INSTRUCTION for medical use of the medicinal product Ibuprom RR (Ibuprom® RR)

Composition:

Active substance: ibuprofen;

One film-coated tablet contains ibuprofen 200 mg;

Excipients: microcrystalline cellulose, maize starch, pregelatinized starch, hydrogenated vegetable oil, crospovidone (type A), talc, colloidal anhydrous silicon dioxide;

Coating: Opadry White 65F280000 (polyvinyl alcohol (E 1203), macrogol 3350 (E 1521), titanium dioxide (E 171), talc (E 553b), aluminium-potassium silicate and titanium dioxide (E 171)), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white or almost white tablets with slight sheen, biconvex, oval-shaped, with the inscription "RR" embossed on one side.

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

ATC code M01AE01.

Pharmacological properties.

Pharmacodynamics.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which exerts analgesic, antipyretic, and anti-inflammatory effects by inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when these drugs 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 acetylsalicylic acid (81 mg) resulted in reduced effects of aspirin (acetylsalicylic acid) on thromboxane formation or platelet aggregation. Although there is uncertainty regarding extrapolation of 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 acetylsalicylic acid. With occasional (non-regular) use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics.

Ibuprofen is well absorbed in the gastrointestinal tract, binds to plasma proteins, and rapidly distributes throughout the body. Maximum plasma concentration is reached within 45 minutes after administration (when taken on an empty stomach). When the drug is administered with food, peak levels occur 1–2 hours after intake. The time may vary depending on the pharmaceutical formulation used.

Ibuprofen is metabolized in the liver and excreted by the kidneys either unchanged or as metabolites. Elimination half-life is approximately 2 hours. In elderly patients, no significant differences in pharmacokinetic profile have been observed.

Clinical Characteristics.

Indications.

Symptomatic treatment of headache, including migraine, toothache, dysmenorrhea (cyclical menstrual pain), neuralgia, back pain, joint pain, muscle pain, as well as symptoms of cold and flu.

Contraindications.

Hypersensitivity to ibuprofen or to any component of the medicinal product.
Hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
Active peptic ulcer disease / gastrointestinal bleeding or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding).
History of gastrointestinal bleeding or perforation associated with previous NSAID therapy.
Severe impairment of liver function, renal function impairment, heart failure (NYHA class IV).
Third trimester of pregnancy.
Cerebrovascular or other hemorrhages.
Disorders of blood formation or blood coagulation.

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, like other NSAIDs, should not be used in combination with the following medicinal products:

acetylsalicylic acid, as this may increase the risk of adverse reactions, except when acetylsalicylic acid (dose not exceeding 75 mg per day) has been prescribed by a physician. Experimental data indicate that concomitant administration of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. However, uncertainty regarding the possibility of extrapolating these data to the clinical setting does not allow definitive conclusions about whether regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Therefore, occasional use of ibuprofen is considered unlikely to produce clinically significant effects;
other NSAIDs, including selective cyclooxygenase-2 inhibitors.

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

anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin;

antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may attenuate the effects of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. When prolonged treatment is necessary, adequate hydration of the patient should be ensured and monitoring of renal function should be performed at the beginning of combined therapy and periodically thereafter. Diuretics increase the risk of nephrotoxic effects of NSAIDs;

corticosteroids: increased risk of gastrointestinal ulceration and bleeding;

lithium: evidence suggests a potential increase in plasma lithium levels;

methotrexate: there is a possibility of increased methotrexate plasma levels;

zidovudine: increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen;

cardiac glycosides: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides;

antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;

cyclosporine, tacrolimus: increased risk of nephrotoxicity;

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

quinolone antibiotics: in patients receiving both ibuprofen and quinolone antibiotics, an increased risk of seizures may occur;

sulfonylurea derivatives and phenytoin: possible potentiation of effect.

Special precautions for use.

Adverse effects associated with ibuprofen can be minimized by using the lowest effective dose required to treat symptoms for the shortest duration necessary.

Caution is advised when treating patients with:

systemic lupus erythematosus and mixed connective tissue disease;
gastrointestinal disorders and chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease);
arterial hypertension and/or heart failure;
impaired kidney function;
impaired liver function;
coagulation disorders (ibuprofen may prolong bleeding time).

Elderly patients are at increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which may be fatal.

Respiratory 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, should be avoided, as this increases the risk of adverse reactions.

Systemic lupus erythematosus and mixed connective tissue disease.

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

Gastrointestinal effects.

NSAIDs should be used cautiously in patients with chronic inflammatory bowel diseases and a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as their condition may worsen.

Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported during NSAID therapy at any stage, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders.

The risk of gastrointestinal bleeding, perforation, or ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer disease (especially complicated by bleeding or perforation), and in elderly patients. These patients should start treatment with the lowest doses.

Caution is advised when treating patients receiving concomitant medications that increase the risk of gastotoxicity or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), or antiplatelet agents (e.g., acetylsalicylic acid).

For long-term treatment, and in patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs increasing gastrointestinal risk, combination therapy with misoprostol or proton pump inhibitors may be necessary, as determined by a physician.

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

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

Cardiovascular and cerebrovascular effects.

Caution is advised when initiating treatment in patients with a history of arterial hypertension and/or moderate to severe congestive heart failure (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 with prolonged treatment, may lead to a small increase in the risk of arterial thrombotic events (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 condition. High doses (2400 mg per day) should be avoided. Careful evaluation of the clinical condition is also recommended before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg per day) are required.

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

Renal effects.

Risk of renal impairment due to worsening kidney function. Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and may provoke the development of renal failure.

Patients at high risk of this reaction include those with impaired kidney function, cardiac disorders, impaired liver function, patients taking diuretics, and elderly patients. Kidney function should be monitored in such patients.

Children and adolescents with dehydration are at risk of developing renal failure.

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 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 should be discontinued immediately and alternative treatment considered (if necessary).

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

Hepatic effects.

Caution is advised when treating patients with impaired liver function.

Effects on female fertility.

Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment.

Long-term use (referring to a dose of 2400 mg per day and treatment duration exceeding 10 days) of ibuprofen may impair female fertility; therefore, the drug is not recommended for women attempting to conceive. The drug should not be used in women experiencing difficulties conceiving or undergoing infertility investigations.

Masking symptoms of underlying infections: Ibuprom PP may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When Ibuprom PP 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.

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 the use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy. In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic/fetal mortality. Additionally, increased incidence of various developmental abnormalities, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

NSAIDs should not be used during the first two trimesters of pregnancy, except when, in the physician’s opinion, the expected benefit to the patient outweighs the potential risk to the fetus. Women attempting to conceive, as well as during the first and second trimesters of pregnancy, should use the lowest possible dose for the shortest duration. In cases where ibuprofen treatment exceeds 48 hours, monitoring of amniotic fluid levels by ultrasound should be considered.

NSAIDs should not be used between the 20th and 28th weeks of pregnancy without medical prescription. The use of NSAIDs from the 20th week of pregnancy onwards may cause rare but serious kidney problems in the unborn child, leading to low amniotic fluid levels and potential complications such as impaired lung maturation and reduced joint movement (limb contractures) in the newborn.

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

for the fetus: cardiopulmonary toxicity (characterized by premature closure of the ductus arteriosus and pulmonary hypertension); impaired kidney function, which may progress to renal failure associated with oligohydramnios;

for the mother near term and the newborn: prolonged bleeding time, antiplatelet effect (which may occur even at very low doses); inhibition of uterine contractions, leading to delayed or prolonged labor.

Ibuprofen is contraindicated during the third trimester of pregnancy.

Numerous studies have demonstrated that ibuprofen and its metabolites are excreted into breast milk in very small amounts (0.0008% of the administered dose). Given the absence of reports on harmful effects of the drug on infants, discontinuation of breastfeeding is not necessary during short-term use of ibuprofen at recommended doses.

Ability to affect reaction speed when driving or operating machinery.

No special precautions are required for short-term use. When used according to recommended doses and treatment duration, the drug does not affect reaction speed when driving or operating machinery. Patients who experience dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery.

Dosage and Administration

For oral use, intended for short-term use only.

Adults and children aged 12 years and older (with body weight over 40 kg): 1–2 tablets every 4–6 hours. Tablets should be taken with water. Do not take more than 6 tablets within 24 hours. The maximum daily dose is 1200 mg.

The lowest effective dose should be used for the shortest possible duration necessary to relieve symptoms (see section "Special precautions"). If symptoms persist for more than 3 days after initiation of treatment or worsen, medical advice should be sought.

Patients with gastrointestinal disorders are advised to take the medication with food.

Patients with mild or moderate renal or hepatic impairment do not require dose adjustment.

Elderly patients do not require special dosage adjustments.

Children

Do not use in children under 12 years of age.

