BRUSTAN

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRUSTAN (BRUSTAN)

Composition:

Active substances: 1 film-coated tablet contains ibuprofen 400 mg, paracetamol 325 mg;

Excipients: calcium hydrogen phosphate, maize starch, povidone, talc, hypromellose, titanium dioxide (E 171), yellow FCF dye (E 110), macrogol 6000, propylene glycol, sodium lauryl sulfate, shellac, black iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: orange-colored, oval-shaped tablets, film-coated, with the imprint "RANBAXY" in black food-grade ink on one side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01A E51.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen exerts an anti-inflammatory effect.

Paracetamol is an analgesic agent that reduces pain by preventing sensitization of nerve endings through inhibition of prostaglandin E synthesis. The combination of ibuprofen and paracetamol provides a potent analgesic effect.

Pharmacokinetics.

Both active components of Brustan do not affect each other's pharmacokinetics and are well absorbed after oral administration. Plasma protein binding is very high for both components. The elimination half-life of paracetamol is 2–2.5 hours, and that of ibuprofen is 2.7–3.5 hours. Both components are mainly metabolized in the liver. They are excreted primarily in the urine, with a small amount eliminated in bile.

Clinical characteristics.

Indications.

For relief of fever and mild to moderate pain associated with inflammatory conditions.

Contraindications.

• Hypersensitivity to any component of the drug.

• History of bronchospasm, bronchial asthma, rhinitis, or skin rash associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).

• History of gastrointestinal bleeding or perforation following the use of NSAIDs.

• Active or past history of peptic ulcer disease and/or gastrointestinal bleeding (two or more distinct episodes of ulceration or bleeding).

• Severe renal, cardiac, or hepatic insufficiency.

• Congenital hyperbilirubinemia.

• Glucose-6-phosphate dehydrogenase deficiency.

• Alcoholism.

• Blood disorders, Gilbert's syndrome, severe anemia, leukopenia.

• Concomitant use of the drug with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors.

• Use during pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Medicinal products containing ibuprofen and paracetamol should be used with caution when administered concomitantly with:

*Glucocorticoids: increased risk of gastrointestinal bleeding or ulceration;

*Antihypertensive agents and diuretics: NSAIDs may reduce the therapeutic effect of these drugs;

*Antiplatelet agents and selective serotonin reuptake inhibitors: may increase the risk of gastrointestinal bleeding;

*Cardiac glycosides: NSAIDs may exacerbate heart failure and increase glycoside levels in plasma;

*Anticoagulants: NSAIDs may potentiate the effects of anticoagulants (e.g., warfarin), increasing the risk of bleeding. Occasional use has no significant effect;

*Lithium and methotrexate: evidence suggests a potential increase in plasma levels of lithium and methotrexate;

*Barbiturates: may reduce the antipyretic effect of medicinal products containing ibuprofen and paracetamol;

*Zidovudine: evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant treatment with zidovudine and ibuprofen;

*Cyclosporine: increased nephrotoxicity;

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

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

*Quinolone antibiotics: concomitant use of NSAIDs and quinolones may increase the risk of seizures.

Probenecid and sulfinpyrazone

Concomitant use with medicinal products containing probenecid or sulfinpyrazone may slow the elimination of ibuprofen from the body.

ACE inhibitors, beta-blockers, and angiotensin II receptor antagonists

NSAIDs may attenuate the effects of 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, beta-blockers, or angiotensin II receptor antagonists may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, especially in elderly patients. When using such combinations, adequate hydration should be ensured, and monitoring of renal function should be performed at the start of treatment and periodically thereafter.

Potassium-sparing diuretics

Concomitant use of ibuprofen and potassium-sparing diuretics may lead to hyperkalemia (monitoring serum potassium levels is recommended).

Sulfonylureas

Clinical studies have demonstrated interactions between nonsteroidal anti-inflammatory drugs and antidiabetic agents (sulfonylureas). Although an interaction between ibuprofen and sulfonylureas has not been specifically described, blood glucose levels should be monitored during concomitant therapy.

