser Healthcare International Limited.

Manufacturer's location and address of business operations.

Nottingham site, Taymount Road, Nottingham, NG90 2DB, United Kingdom.