INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ORAFEN

Composition:

Active substance: ibuprofen;

5 ml of suspension contains ibuprofen 100 mg;

Excipients: glycerol, liquid maltitol, microcrystalline cellulose, xanthan gum, anhydrous citric acid, sodium citrate, sodium benzoate (E 211), polysorbate 80,
sodium saccharin, orange flavor, purified water.

Pharmaceutical form. Orange-flavored oral suspension.

Main physicochemical properties: after shaking, a homogeneous white or almost white suspension with an orange taste.

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.

It exerts analgesic, anti-inflammatory, and antipyretic effects. In addition, ibuprofen inhibits platelet aggregation. The mechanism of action involves inhibition of prostaglandin synthesis—mediators of pain, inflammation, and temperature response.

Pharmacokinetics.

After oral administration, ibuprofen is rapidly and almost completely absorbed, reaching maximum blood concentration within 1–2 hours. Ibuprofen is 90–99% bound to plasma proteins and slowly penetrates into synovial cavities, where its concentration may remain high while plasma concentration decreases. Ibuprofen is metabolized in the liver to two inactive metabolites, which are rapidly and almost completely excreted by the kidneys. A small amount (10%) is excreted unchanged. The half-life in healthy individuals is approximately 1.8 hours; in patients with liver or kidney disease, it ranges from 1.8 to 3.5 hours.

Clinical characteristics.

Indications.

Symptomatic treatment of fever and pain of various origins in children aged 6 months to 12 years (including post-vaccination fever, acute respiratory viral infections, influenza, teething pain, dental pain, post-extraction dental pain, headache, sore throat, ligament sprain pain, and other types of pain, including those of inflammatory origin).

Contraindications.

Hypersensitivity to ibuprofen or to other non-steroidal anti-inflammatory drugs (NSAIDs), or to any component of the medicinal product;
History of hypersensitivity reactions (e.g., bronchospasm, rhinitis, bronchial asthma, angioedema, or urticaria) following administration of acetylsalicylic acid (aspirin) or other NSAIDs;
Active peptic ulceration of the gastrointestinal tract or history of recurrent ulcers;
History of gastrointestinal bleeding or perforation following NSAID therapy;
Hereditary fructose intolerance;
Severe renal, hepatic, or cardiac insufficiency;
Dehydration caused by vomiting, diarrhea, or insufficient fluid intake;
Cerebrovascular or other hemorrhages;
Unexplained disorders of hematopoiesis or blood coagulation;
Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is not recommended with:

Acetylsalicylic acid (aspirin), except when aspirin (dose not exceeding 75 mg per day) has been prescribed by a physician. Experimental data indicate that ibuprofen may inhibit the antiplatelet effect of low-dose aspirin. However, limited data and uncertainty regarding extrapolation of ex vivo data to clinical settings preclude definitive conclusions about the systemic use of ibuprofen. Therefore, clinically significant effects are considered unlikely with occasional use of ibuprofen;
Other NSAIDs, including selective cyclooxygenase-2 inhibitors. Concomitant use of two or more NSAIDs should be avoided, as this may increase the risk of adverse effects;
Glucocorticosteroids. These may increase the risk of gastrointestinal adverse effects;
Anticoagulants. There is some evidence of enhanced effect of oral anticoagulants and increased risk of bleeding;
Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone intake, as NSAIDs may reduce its efficacy.

Use with caution concomitantly with:

Antihypertensive agents and diuretics. There may be an increased risk of renal adverse reactions. NSAIDs may reduce the therapeutic effect of these agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of ACE inhibitors or angiotensin II antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. