Darfen® ultracap 200: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Darfen® Ultracap 200 (Darfen Ultracap 200)

Composition:

Active ingredient: ibuprofen;

1 soft capsule contains ibuprofen 200 mg;

Excipients: polyethylene glycol 600, polysorbate 80, potassium hydroxide, butylated hydroxytoluene, purified water;

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

Pharmaceutical form. Soft capsules.

Main physicochemical properties: soft gelatin capsules of oval shape, green in color, containing a solution ranging from clear to pale green.

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 suppressing 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 (ASA) on platelet aggregation when these medicinal products are used concomitantly. In some pharmacodynamic studies, administration of single doses of ibuprofen 400 mg within 8 hours before or within 30 minutes after immediate-release ASA (81 mg) was associated with reduced ASA effects on thromboxane formation or platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to the clinical setting, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose ASA. With occasional, non-systematic 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, resulting in the release of already dissolved ibuprofen.

Pharmacokinetics.

After oral administration, ibuprofen is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration of ibuprofen is reached approximately 1–2 hours after intake. Ibuprofen is metabolized in the liver and excreted by the kidneys (90%) both unchanged and as metabolites, as well as in bile. The elimination half-life in healthy individuals is about 1.8 hours; in patients with hepatic or renal disease, it ranges from 1.8 to 3.5 hours. Ibuprofen is highly bound (99%) to plasma proteins and slowly penetrates into synovial cavities, where its concentration may remain high even as plasma concentration decreases.

In two pharmacokinetic studies, the time to reach maximum plasma concentration (Tmax) for ibuprofen in tablet form was 60 and 90 minutes, compared to 35 and 40 minutes, respectively, for ibuprofen in soft capsules. The average Cmax is achieved twice as fast with ibuprofen in soft capsules compared to the conventional immediate-release tablet formulation. Ibuprofen in soft capsule form remains detectable in blood plasma for more than 8 hours after administration.

Clinical characteristics.

Indications.

For the treatment of headache, dental and menstrual pain symptoms, as well as for fever and muscle pain associated with colds.

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 or past history of peptic ulcer/gastrointestinal bleeding (two or more distinct episodes of ulceration or bleeding in the past).
Severe renal, hepatic, or cardiac [NYHA Class IV] insufficiency.
Active cerebrovascular or other bleeding conditions.
Blood dyscrasias of unknown origin.
Hemorrhagic diathesis or coagulation disorders.
Active inflammatory bowel disease.
Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).
Children under 6 years of age weighing less than 20 kg.
Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interactions.

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 effects, except when low-dose ASA (not exceeding 75 mg daily) 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 the clinical setting, it cannot be ruled out 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-regular 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:

Glucocorticoids. Increase the risk of gastrointestinal ulcers and bleeding.

Antihypertensive agents (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, β-blockers) and diuretics. NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. 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 drugs that inhibit COX may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. In cases of prolonged 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.

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

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding when taken 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. There is evidence of an increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. There are reports of 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.

Oral hypoglycemic agents of the sulfonylurea group and phenytoin. Possible potentiation of the effects of these agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas during ibuprofen therapy. Blood glucose levels should be monitored during concomitant use.

Digoxin. Plasma levels of both medicinal products may be increased.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

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

Potassium-sparing diuretics. Concomitant use 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%. Dose reduction of ibuprofen should be considered when co-administered with strong CYP2C9 inhibitors, especially when high doses of ibuprofen are prescribed along 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. When cholestyramine and ibuprofen are used concomitantly, absorption of ibuprofen is delayed and reduced by 25%. Ibuprofen should be administered with a several-hour interval.

Caffeine. Concomitant use may enhance the analgesic effect.

Special precautions for use.

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

The drug 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 gastrointestinal (GI) disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn's disease) (see section "Adverse reactions");
with a history of arterial hypertension and/or heart failure associated with fluid retention and edema during NSAID use (see sections "Contraindications" and "Adverse reactions");
with impaired renal and/or hepatic function (see sections "Contraindications" and "Adverse reactions");
suffering from hay fever, nasal polyps, chronic obstructive respiratory diseases, or with a history of allergic conditions, due to increased risk of allergic reactions. In such patients, asthma attacks (so-called analgesic-induced asthma), Quincke's edema (angioedema), or urticaria may occur;
following surgical procedures.

Elderly patients.

The frequency of adverse reactions with NSAIDs is higher in elderly patients, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Respiratory effects.

Ibuprofen should be prescribed with caution in patients with bronchial asthma, chronic rhinitis, allergic conditions, or a history thereof, as NSAIDs have been reported to provoke bronchospasm.

Other NSAIDs.

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

Systemic lupus erythematosus and mixed connective tissue diseases.

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

Renal effects.

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

Hepatic effects.

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

Surgical procedures.

