Gofen 400

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HOFEN 400

Composition:

Active ingredient: ibuprofen;

1 soft capsule contains ibuprofen 400 mg;

Excipients: polyethylene glycol 600, potassium hydroxide, purified water;

gelatin capsule shell: gelatin, non-crystallizing sorbitol solution (E 420), purified water.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: elongated soft capsules with transparent, naturally colored shells; the capsule contents are a clear, colorless, oily liquid.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. 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 reduce the effect of low-dose acetylsalicylic acid on platelet aggregation when both agents are administered concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) was associated with reduced effects of acetylsalicylic acid (aspirin) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding extrapolation of these data to clinical settings, the possibility that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. With occasional, non-regular use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics

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

Following metabolism in the liver (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are excreted predominantly in urine (90%) and also via 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 immediate-release dosage form, maximum plasma concentration is reached within 1–2 hours. Ibuprofen remains detectable in plasma for more than 8 hours after drug intake.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origins (headache, toothache, painful menstruation), 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, angioneurotic edema, 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 NSAID therapy.

• 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.

• Blood dyscrasias of unknown etiology.

• 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 may increase the risk of adverse reactions, except when aspirin (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 do not allow definitive conclusions on 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 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 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 ACE inhibitors or angiotensin II antagonists 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 used with caution, particularly 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 start of combination 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 monitoring is recommended);

• corticosteroids: increased risk of gastrointestinal ulcers and bleeding;

• antiplatelet agents and selective serotonin reuptake inhibitors: 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;

• methotrexate: administration of ibuprofen within 24 hours before or after methotrexate dosing 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: possible increased risk of nephrotoxicity when used concomitantly with NSAIDs and tacrolimus;

• zidovudine: increased risk of hematological toxicity is known with concomitant use of zidovudine and NSAIDs. Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen;

• quinolone antibiotics: concomitant use with ibuprofen may increase the risk of seizures;

• sulfonylureas: blood glucose monitoring is recommended as a precautionary measure during concomitant use;

• probenecid and sulfinpyrazone: may delay the elimination of ibuprofen.

• CYP2C9 inhibitors: 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 used concomitantly with potent CYP2C9 inhibitors, especially when high doses of ibuprofen are used 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 relieve 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 or 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 are also at increased risk of hypersensitivity reactions when using the drug;
• suffering from hay fever, nasal polyps, chronic obstructive respiratory diseases, or with a history of allergic conditions, due to increased risk of allergic reactions. These patients may experience asthma attacks (so-called analgesic-induced asthma), Quincke's edema, or urticaria.

Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be fatal.

• Respiratory system effects. Bronchospasm may occur in patients with bronchial asthma or allergic conditions, or with a history of such diseases.
• 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 porphyrin metabolism disorders (e.g. acute intermittent porphyria).
• Cardiovascular and cerebrovascular effects. Patients with a history of arterial hypertension and/or heart failure should begin treatment cautiously (physician consultation 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, especially at high doses (2400 mg per day), may be associated with a slightly increased risk of arterial thrombotic complications (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 be treated with ibuprofen only after careful assessment of the clinical picture. High doses (2400 mg per day) should be avoided.

Clinical evaluation should also be carefully performed 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.

Cardiovascular and cerebrovascular effects. Cases of Kounis syndrome have been reported in patients receiving treatment with GOHFEN 400. 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.

• Renal effects. Ibuprofen should be used with caution in patients with impaired renal function, as kidney function may deteriorate. There is a risk of renal dysfunction in adolescents with dehydration.
• Hepatic effects. Impaired liver function may occur.
• Surgical procedures. Caution is advised immediately after major surgical interventions.
• Effects on female fertility. Limited data suggest that drugs which inhibit cyclooxygenase/prostaglandin synthesis, when used long-term (referring to a dose 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.
• Gastrointestinal effects. NSAIDs should be used cautiously in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated. 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 those 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).

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued immediately.

• Serious skin reactions.

Rare but serious skin reactions, potentially fatal, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been reported with the use of nonsteroidal anti-inflammatory drugs (see section "Adverse reactions").

