INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IBUPROFEN

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 on capsule Opacode WB white NSP-78-18022.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: oval soft capsule with red gelatin shell bearing a logo printed in white ink, filled with a clear liquid.

Pharmacotherapeutic group.

Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives.

ATC code M01A E01.

Pharmacological Properties.

Pharmacodynamics. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, 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 administered concomitantly. Some pharmacodynamic studies have shown that administration of single doses of ibuprofen 400 mg within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) was associated with reduced effect of acetylsalicylic acid (aspirin) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding the possibility of extrapolating these findings to the clinical setting, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional use of ibuprofen, such a clinically significant effect is considered unlikely.

The capsule contains 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 more completely in the small intestine.

Following metabolism in the liver (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are excreted predominantly in 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. Protein binding to plasma proteins 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 levels (Tmax) on an empty stomach was 90 minutes for the tablet formulation and 40 minutes for soft capsules. Ibuprofen can be detected in plasma for more than 8 hours after administration of the ibuprofen soft capsules.

Clinical characteristics.

Indications.

For symptomatic treatment of mild to moderate pain of various origin (headache, toothache, dysmenorrhea), including pain associated with colds and fever.

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 associated with previous use of NSAIDs.
Severe hepatic impairment, severe renal impairment, severe heart failure (NYHA Class IV — New York Heart Association classification).
Third trimester of pregnancy.
Active cerebrovascular or other hemorrhages.
Hemorrhagic diathesis or coagulation disorders.
Unexplained disturbances of 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 (dose not exceeding 75 mg per day) is prescribed by a physician.

Experimental data indicate that concomitant use of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. However, uncertainty regarding the possibility of extrapolating these data to clinical situations does not allow definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional use of ibuprofen, such clinically significant effects are considered unlikely;

other NSAIDs, including selective cyclooxygenase-2 inhibitors: concomitant use of multiple NSAIDs increases 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 renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed cautiously, particularly in elderly patients. In cases of long-term treatment, adequate hydration should be ensured and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter. Diuretics 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 monitored).

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased 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 mifepristone administration, as they may reduce its efficacy.

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

Zidovudine: increased risk of hematological toxicity is known when zidovudine is used concomitantly with NSAIDs. Evidence suggests 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 increases the risk of seizures.

Sulfonylureas: glucose levels in blood should be monitored during concomitant use.

Probenecid and sulfinpyrazone: may delay the elimination of ibuprofen.

CYP2C9 inhibitors: concomitant use of ibuprofen with CYP2C9 inhibitors may increase the effects of ibuprofen (ibuprofen is a CYP2C9 substrate). In studies with voriconazole and fluconazole (CYP2C9 inhibitors), the effect of S(+)-ibuprofen was increased by approximately 80–100%. 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 advised 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 worsen (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 taking the medicinal product;
who suffer from hay fever, nasal polyps, chronic obstructive respiratory diseases, or have a history of allergic conditions, as they are at increased risk of allergic reactions. These may manifest as asthma attacks (so-called analgesic-induced asthma), angioedema, or urticaria.

Elderly patients have an increased frequency 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 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 is advised in patients with congenital disorders of porphyrin metabolism (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 required), as fluid retention, 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), is 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 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 clinical assessment. High doses (2400 mg per day) should be avoided.

Cases of Kounis syndrome have been reported in patients receiving 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.

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

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

Impaired liver function may occur.

Surgical procedures

Caution is advised immediately after major surgical procedures.

Effects on female fertility

Some data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis, when used long-term (doses of 2400 mg per day and treatment duration exceeding 10 days), may impair fertility in women 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, including fatal outcomes, have been reported during NSAID therapy at any stage, regardless of prior 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 if 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 those requiring concomitant use of low-dose acetylsalicylic acid or other drugs that 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 advised when treating patients receiving concomitant medications that 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 cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), 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 with ibuprofen use (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).

In rare cases, varicella may lead to severe skin and soft tissue infections. At present, the potential influence of NSAIDs on worsening the course of these infections cannot be excluded; therefore, the use of ibuprofen in cases of varicella is not recommended.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious disease, potentially delaying appropriate treatment and thereby worsening the course of the illness. Such masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief during infection, monitoring for infection progression is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Allergy

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

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

This medicinal product contains sorbitol. If the patient has been diagnosed with intolerance to certain sugars, a physician should be consulted 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) have been observed. If the first signs of hypersensitivity occur after taking ibuprofen, treatment must be discontinued. Symptomatic and specialized therapy should be initiated in such cases.

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

During long-term use of ibuprofen, liver and kidney function tests, as well as blood counts, should be monitored regularly.

Prolonged use of any analgesic for headache treatment may worsen the condition. If such worsening 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 due to) regular use of headache medications.

Chronic use of analgesics, especially 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 NSAIDs with alcohol increases the risk of adverse effects related to the active substance, particularly on the gastrointestinal tract or CNS (central nervous system).

There is a risk of impaired kidney function in adolescents with dehydration.

Use during pregnancy or breastfeeding

Inhibition of prostaglandin synthesis may negatively 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.

Use of ibuprofen from week 20 of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug.

Cases of ductus arteriosus constriction during second-trimester treatment have also been reported, most of which resolved after stopping treatment.

Therefore, NSAIDs should not be used during the first two trimesters of pregnancy unless, in the physician’s opinion, the potential benefit to the patient outweighs the potential risk to the fetus. If ibuprofen is used by a woman trying to conceive or during the first or second trimester of pregnancy, the lowest possible dose should be used for the shortest possible duration.

Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after several days of ibuprofen use starting from week 20 of pregnancy. Ibuprofen should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

to the fetus: cardiopulmonary toxicity (characterized by premature constriction/closure of the ductus arteriosus and pulmonary hypertension); impaired renal function, which may progress to renal failure associated with oligohydramnios (see above);
to the mother near term and the newborn: prolonged bleeding time, antiplatelet effect (which may occur even at very low doses), and inhibition of uterine contractions, leading to delayed or prolonged labor.

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

In some studies, ibuprofen has been detected in breast milk at very low concentrations; therefore, it is unlikely to have a negative effect on the breastfed infant.

NSAIDs are not recommended during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

Patients experiencing 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 with alcohol.

When used according to recommended doses and treatment duration, the medicinal product does not affect reaction speed when 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").

Administer 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 required 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 (body weight > 40 kg) and 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). Use the minimum effective dose required to treat symptoms for the shortest possible duration.

If symptoms worsen or persist for more than 3 days in adolescents, medical advice should be sought to confirm diagnosis and adjust treatment.

If in adults fever persists for more than 3 days, pain does not resolve within 4 days, or symptoms worsen, medical advice should be sought to confirm diagnosis and adjust treatment.

The duration of treatment should be 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 potential for 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 necessary for patients with mild or moderate hepatic impairment; for patients with severe renal impairment, see section "Special Warnings and Precautions for Use".

Children

Do not administer to children under 12 years of age or to children with body weight < 40 kg.

Overdose

Administration of ibuprofen to children in doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, the dose-related effects are 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 occur. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, manifesting as vertigo, drowsiness, occasionally agitation, disorientation, or coma. Seizures may sometimes occur. Severe intoxication 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, disease exacerbation may occur.

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

There is no specific antidote.

Side effects.

The list of adverse reactions observed after treatment with ibuprofen includes all side effects reported during short-term use as well as those observed during long-term, high-dose therapy in patients with rheumatism. The frequencies stated beyond very rare reports refer 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 reactions to the medicinal product primarily depends on the dose and individual patient characteristics.

The most commonly observed adverse reactions are related to the gastrointestinal tract. Peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes with fatal outcomes, may occur, particularly in elderly patients. During use of the drug, 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 mainly depends on the dose and duration of treatment. Reports have been documented regarding edema, arterial hypertension, and heart failure associated with NSAID therapy.

Clinical studies indicate that the use of ibuprofen, especially 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, exacerbation 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 use of the medicinal product in case of any of the above-mentioned manifestations and inform their physician.

Adverse reactions observed during the use of ibuprofen are listed by organ systems and frequency of occurrence. The 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 based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and parasitic diseases.

Very rare: exacerbation of inflammation associated with infection.

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

Aseptic meningitis symptoms, 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 disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include sore throat, oral mucosal ulceration, influenza-like symptoms, severe fatigue, unexplained bleeding, and bruising.

In such cases, patients should be advised to discontinue use of this medicinal product 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, and laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylactic reactions, angioedema, or severe shock; exacerbation of asthma, 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, gastrointestinal perforation or bleeding, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis;

Very rare: esophagitis, pancreatitis, formation of intestinal diaphragm-like strictures.

The patient must immediately discontinue use of the medicinal product and seek medical advice if upper abdominal pain, melena, or hematemesis occurs.

Hepatic disorders.

Very rare: liver function abnormalities, liver damage (especially with long-term therapy), liver failure, acute hepatitis.

Skin and subcutaneous tissue disorders.

Uncommon: various skin rashes;

Very rare: severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, alopecia);

In some cases, varicella may lead to serious skin and soft tissue infections;

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP); 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, renal function should be monitored regularly.

Laboratory investigations.

Rare: decreased hemoglobin levels.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Packaging.

10 soft capsules in a blister, 1 or 2 blisters per cardboard carton.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

Catalent Germany Eberbach GmbH / Catalent Germany Eberbach GmbH.

Manufacturer's address.

Gammelsbacher Str. 2, 69412 Eberbach, Germany.