Darfen ultracap 400

Ukraine
Brand name Darfen ultracap 400
Form capsules, soft gelatin
Active substance / Dosage
ibuprofen · 400 mg
Prescription type over-the-counter (OTC)
ATC code
M01AE01
Registration number UA/20095/01/02
Manufacturer Phil Inter Pharma Co., Ltd. (manufacturing of finished products, primary and secondary packaging, quality control and batch release; quality control)
Darfen ultracap 400 capsules, soft gelatin

Table of Contents

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Darfen® Ultracap 400 (Darfen Ultracap 400)

Composition:

Active substance: ibuprofen;

1 soft capsule contains 400 mg of ibuprofen;

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

capsule shell: gelatin, partially dehydrated liquid sorbitol (polysorb 85/70/00), purified water, brilliant blue FCF.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: elongated soft gelatin capsules of dark blue color, containing a solution ranging from clear to pale blue.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Ibuprofen. 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 reduce the effect of low-dose acetylsalicylic acid (ASA) on platelet aggregation when these medicinal products are used concomitantly. In some pharmacodynamic studies, administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release ASA (81 mg) was associated with reduced effect of ASA on thromboxane formation or platelet aggregation. Although there is uncertainty about extrapolating these data to the clinical setting, it cannot be ruled out that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose ASA. With occasional, non-regular use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics.

The soft gelatin capsule contains ibuprofen dissolved in a hydrophilic solvent. After oral administration, the gelatin capsule disintegrates under the influence of gastric juice, thereby releasing the pre-dissolved ibuprofen.

Ibuprofen is rapidly absorbed partially 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 the urine (90%) and also in bile. The elimination half-life in healthy volunteers, as well as in patients with hepatic or renal impairment, 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 levels (Tmax) on an empty stomach was 90 minutes for the tablet formulation, whereas for the soft capsule formulation it was 40 minutes. Ibuprofen in the form of soft capsules remains detectable in plasma for more than 8 hours after administration.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origins (headache, toothache, dysmenorrhea), as well as for cold and fever.

Contraindications.

  • Hypersensitivity to ibuprofen or to any component of the medicinal product.
  • Patients with a history of hypersensitivity reactions (including asthma, rhinitis, angioedema, or urticaria) associated with the use of acetylsalicylic acid (ASA) or other NSAIDs.
  • Patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy.
  • Concomitant use with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors.
  • Active peptic ulcer/gastrointestinal bleeding or history thereof (two or more distinct episodes of peptic ulceration or bleeding).
  • Severe renal, hepatic, or cardiac insufficiency [NYHA functional class IV].
  • Active cerebrovascular or other hemorrhages.
  • Hematopoietic disorders of unknown etiology.
  • Hemorrhagic diathesis or coagulation disorders.
  • Active inflammatory bowel disease.
  • Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
  • Children under 12 years of age weighing less than 40 kg.
  • Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

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

ASA. Concomitant use of ibuprofen with ASA is generally not recommended due to the potential for increased adverse reactions, except when low-dose ASA (not exceeding 75 mg per day) has been prescribed by a physician.

According to experimental data, ibuprofen may competitively inhibit the effect of low-dose ASA on platelet aggregation when administered concomitantly. Although uncertainty exists regarding extrapolation of these data to clinical practice, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose ASA. Such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

Other NSAIDs, including selective COX-2 inhibitors. Concomitant use of two or more NSAIDs should be avoided, as this increases the risk of gastrointestinal ulcers and bleeding due to synergistic effects.

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

Corticosteroids. Increase the risk of gastrointestinal ulcers and bleeding.

Antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II antagonists, and β-blockers) 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 reduced renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist and drugs inhibiting COX may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, particularly in elderly patients. If prolonged treatment is necessary, 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.

Anticoagulants. NSAIDs may enhance the therapeutic effect of anticoagulants such as warfarin.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding when used concomitantly with NSAIDs.

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 may increase methotrexate concentrations and enhance its toxicity.

Cyclosporine, tacrolimus. Increased risk of nephrotoxicity.

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

Zidovudine. Increased risk of hematological toxicity is known with concomitant use of zidovudine and 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. Animal studies indicate that NSAIDs increase the risk of seizures associated with quinolone antibiotics.

Sulfonylurea agents and phenytoin. Possible potentiation of the effects of these drug groups. Rare cases of hypoglycemia have been reported in patients receiving sulfonylureas during ibuprofen therapy. Blood glucose levels should be monitored during concomitant use.

Digoxin. Increased plasma levels of both medicinal products.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Probenecid and sulfinpyrazone. Concomitant use with ibuprofen may delay its excretion.