The risk of these reactions is highest at the beginning of therapy. Most cases occur within the first month of treatment. Cases of acute generalized exanthematous pustulosis have also been reported following administration of ibuprofen-containing medications.

Ibuprofen should be discontinued at the first signs or symptoms of skin involvement, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

In rare cases, chickenpox may lead to severe skin and soft tissue infections. At present, a negative influence of NSAIDs on the course of these infections cannot be ruled out; therefore, the use of ibuprofen in chickenpox is not recommended.

• Masking symptoms of underlying infections.

GOHFEN 400 may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and thereby complicating the disease course. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. When GOHFEN 400 is used for fever or pain relief during infection, monitoring for infectious disease 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 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 conditions have an increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic-induced asthma), Quincke's edema, or urticaria.

This medicinal product contains sorbitol. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or deficiencies of sucrase or isomaltase enzymes must not take this medicinal product.

• Other. Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are very rarely observed. If the first signs of a hypersensitivity reaction occur after drug administration, treatment must be discontinued immediately. 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 use of the drug, 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 situation is suspected or confirmed, medical advice should be sought and treatment discontinued. Medication-overuse headache should be considered in patients suffering from 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 risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration.

Concomitant alcohol consumption during NSAID use may increase the risk of adverse effects related to the active substance, particularly gastrointestinal or central nervous system effects.

Use during pregnancy or breastfeeding.

Pregnancy.

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, cases of ductus arteriosus constriction have been reported after second-trimester treatment, most of which resolved after stopping therapy. 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 ductus arteriosus constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

Risks to the fetus:

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

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

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

Therefore, GOHFEN 400 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 the breastfed infant. NSAIDs are not recommended during breastfeeding.

Fertility.

The use of ibuprofen may affect female fertility. This effect is reversible upon discontinuation of treatment. Therefore, ibuprofen use 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 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 Precautions").

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 needed 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). Use the lowest effective dose required to treat symptoms for the shortest possible duration.

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

If fever persists for more than 3 days in adults, or if pain persists for more than 4 days, or if symptoms worsen, consult a physician for diagnosis clarification and treatment adjustment.

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 risk 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 Precautions".

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

Children

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

Overdose

Administration of the drug to children at doses exceeding 400 mg/kg may cause symptoms of intoxication. In adults, the dose effect 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. 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 injury, 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 ensuring airway patency and monitoring 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, administration of alkaline agents may enhance renal elimination of acidic ibuprofen. For 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.

Adverse reactions.

The list of adverse reactions observed after 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 rheumatism. The specified frequencies exceeding 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 the 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, worsening of asthma, bronchospasm, dyspnea;
• various skin reactions, for example, pruritus, urticaria, angioneurotic edema, and rarely – 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 ibuprofen use 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 should seek immediate medical advice. It is necessary to determine whether antimicrobial/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 ulceration, influenza-like symptoms, severe fatigue, unexplained bleeding, and bruising.

In such cases, patients should be advised to discontinue the 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, angioneurotic edema, 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.

Vascular disorders.

Very rare: arterial hypertension, vasculitis;

Frequency not known: edema, Coombs syndrome (frequency "not known").

Gastrointestinal disorders.

Common: dyspepsia, heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, and 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 the use of the medicinal product and seek medical advice if upper abdominal pain, melena, or hematemesis occurs.

Hepatobiliary disorders.

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

Skin and subcutaneous tissue disorders.

Uncommon: various skin rashes;

Very rare: severe skin reactions, such as bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), 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 function impairment, papillary necrosis, particularly with prolonged use, associated with increased serum urea levels;

Very rare: edema, especially 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.

Investigations.

Rare: decreased hemoglobin levels.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 capsules in a blister, 1 blister in a cardboard sleeve. 5 or 6 cardboard sleeves in a cardboard box.

Availability.

Over-the-counter (without prescription).

Manufacturer.

Mega Lifesciences Public Company Limited.

Manufacturer's address and location of operations.

Plant 2, 515/1 Moo 4, Soi 8, Bangpoo Industrial Estate, Pattana 3 Road, Phraeksa, Mueang, Samutprakarn 10280, Thailand.