Caution should be exercised immediately after major surgical interventions.

Cardiovascular and cerebrovascular effects.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure should begin treatment cautiously (medical 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 indicate that the use of ibuprofen, particularly at high doses (2400 mg daily) and over prolonged periods, moderately 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 daily) 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 condition. High doses (2400 mg daily) should be avoided. A careful evaluation of the clinical condition is also required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high-dose ibuprofen (2400 mg daily) is needed.

Cases of Kounis syndrome have been reported in patients receiving Darfen® Ultracap 200. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Gastrointestinal 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, sometimes fatal, have been reported during NSAID therapy at any stage, regardless of prior warning symptoms or history of severe GI 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 doses. For these patients, as well as for those requiring concomitant use of low-dose acetylsalicylic acid (ASA) or other drugs increasing GI risk, combined therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

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

Caution is required when treating patients receiving concomitant medications that increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents (e.g., ASA).

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

Severe skin reactions

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 indicating these reactions appear, ibuprofen should be discontinued immediately and alternative treatment considered (if necessary).

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

Allergic reactions

Caution is advised in patients with allergic reactions to other substances, as such patients have an increased risk of hypersensitivity reactions with 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.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious diseases, leading to delayed initiation of appropriate treatment and potentially worsening the course of illness. Such symptom masking has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella.

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

Porphyria.

Caution is advised in patients with congenital porphyrin metabolism disorders (e.g., acute intermittent porphyria).

Other

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rare. If early signs of hypersensitivity occur after ibuprofen administration, treatment must be discontinued. Symptomatic and specialized treatment should be initiated in such cases.

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

During prolonged ibuprofen use, regular monitoring of blood laboratory parameters, liver, and kidney function is necessary.

Long-term use of any analgesic for headache treatment may worsen the condition. If worsening is suspected or confirmed, ibuprofen should be discontinued and medical advice sought. 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, may lead to kidney dysfunction with risk of renal failure (analgesic nephropathy). This risk may be increased by low salt concentration and dehydration. Such patients should receive the lowest possible ibuprofen dose, and kidney function should be monitored regularly. Adequate fluid intake should be ensured in case of dehydration. There is a risk of renal failure in dehydrated children (from 6 years of age) and adolescents.

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.

Darfen® Ultracap 200 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 suggest an increased risk of miscarriage and congenital malformations (e.g., cardiac defects, 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 believed to increase with higher doses and longer duration of treatment.

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

From the 20th week of pregnancy, use of Darfen® Ultracap 200 may cause oligohydramnios due to fetal renal dysfunction. This condition may occur early in treatment and is usually reversible upon discontinuation. There are also reports of arterial duct constriction after treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Darfen® Ultracap 200 should not be used during the first and second trimesters of pregnancy, except when absolutely necessary. Women attempting to conceive and those in the first and second trimesters of pregnancy should use the lowest possible dose for the shortest possible duration.

Oligohydramnios and arterial duct constriction should be monitored for several days after administration of Darfen® Ultracap 200, starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, the drug should be discontinued.

Third trimester of pregnancy. Use of prostaglandin synthesis inhibitors during the third trimester of pregnancy is associated with the following risks:

for the fetus:

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

for the mother near term and the newborn:

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

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

Lactation period. Ibuprofen has been detected in breast milk at very low concentrations in some studies, making it unlikely to adversely affect 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 with fertility problems (see section "Special precautions for use").

Ability to influence reaction speed when driving or operating machinery.

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

Single-dose administration or short-term use of ibuprofen generally does not require special precautions. This primarily applies to concomitant use of the drug with alcohol. When used according to recommended dosage and treatment duration, the drug does not affect reaction speed when driving or operating machinery.

Method of Administration and Dosage

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms (see section "Special Precautions").

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

Adults and children with body weight ≥ 40 kg. The recommended initial dose is 1–2 capsules, followed if necessary by 1–2 capsules (200–400 mg of ibuprofen) every 4–6 hours. Do not exceed 6 capsules (1200 mg) within 24 hours.

Children with body weight ≤ 39 kg. The medicinal product may be used in children with body weight of at least 20 kg. The maximum daily dose of ibuprofen is 20–30 mg per kilogram of body weight, divided into 3–4 doses administered at intervals of 6–8 hours. Do not exceed the maximum recommended daily dose.

Children with body weight from 30 to 39 kg. The recommended initial dose is 1 capsule (equivalent to 200 mg of ibuprofen). The maximum daily dose is 4 capsules (equivalent to 800 mg of ibuprofen).

Children with body weight 20–29 kg. The recommended initial dose is 1 capsule (equivalent to 200 mg of ibuprofen). The maximum daily dose is 3 capsules (equivalent to 600 mg of ibuprofen).