Potassium-sparing diuretics. Concomitant administration of ibuprofen with potassium-sparing diuretics may lead to hyperkalemia (monitoring of plasma potassium levels is recommended).

Baclofen. Increased risk of toxic effects of baclofen after initiation of ibuprofen therapy.

Cytochrome CYP2C9 inhibitors. Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). In one study, voriconazole and fluconazole (CYP2C9 inhibitors) increased S(+)-ibuprofen exposure by approximately 80–100%. Consideration should be given to reducing the dose of ibuprofen when co-administered with strong CYP2C9 inhibitors, especially when high doses of ibuprofen are prescribed concurrently with voriconazole or fluconazole.

Oral hypoglycemic agents. Inhibition of metabolism of sulfonylurea drugs, prolonged elimination half-life, and increased risk of hypoglycemia.

Antacids and cholestyramine. Concomitant use of cholestyramine and ibuprofen delays and reduces ibuprofen absorption by 25%. Ibuprofen should be administered with a several-hour interval.

Caffeine. Possible enhancement of analgesic effect with concomitant use.

Special precautions for use.

Undesirable effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The medicinal product should be used with caution in patients:

  • with systemic lupus erythematosus and mixed connective tissue disease — increased risk of aseptic meningitis (see section "Adverse reactions");
  • with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria);
  • with chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) and gastrointestinal disorders (see section "Adverse reactions");
  • with arterial hypertension and/or heart failure associated with fluid retention and edema during previous NSAID use (see sections "Contraindications" and "Adverse reactions");
  • with impaired kidney and/or liver function (see sections "Contraindications" and "Adverse reactions");
  • suffering from hay fever, nasal polyps, chronic obstructive respiratory diseases, or with a history of allergic conditions, as they have an increased risk of allergic reactions. These patients may experience asthma attacks (so-called analgesic asthma), Quincke's edema, or urticaria;
  • following surgical procedures.

Elderly patients.

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

Respiratory system effects.

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

Other NSAIDs.

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

Systemic lupus erythematosus and mixed connective tissue diseases.

Patients with systemic lupus erythematosus and mixed connective tissue diseases may have an increased risk of developing aseptic meningitis (see section "Adverse reactions").

Kidney effects.

Prolonged and uncontrolled use of analgesics, especially combinations of different analgesic active substances, may lead to chronic kidney damage with a risk of renal failure (analgesic nephropathy). There is a risk of renal failure in dehydrated children and adolescents.

Liver effects.

Liver function impairment is possible (see sections "Contraindications" and "Adverse reactions").

Surgical procedures.

Caution should be exercised immediately after major surgical procedures.

Cardiovascular and cerebrovascular system effects.

Patients with a history of arterial hypertension and/or moderate to severe congestive heart failure should begin treatment with caution (medical consultation required), as fluid retention, arterial hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs. Clinical trial data and epidemiological evidence suggest that the use of ibuprofen, particularly at high doses (2400 mg per day) and long-term treatment, slightly increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Overall, epidemiological data 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), 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. Careful evaluation of the clinical picture is also required 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 Darfen® Ultracap 400. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic reaction or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Gastrointestinal system effects.

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 ones, have been reported during NSAID therapy at any stage of treatment, regardless of the presence of warning symptoms or a 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. These patients should start treatment with the lowest doses. For such patients, as well as for those requiring concomitant use of low-dose aspirin or other medicinal products increasing gastrointestinal risk, consideration should be given to combined 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 should be exercised when treating patients receiving concomitant medicinal products that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents (e.g., aspirin).

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

Severe skin reactions.

Severe skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug-induced eosinophilia with 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 and symptoms indicating these reactions appear, ibuprofen should be discontinued immediately, and alternative treatment options should be considered (if necessary).

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

Allergic reactions.

Caution should be exercised in patients with allergic reactions to other substances, as these patients have an increased risk of hypersensitivity reactions when using ibuprofen.

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

Masking symptoms of underlying infections.

Ibuprofen may mask symptoms of infectious diseases and thereby delay the initiation of appropriate treatment, complicating the course of the disease. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. In cases of varicella, treatment with ibuprofen should be avoided.

When ibuprofen is used for fever or pain relief during infection, monitoring of the infectious disease is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Porphyria.

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

Other.

Very rarely, severe acute hypersensitivity reactions (e.g., anaphylactic shock) occur. If the first signs of hypersensitivity occur after ibuprofen administration, therapy should be discontinued. In such cases, both symptomatic and specialized treatment should be provided.

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, regular monitoring of blood laboratory parameters, liver, and kidney function is necessary.

Prolonged use of any analgesic for headache treatment may worsen this condition. If worsening is suspected or confirmed, patients should consult a physician and discontinue treatment. Medication-overuse headache should be suspected in patients suffering from frequent or daily headaches despite (or due to) regular use of headache medications.

Chronic use of analgesic medicinal products, especially their combinations, may lead to kidney function impairment with a risk of developing renal failure (analgesic nephropathy). This risk may be increased due to low salt concentration and dehydration. Such patients should use the lowest possible dose of ibuprofen and regularly monitor kidney function. In case of dehydration, adequate fluid intake should be ensured.

Concomitant use of NSAIDs and alcohol increases the risk of adverse effects on the gastrointestinal tract or central nervous system (CNS).

Important information about excipients.

The medicinal product contains sorbitol; therefore, patients with rare hereditary fructose intolerance should consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

First and second trimesters of pregnancy. Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from 1% to approximately 1.5%. The risk is believed to increase with higher doses and longer duration of treatment.

In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation loss and embryonic/fetal mortality. Additionally, increased incidence of various developmental abnormalities, including cardiovascular defects, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, use of Darfen® Ultracap 400 may cause oligohydramnios due to fetal kidney dysfunction. This condition may occur at the beginning of treatment and is usually reversible after discontinuation of therapy. Additionally, there have been reports of arterial duct constriction after treatment in the second trimester, most of which resolved after discontinuation of therapy. Therefore, Darfen® Ultracap 400 should not be taken during the first and second trimesters of pregnancy, except when absolutely necessary. If the medicinal product is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the lowest possible dose for the shortest possible duration should be used.

Fetal monitoring for oligohydramnios and arterial duct constriction should be performed for several days after administration of Darfen® Ultracap 400, starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, the medicinal product should be discontinued.

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

for the fetus:

  • cardiopulmonary toxicity (characterized by premature constriction/closure of the arterial duct and pulmonary hypertension);
  • impaired kidney function, which may progress to renal failure accompanied by oligohydramnios;

for the mother and newborn:

  • possible prolongation of bleeding time, antiplatelet effect, which may develop 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.

Breastfeeding period. In some studies, ibuprofen was detected in breast milk at very low concentrations, so it is unlikely to have a negative effect on the infant. NSAIDs are not recommended during breastfeeding.

Fertility. The use of ibuprofen may affect female fertility. This effect is reversible after discontinuation of treatment. Therefore, the use of ibuprofen is not recommended in women with difficulty conceiving (see section "Special precautions for use").

Ability to influence reaction rate when driving or operating machinery.

With short-term use, the medicinal product does not affect the ability to drive or operate machinery. However, adverse effects such as dizziness, drowsiness, or visual disturbances may occur after taking NSAIDs. If such adverse reactions occur, driving and operating machinery should be avoided.

Single or short-term use of ibuprofen usually does not require special precautions — this mainly applies to concomitant use of the drug with alcohol. Provided dosage and treatment duration recommendations are followed, ibuprofen does not affect reaction speed when driving or operating machinery.

Method of Administration and Dosage

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

Capsules should preferably be taken during or after food intake. They must not be chewed and should be swallowed with water.

The single dose for children aged 12 years and older with body weight > 40 kg, as well as for adults, is 1 capsule (400 mg of ibuprofen). If necessary, 1 capsule may be administered every 6–8 hours. The maximum daily dose is 1200 mg (3 capsules per day). Do not exceed the maximum recommended daily dose.

If symptoms persist for more than 3 days or worsen in adolescents (aged 12 years and older), medical advice should be sought for diagnosis clarification and treatment adjustment.

If elevated body temperature persists for more than 3 days in adults, or if pain does not resolve within 4 days, or if symptoms worsen, medical advice should be sought 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 impairment of renal and/or hepatic function do not require dose reduction, unlike patients with severe renal and/or hepatic insufficiency — see section "Special Precautions".

Children

Darfen® Ultracap 400 should not be used in children under 12 years of age or in children with body weight < 40 kg.

Overdose

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

Symptoms. In most patients who have taken clinically significant amounts of NSAIDs, nausea, vomiting, epigastric pain, or very rarely diarrhea, may occur. Tinnitus, headache, dizziness, and gastrointestinal bleeding are also possible. In more severe poisoning, toxic CNS effects may develop, manifesting as vertigo, drowsiness, nystagmus, blurred vision, and occasionally agitation, disorientation, coma; seizures may occur in some patients. Severe intoxication may lead to hyperkalemia with cardiac rhythm disturbances, metabolic acidosis, elevated body temperature, prolonged prothrombin time/increased prothrombin index (possibly due to effects on circulating blood coagulation factors), hemolytic anemia, granulocytopenia, and thrombocytopenia. Acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis may also develop. In patients with bronchial asthma, disease exacerbation is possible.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring of cardiac function and vital signs until stabilization. Monitoring for signs of gastrointestinal bleeding, metabolic acidosis, and CNS disturbances is essential. Oral activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen absorption has already occurred, alkalizing agents may be administered to enhance urinary excretion of the acidic ibuprofen. For 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.

