Ibuprofen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IBUPROFEN

Composition:

Active substance: ibuprofen;

1 capsule contains 200 mg of ibuprofen;

Excipients: macrogol 600, potassium hydroxide, purified water, gelatin, sorbitol solution partially dehydrated (E 420), Ponceau 4R (E 124), printing ink for capsule Opacode WB white NSP-78-18022.

Pharmaceutical form. Soft capsules.

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

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Exerts analgesic, antipyretic, and anti-inflammatory effects. The mechanism of action is based on inhibition of prostaglandin synthesis — mediators of pain, inflammation, and temperature response.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when these agents are used concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsallylic acid (81 mg) resulted in reduced effects of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding the extrapolation of these data to clinical situations, it cannot be ruled out that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

Pharmacokinetics.

After oral administration, ibuprofen is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration of the active substance is reached within 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 approximately 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 spaces, where its concentration may remain high even as plasma concentrations decline.

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

Clinical characteristics.

Indications.

For symptomatic treatment of headache, toothache, and periodic menstrual pain. Fever and muscle pain associated with colds.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product.
• History of bronchospasm, asthma, rhinitis, angioedema, or skin rash associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Active or past peptic ulcer/gastrointestinal bleeding (two or more distinct episodes of ulceration or bleeding).
• Severe renal, hepatic, or cardiac failure (NYHA class IV — New York Heart Association).
• Patient body weight less than 20 kg.
• Active cerebrovascular or other bleeding.
• Blood dyscrasias of unknown etiology.
• Dehydration caused by vomiting, diarrhea, or insufficient fluid intake.
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen (like other NSAIDs) should be used with caution when administered concomitantly with the following agents:

• Other NSAIDs, including salicylates: increased risk of gastrointestinal ulcers and bleeding;
• Digoxin: increased plasma levels of both drugs;
• Corticosteroids: increased risk of gastrointestinal bleeding or ulceration;
• Antithrombotic agents: increased risk of gastrointestinal bleeding;
• Anticoagulants: NSAIDs may enhance the effect of anticoagulants, such as warfarin;
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;
• Acetylsalicylic acid or other NSAIDs and glucocorticosteroids: increased risk of gastrointestinal adverse effects associated with these medicinal products.

Experimental data indicate that concomitant use of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid (aspirin) on platelet aggregation. However, uncertainty regarding the extrapolation of these data to clinical settings prevents definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically significant effects are considered unlikely with occasional, short-term use of ibuprofen;

• Antihypertensive and diuretic agents: NSAIDs may reduce the therapeutic effect of these drugs; in patients with impaired renal function, concomitant use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin II receptor antagonists, and cyclooxygenase inhibitors may lead to further deterioration of renal function. Therefore, such combinations should be used with caution, especially in elderly patients;
• Lithium and methotrexate: evidence suggests a potential increase in plasma levels of lithium and methotrexate;
• Probenecid and sulfinpyrazone: may delay elimination of ibuprofen;
• Potassium-sparing diuretics: hyperkalemia may occur (plasma potassium levels should be monitored);
• Cyclosporine and tacrolimus: increased risk of nephrotoxicity;
• Zidovudine: evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant treatment with zidovudine and ibuprofen;
• Sulfonylureas: blood glucose levels should be monitored;
• Quinolone antibiotics: increased risk of seizures;
• Cytochrome CYP2C9 inhibitors, such as voriconazole or fluconazole: may enhance the effect of ibuprofen.

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 systemic connective tissue disorders;
• inherited disorders of porphyrin metabolism (e.g., acute intermittent porphyria);
• arterial hypertension and/or heart failure in medical history, associated with fluid retention and edema during NSAID use;
• impaired renal and/or hepatic function;
• immediately following surgery.

This medicinal product contains sorbitol. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

Allergic reactions may occur due to the presence of "Ponso 4R" in the formulation.

Elderly patients have an increased risk of adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

Gastrointestinal bleeding, ulceration, or perforation, potentially fatal, have been reported with the use of all NSAIDs, regardless of treatment duration or history of serious gastrointestinal complications.

Increased NSAID dosage, advanced age, and history of peptic ulcer disease are risk factors for gastrointestinal adverse reactions. The use of the lowest effective doses is recommended during treatment in such cases.

Consideration should be given to the need for concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors), especially in patients requiring long-term low-dose acetylsalicylic acid or other drugs that increase the risk of gastrointestinal adverse effects.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), is associated with an increased 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), 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.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which may potentially lead to myocardial infarction.

Careful clinical evaluation is also required before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg per day) are needed.

Patients who experience gastrointestinal disturbances, as well as elderly individuals, should discontinue treatment and consult a physician if any adverse symptoms occur (especially gastrointestinal bleeding).

Ibuprofen should be used with caution in patients receiving medications that increase the risk of peptic ulceration or bleeding, including oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

NSAIDs should be used cautiously in patients with a history of ulcerative colitis or Crohn’s disease, as their condition may worsen.

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), 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 during 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 should be discontinued immediately and alternative therapy considered (if necessary).

Masking symptoms of underlying infections

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

Bronchospasm may occur in patients with or who have had bronchial asthma or allergic diseases.

Prolonged use of analgesics in high doses may lead to headache that cannot be treated by increasing the drug dose.

Long-term 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 some evidence that drugs inhibiting cyclooxygenase-prostaglandin synthesis may impair female fertility by affecting ovulation. In such cases, use of these drugs should be discontinued.

Ibuprofen may temporarily suppress blood/coagulation function (platelet aggregation). Therefore, special monitoring is recommended in patients with coagulation disorders.

With prolonged use of the drug, regular monitoring of liver function, kidney function, and blood cell counts is required.

In cases of varicella, treatment with this drug should be avoided.

Concomitant alcohol consumption may enhance adverse effects, particularly those affecting the gastrointestinal tract or central nervous system, after NSAID use.

NSAIDs may mask symptoms of infection and fever.

There is a risk of renal failure in dehydrated children and adolescents.

Use during pregnancy or breastfeeding

Pregnancy. Inhibitors of prostaglandin synthesis may adversely affect pregnant women and/or embryonic/fetal development. Epidemiological data indicate an increased risk of pregnancy loss and congenital heart defects following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with higher doses and longer duration of treatment.

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

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

Therefore, during the first and second trimesters of pregnancy, ibuprofen should be used only when, in the physician’s opinion, the benefit to the mother clearly outweighs the potential risk to the fetus. If ibuprofen is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

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

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following risks.

Risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above).

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

• prolonged bleeding time, anti-aggregatory effect, which may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Ibuprofen is contraindicated during the third trimester of pregnancy.

Breastfeeding period. Ibuprofen and its metabolites may pass into breast milk in low concentrations. To date, no harmful effects on infants have been reported; therefore, breastfeeding generally does not need to be discontinued during short-term treatment for pain and fever at recommended doses.

Ability to influence reaction speed when driving or operating machinery.

With short-term use, ibuprofen has no effect or only a negligible effect on the ability to drive or operate machinery. However, with prolonged use, adverse effects on the central nervous system such as increased fatigue and dizziness may occur.

Dosage and Administration

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

The medicinal product is recommended for 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 administered to 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. The maximum daily dose should not be exceeded.

For 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).

For children with body weight 30–39 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).

Capsules should generally be taken during meals, without chewing, and swallowed with water.

Elderly patients do not require special dose adjustment.

If symptoms persist for more than 3 days, or pain for more than 4 days during treatment, consult a physician for diagnosis clarification and treatment adjustment. Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Children. The use of the medicinal product is contraindicated in children with body weight less than 20 kg.

Overdose.

In case of acute overdose, symptoms depend on the amount ingested and the time elapsed since ingestion. The initial symptoms commonly observed are: nausea, vomiting, headache, dizziness, epigastric pain, or less frequently, diarrhea, drowsiness, nystagmus, blurred vision, tinnitus, gastrointestinal bleeding. In cases of overdose, coma, arterial hypotension, hyperkalemia with cardiac rhythm disturbances, metabolic acidosis, elevated body temperature, respiratory depression, and cyanosis may occur, as well as impaired kidney function and liver damage. Occasionally, agitation, disorientation, and seizures may occur. After prolonged use, hemolytic anemia, granulocytopenia, and thrombocytopenia may rarely be observed.