Overdose

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

Symptoms
In most patients, ingestion of clinically significant amounts of NSAIDs causes only nausea, vomiting, epigastric pain, or less commonly, diarrhea. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In severe poisoning, toxic effects on the central nervous system may occur, manifesting as drowsiness, occasionally excitement, disorientation, or coma. Seizures may develop in some patients. In more severe cases, hyperkalemia and metabolic acidosis, acute renal failure, liver damage, arterial hypotension, respiratory insufficiency, and cyanosis may occur. Prothrombin time may be prolonged. In patients with bronchial asthma, an exacerbation of asthma may occur.

Prolonged use at doses exceeding the recommended levels or overdose may lead to renal tubular acidosis and hypokalemia.

Treatment
There is no specific antidote. Treatment should be symptomatic and supportive, including maintenance of airway patency and continuous monitoring of cardiac function and vital signs until the patient's condition stabilizes. Oral administration of activated charcoal is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, alkalizing agents may be administered to enhance renal excretion of the acidic ibuprofen.

In cases of frequent or prolonged muscle spasms, treatment should include intravenous administration of diazepam or lorazepam. In cases of bronchial asthma, bronchodilators should be used.

Side effects.

Gastrointestinal adverse reactions are the most commonly observed and are mostly dose-dependent. Adverse reactions are least frequent when the maximum daily dose is 1200 mg.

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

Adverse reactions associated with the use of ibuprofen are classified by organ systems and frequency. Frequency is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000; frequency not known (cannot be estimated from available data).

Cardiac system.

Frequency not known: heart failure, edema, Conn’s syndrome.

Gastrointestinal system.

Uncommon: abdominal pain, nausea, dyspepsia. Rare: diarrhea, flatulence, constipation, vomiting. Very rare: gastric and duodenal ulceration, gastrointestinal perforation or gastrointestinal hemorrhage, melena, hematemesis, sometimes fatal (particularly in elderly patients); ulcerative stomatitis, gastritis, pancreatitis, exacerbation of colitis and Crohn’s disease.

Nervous system.

Uncommon: headache. Rare: dizziness. Very rare: aseptic meningitis², individual symptoms of which (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) may occur in patients with autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease. Frequency not known: paresthesia, somnolence.

Renal and urinary system.

Very rare: acute renal impairment, papillary necrosis (especially with prolonged use), associated with increased plasma urea levels, edema, hypernatremia (sodium retention), oliguria. Frequency not known: renal failure, nephrotoxicity including interstitial nephritis and nephrotic syndrome.

Hepatic system.

Very rare: hepatic function abnormalities. Frequency not known: hepatitis and jaundice may occur during prolonged treatment.

Vascular system.

Very rare: arterial hypertension. Frequency not known: arterial thrombosis (myocardial infarction or stroke).

Skin and subcutaneous tissue.

Rare: various types of skin rashes. Very rare: severe skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis). Frequency not known: drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

Blood and lymphatic system.

Very rare: anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, which may occur during prolonged treatment, with initial signs including fever, sore throat, ulcerative stomatitis in the oral cavity, flu-like symptoms, severe exhaustion, unexplained bleeding, and bruising.

Psychiatric disorders.

Rare: psychiatric disorders, depression, insomnia, agitation, hallucinations, confusion.

Eye disorders.

Frequency not known: visual disturbances, optic neuritis may occur during prolonged treatment.

Ear and labyrinth disorders.

Rare: tinnitus and vertigo may occur during prolonged treatment.

Immune system.

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, angioneurotic edema, or severe shock). Frequency not known: respiratory tract reactivity, including asthma, bronchospasm, or dyspnea.

General disorders.

Rare: malaise, fatigue, irritability.

Laboratory investigations.

Very rare: decreased hemoglobin levels.

Description of selected adverse reactions

¹ There have been reports of hypersensitivity reactions associated with the use of ibuprofen. Hypersensitivity reactions may include: (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity, including asthma, asthma exacerbation, bronchospasm, or dyspnea, or (c) various forms of skin reactions, including pruritus, urticaria, purpura, angioneurotic edema, and less frequently, exfoliative and bullous dermatoses, including toxic epidermal necrolysis, Stevens-Johnson syndrome, 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 administration and resolution of symptoms after drug discontinuation). Isolated cases of aseptic meningitis symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with autoimmune disorders (systemic lupus erythematosus and mixed connective tissue disease).

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 1, 2, or 3 blisters per cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer.

TOV US Farmatsiya, Poland / US Pharmacia Sp. z o.o., Poland.

Manufacturer's address.

Ul. Ziebicka 40, 50-507 Wroclaw, Poland.

Marketing authorization holder.

Unilab, LP, USA.

Address of marketing authorization holder and/or its representative.

966 Hungerford Drive, Suite 3B, Rockville, MD 20850, USA.

Ibuprom rr