Side effects.

The list of adverse reactions observed following 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 frequency indicated beyond rare reports refers to short-term use of doses (up to 1200 mg ibuprofen per day) of oral dosage forms.

The development of adverse reactions to the medicinal product primarily depends on the dose and individual characteristics of the organism.

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 ibuprofen use, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn’s disease have been reported. Gastritis may occur less frequently. The risk of gastrointestinal bleeding mainly depends on the dose and duration of treatment. Cases of edema, arterial hypertension, and heart failure associated with NSAID therapy have been reported.

Clinical trial data indicate that the use of ibuprofen, especially at high doses of 2400 mg per day, increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

The patient should immediately discontinue the use of the medicinal product in case of any of the above-mentioned symptoms and inform their physician.

All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 — < 1/10), uncommon (≥ 1/1,000 — < 1/100), rare (≥ 1/10,000 — < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Eye disorders: uncommon — visual disturbances (toxic optic neuropathy, blurred vision or diplopia, scotoma, dryness and irritation of eyes, allergic conjunctival and eyelid edema).

Ear and labyrinth disorders: rare — hearing disturbances (hearing loss, tinnitus or ear ringing).

Gastrointestinal disorders: common — abdominal pain, nausea, dyspepsia, diarrhea, flatulence, constipation, heartburn, vomiting, and minor gastrointestinal blood loss, which in exceptional cases may lead to anemia; uncommon — gastric ulcer, gastrointestinal perforation, or gastrointestinal bleeding. Ulcerative stomatitis, gastritis. Exacerbation of ulcerative colitis and Crohn’s disease; rare — esophagitis, formation of intestinal diaphragm-like strictures, pancreatitis.

The patient must immediately discontinue the use of the medicinal product and consult a physician if upper abdominal pain, melena, or hematemesis occurs.

Hepatobiliary disorders: rare — liver function abnormalities, liver damage (especially with prolonged therapy), liver failure, acute hepatitis.

Renal and urinary disorders: rare — acute renal function impairment, papillary necrosis (particularly with long-term use of NSAIDs), associated with increased serum urea levels; rare — development of 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.

Nervous system disorders: uncommon — headache, dizziness, insomnia, psychomotor agitation, irritability, fatigue; rare — aseptic meningitis2.

Psychiatric disorders: rare — psychotic reactions, depression.

Cardiovascular disorders: rare — heart failure, palpitations, myocardial infarction, edema, arterial hypertension, vasculitis; frequency not known — Kounis syndrome.

Blood and lymphatic system disorders: rare — blood formation disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs include: high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, nosebleeds, and bruising. In such cases, the patient should discontinue the use of this medicinal product and consult a physician.

During long-term therapy, blood parameters should be monitored regularly.

Immune system disorders: uncommon — hypersensitivity reactions accompanied by urticaria and pruritus1; rare — severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, airway narrowing, dyspnea, tachycardia, arterial hypotension (anaphylaxis, angioedema, or severe shock), asthma exacerbation; frequency not known — respiratory tract reactivity, including asthma, bronchospasm, or dyspnea.

Skin and subcutaneous tissue disorders: uncommon — various skin rashes; very rare — severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), alopecia; frequency not known — drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions. In some cases, varicella may be a source of serious skin and soft tissue infections.

Infections and infestations: rare — exacerbation of infection-related inflammation (e.g., necrotizing fasciitis). If signs of infection occur or worsen during treatment, the patient is advised to seek immediate medical attention.

Investigations: rare — decreased hemoglobin levels.

1 Hypersensitivity reactions may include: non-specific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, asthma exacerbation, bronchospasm, and dyspnea; various forms of skin reactions, including pruritus, urticaria, purpura, angioedema, and less frequently, exfoliative and bullous dermatoses (including toxic epidermal necrolysis and erythema multiforme).

2 The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. Available data on aseptic meningitis associated with NSAID use suggest a hypersensitivity reaction (based on temporal association with drug intake and symptom resolution after discontinuation of the drug). Isolated cases of aseptic meningitis symptoms (neck stiffness, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with autoimmune diseases (systemic lupus erythematosus and mixed connective tissue disease).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

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, 1 blister per carton.

Prescription status. Over-the-counter.

Manufacturer. Phil Inter Pharma Co., Ltd.

Manufacturer's address and location of business operations.

No. 20, Huu Nghia Boulevard, VSIP, Thuan An, Binh Duong, VN-590000, Vietnam.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnitsya".

Address of the Marketing Authorization Holder.

13, Boryspilska St., Kyiv, 02093, Ukraine.