If symptoms persist for more than 3 days, or pain does not subside within 4 days, or if symptoms worsen, consult a physician for diagnosis clarification and treatment adjustment.

Elderly patients do not require special dose adjustment.

Children.

The medicinal product Darfen® Ultracap 200 is contraindicated in children with body weight less than 20 kg.

Overdose.

Administration of the drug to children in 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 taken clinically significant amounts of NSAIDs, nausea, vomiting, epigastric pain, or very rarely diarrhea may develop. Tinnitus, headache, dizziness, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic CNS effects may occur, manifesting as vertigo, drowsiness, nystagmus, blurred vision, occasionally agitation, disorientation, coma, and sometimes seizures. In severe poisoning, hyperkalemia with cardiac arrhythmia, 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 may develop. Acute renal failure, liver damage, arterial hypotension, respiratory failure, and cyanosis may occur. In patients with bronchial asthma, exacerbation of the disease may occur.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac function and vital signs until condition stabilizes. Continuous monitoring is required to detect signs of possible gastrointestinal bleeding, metabolic acidosis, and CNS disturbances. Oral administration of activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen absorption has already occurred, alkaline agents may be administered to enhance urinary excretion of acidic ibuprofen. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used to treat exacerbations of bronchial asthma.

There is no specific antidote.

Adverse Reactions

The adverse reactions listed below were observed during short-term use of ibuprofen doses not exceeding 1200 mg per day. Additional adverse effects may occur during chronic disease treatment with long-term use.

Gastrointestinal adverse reactions are the most commonly observed and are mostly dose-dependent. In particular, the risk of gastrointestinal bleeding depends on both the dose and duration of treatment.

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

All adverse reactions are listed by organ systems and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and 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 noise).

Gastrointestinal disorders:
Uncommon – dyspepsia, abdominal pain, nausea;
Rare – diarrhea, flatulence, constipation, vomiting;
Very rare – gastric ulcer, gastrointestinal perforation or gastrointestinal hemorrhage, melena, hematemesis, sometimes fatal, especially in elderly patients; ulcerative stomatitis, gastritis; exacerbation of ulcerative colitis and Crohn’s disease, esophagitis, formation of intestinal diaphragm-like strictures; irritation or dryness of oral mucosa, gingival mucosal ulcers, aphthous stomatitis, pancreatitis.

Patients should immediately discontinue the drug and consult a physician if they experience upper abdominal pain, melena, or vomiting blood.

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

Renal and urinary disorders:
Very rare – allergic nephritis, glomerulonephritis, oliguria, polyuria, cystitis, hematuria, acute renal impairment, papillary necrosis (especially with long-term use of NSAIDs), associated with increased serum urea levels, edema formation (particularly in patients with hypertension or renal insufficiency), nephrotic syndrome, interstitial nephritis (which may be accompanied by acute renal failure);
Frequency not known – renal failure.

Nervous system disorders:
Uncommon – headache, dizziness, anxiety, drowsiness, confusion, hallucinations, insomnia, psychomotor agitation, irritability, fatigue;
Very rare – aseptic meningitis².

Psychiatric disorders:
Rare – psychotic reactions, depression.

Cardiovascular disorders:
Frequency not known – tachycardia, vasculitis, myocardial infarction, heart failure, arterial hypertension, edema, Kounis syndrome.

Blood and lymphatic system disorders:
Very rare – blood dyscrasias (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs include high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, epistaxis, and bruising. In such cases, patients should be advised to discontinue the drug and seek immediate medical attention.

Regular blood monitoring is recommended during long-term therapy.

Immune system disorders:
Uncommon – hypersensitivity reactions accompanied by urticaria and pruritus¹;
Very rare – severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension (anaphylaxis, angioedema, or severe shock);
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 lead to serious skin and soft tissue infections.

Infections and infestations:
Rare – exacerbation of infection-related inflammation. If signs of infection occur or worsen during treatment, patients are advised to seek immediate medical attention. The need for anti-infective/antibacterial therapy should be assessed.

Aseptic meningitis symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or altered consciousness) have been observed in patients with autoimmune diseases (e.g., systemic lupus erythematosus, mixed connective tissue disease) during ibuprofen use.

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 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 NSAIDs suggest a hypersensitivity reaction (based on temporal association with drug intake and symptom resolution after drug discontinuation). Cases of aseptic meningitis (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been reported in patients with autoimmune diseases (systemic lupus erythematosus and mixed connective tissue disease).

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is crucial for ongoing monitoring of the benefit-risk balance. Healthcare professionals, pharmacists, patients, and 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 per blister, 1 blister per carton.

Prescription status. Over-the-counter (without prescription).

Manufacturer.
Phil Inter Pharma Co., Ltd.

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

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

Address of the Marketing Authorization Holder.
13, Boryspilska St., Kyiv, 02093, Ukraine.