Concomitant use of medicinal products containing ibuprofen and paracetamol with acetylsalicylic acid should be avoided, unless low-dose acetylsalicylic acid (not more than 75 mg per day) has been prescribed by a physician, and with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as this may increase the risk of adverse effects.

Concomitant use of medicinal products containing ibuprofen and paracetamol with alcohol should be avoided.

The absorption rate of paracetamol may be increased by metoclopramide and domperidone, and decreased by cholestyramine.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine) that stimulate hepatic microsomal enzyme activity may enhance the hepatotoxic effects of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic potential of these drugs.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

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

Caution is necessary when treating patients:

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

Elderly patients

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

Respiratory system effects

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

Other NSAIDs

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

Systemic lupus erythematosus and mixed connective tissue diseases

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

Porphyrin metabolism

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

Cardiovascular and cerebrovascular effects

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

Renal tubular acidosis and hypokalemia may develop after acute overdose or in patients taking high doses of ibuprofen over a prolonged period (usually longer than 4 weeks), including doses exceeding the recommended daily dose.

Clinical trial data and epidemiological evidence suggest that ibuprofen use, particularly 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 clinical assessment. High doses (2400 mg per day) should be avoided.

Careful clinical assessment 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 doses of ibuprofen (2400 mg per day) are required.

Cases of Kounis syndrome have been reported in patients treated with the medicinal product Brustan. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Renal effects

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

Hepatic effects

Liver function impairment is possible.

Surgical procedures

Caution is required immediately after major surgical procedures.

Effects on female fertility

Limited data suggest that medicinal products inhibiting cyclooxygenase/prostaglandin synthesis, when used long-term (doses ≥2400 mg per day for more than 10 days), may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal (GI) 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, which may be fatal, have been reported at any stage of NSAID therapy, 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 increasing 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 ulcers or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., aspirin).

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

Severe skin reactions

Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported with ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month of treatment. If signs or symptoms suggestive of these reactions appear, ibuprofen use should be discontinued immediately, and alternative treatment should be considered (if necessary).

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 excluded; therefore, the use of ibuprofen in chickenpox is not recommended.

Allergy

Caution is required 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 diseases 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

Like other NSAIDs, ibuprofen may mask symptoms of infectious diseases, potentially delaying appropriate treatment and worsening disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. 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.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with long-term therapeutic doses of paracetamol or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close patient monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Excipients

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

This medicinal product contains less than 1 mmol (39 mg)/dose of potassium, i.e., it is practically potassium-free.

Other

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rarely observed. At the first signs of hypersensitivity after taking ibuprofen, treatment must be discontinued. Symptomatic and specialized therapy should be initiated in such cases.

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

During long-term use of ibuprofen, 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 this condition. In case of suspicion or confirmation of this situation, medical advice should be sought and treatment discontinued. Medication-overuse headache should be considered in patients with frequent or daily headaches despite (or due to) regular use of headache medications.

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

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

Use during pregnancy or breastfeeding

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from 1% to approximately 1.5%. The risk is believed 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 condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of arterial duct constriction have been reported after second-trimester treatment, which in most cases resolved after stopping treatment.

Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after ibuprofen exposure for several days starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

• to the fetus: cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension); renal dysfunction (see above);
• to the mother and newborn, near term: possible prolonged 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 (see section "Contraindications").

In limited studies, ibuprofen was detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant. Use of Brustan during pregnancy or breastfeeding is contraindicated.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

Patients who experience dizziness, somnolence, vertigo, 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 when driving or operating machinery.

Dosage and Administration

The medication is intended for oral use. The tablet should be taken whole, without chewing, with a glass of water, during or after meals.

The recommended dose for adults and children aged 16 years and older is 1 tablet 3 times daily. Do not exceed 3 tablets per day. If the patient's condition does not improve with the recommended doses, medical advice should be sought.

The duration of treatment should be determined individually by a physician.

Children.

Brustan is not recommended for children under 16 years of age.

Overdose.

Hepatic injury is possible in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. In patients with risk factors (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione deficiency (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)), ingestion of 5 g or more of paracetamol may lead to hepatic injury.