If less than 1 hour has passed since acute overdose, it is recommended to induce vomiting, perform gastric lavage, or administer activated charcoal.

There is no specific antidote or specific treatment for ibuprofen overdose. Symptomatic treatment should be based on monitoring vital functions, including measurement of arterial blood pressure, ECG monitoring, and assessment of symptoms indicating possible gastrointestinal bleeding, metabolic acidosis, or central nervous system disturbances.

Side effects.

Below is a list of adverse reactions observed in individuals who used ibuprofen for short-term treatment of mild to moderate pain and fever, as well as those observed during long-term, high-dose therapy in patients with rheumatic diseases.

Clinical trial data indicate that the use of ibuprofen, particularly at high doses of 2400 mg per day, is associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

The frequency of adverse effects is defined as follows:

Very common: ≥1/10;
Common: ≥1/100, <1/10;
Uncommon: ≥1/1000, <1/100;
Rare: ≥1/10,000, <1/1000;
Very rare: <1/10,000, including isolated case reports.

General disorders. Uncommon: hypersensitivity reactions such as urticaria and pruritus, increased sweating. Very rare: severe hypersensitivity reactions including facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylactoid reactions (anaphylaxis, Quincke's edema up to shock). Asthma exacerbation, bronchospasm or dyspnea, allergic rhinitis, eosinophilia.

Sensory organs. Rare: hearing disturbances (hearing loss, tinnitus). Uncommon: visual disturbances (toxic optic neuropathy, blurred vision or diplopia, scotoma, dryness and irritation of the eyes, allergic-type conjunctival and eyelid edema).

Gastrointestinal tract. Uncommon: abdominal pain, melena, hematemesis, dyspepsia, nausea. Rare: diarrhea, flatulence, constipation, vomiting. Very rare: heartburn, ulcerative stomatitis, gastritis, gastrointestinal perforation or bleeding (which may lead to anemia), potentially fatal in some cases, especially in elderly patients. Exacerbation of ulcerative colitis and Crohn's disease, esophagitis, formation of intestinal diaphragm-like strictures. Irritation or dryness of the oral mucosa, gingival mucosal ulcers, aphthous stomatitis, pancreatitis.

Neurological disorders. Uncommon: headache, dizziness, insomnia, anxiety, depression, nervousness and irritability, fatigue, psychomotor agitation, somnolence, confusion, hallucinations. Rare: aseptic meningitis (more frequently in patients with autoimmune disorders).

Cardiovascular system. Very rare: heart failure, tachycardia, increased blood pressure, vasculitis, myocardial infarction. Unknown: Couney's syndrome.

Urinary system. Very rare: reduced urea excretion and edema. Acute renal failure, allergic nephritis, glomerulonephritis, oliguria, polyuria, cystitis, hematuria. Papillary necrosis, particularly with prolonged use. Increased serum urea levels.

Hepatobiliary system. Very rare: liver function abnormalities, especially with long-term use. Hepatitis, pancreatitis, duodenitis, esophagitis.

Blood and lymphatic system. Very rare: blood-forming disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial symptoms include high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, nosebleeds, and bruising.

Skin and subcutaneous tissue. Very rare: severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis), alopecia. Unknown: drug-induced eosinophilia with systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP); photosensitivity reactions.

Immune system. Uncommon: in patients with autoimmune disorders (systemic lupus erythematosus, connective tissue diseases), isolated cases of aseptic meningitis symptoms have been observed during ibuprofen treatment (nuchal rigidity, headache, nausea, vomiting, high fever, or disorientation), facial, tongue, and laryngeal swelling, dyspnea, tachycardia. Allergic reactions manifesting as skin rash, pruritus, bronchial asthma attack, hypotension.

Infections and parasitic diseases. Very rare: exacerbation of infection-related inflammation.

Laboratory investigations. Rare: decreased hemoglobin levels.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.
Keep out of reach of children.

Packaging. 10 soft capsules in a blister pack, 1 or 2 blisters per cardboard box.

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

Manufacturer. Catalent Germany Eberbach GmbH.

Manufacturer's address.
Gammelsbacher Str. 2, 69412 Eberbach, Germany.