Symptoms within the first 24 hours: pallor, nausea, vomiting, anorexia, and abdominal pain. Hepatic damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the drug in high doses, hematological disorders may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

In case of overdose, prompt medical attention is required. The patient should be taken to a hospital immediately, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or risk of organ damage. Administration of activated charcoal should be considered if the excessive dose of paracetamol was ingested within 1 hour. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are not reliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol intake, but the maximum protective effect is achieved when administered within 8 hours after ingestion; beyond this time, the efficacy of the antidote decreases sharply. If required, intravenous N-acetylcysteine should be administered at doses established by current guidelines. In the absence of vomiting, oral methionine may be used as an appropriate alternative in remote areas outside hospital settings.

Side effects

The following reactions may occur during the use of medicinal products containing ibuprofen or paracetamol.

General disorders: severe hypersensitivity reactions including: facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylaxis, Quincke's edema progressing to shock, exacerbation of bronchial asthma, bronchospasm, dyspnea.

Gastrointestinal disorders: epigastric pain, dyspepsia, nausea, diarrhea, flatulence, constipation, vomiting, heartburn, ulcerative stomatitis, peptic ulcers, melena, gastrointestinal perforation or gastrointestinal hemorrhage, which in some cases may be fatal, particularly in elderly patients.

Crohn’s disease and exacerbation of ulcerative colitis.

Neurological disorders: headache, aseptic meningitis (in isolated cases), dizziness, irritability, nervousness, tinnitus, depression, drowsiness, insomnia, anxiety, psychomotor agitation, emotional instability, convulsions.

Endocrine system disorders: hypoglycemia up to hypoglycemic coma.

Urinary system disorders: acute renal failure, papillary necrosis, particularly with prolonged use, associated with increased blood urea levels and edema. There have been reports that medicinal products containing ibuprofen may cause cystitis, hematuria, interstitial nephritis, nephrotic syndrome, oliguria, polyuria, tubular necrosis, glomerulonephritis.

Hepatobiliary disorders: liver function disorders, particularly with prolonged use, manifesting as hepatitis, jaundice, pancreatitis, duodenitis, esophagitis, hepatorenal syndrome, hepatic necrosis, liver failure, elevated liver enzyme activity, usually without development of jaundice.

Blood and lymphatic system disorders: blood formation disorders (anemia, neutropenia, aplastic anemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain, hemolytic anemia), eosinophilia, decreased hematocrit and hemoglobin levels, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include high fever, sore throat, oral ulcers, flu-like symptoms, excessive fatigue, unexplained bleeding, and bruising. Reversible platelet aggregation, alveolitis, pulmonary eosinophilia, pancreatitis.

Skin and subcutaneous tissue disorders: non-specific allergic reactions, pruritus, skin and mucosal rashes (usually generalized or erythematous, urticaria); very rarely, severe skin adverse reactions (SSARs) may occur, including erythema multiforme, exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis; drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (frequency unknown); skin desquamation, alopecia, photosensitization; frequency unknown: photosensitivity reactions.

Immune system disorders: in patients with autoimmune disorders (systemic lupus erythematosus, connective tissue diseases), isolated cases of aseptic meningitis symptoms have been observed during treatment with ibuprofen-containing products, including nuchal rigidity, headache, nausea, vomiting, high fever, or disorientation.

Cardiovascular and cerebrovascular reactions: edema, arterial hypertension, heart failure, cerebrovascular complications, arterial hypotension, palpitations, Kounis syndrome (frequency unknown). Long-term use of ibuprofen-containing products at high doses (2400 mg/day) may lead to a slight increase in the risk of arterial thromboembolism or stroke.

Eye disorders: blurred vision, color vision disturbances, toxic amblyopia.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap – frequency unknown (cannot be estimated from available data).

Other: endocrine system and metabolic disturbances, decreased appetite, dryness of ocular and oral mucous membranes, rhinitis, hearing disturbances.

The drug should be discontinued immediately upon the appearance of any adverse reactions, and medical advice should be sought promptly.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a dry place, out of reach of children.

Packaging.

10 tablets in a blister pack; 1 blister pack in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

San Pharmaceutical Industries Limited / Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

Industrial Area 3, Dewas - 455001, India / Industrial Area 3, Dewas, 455001, India.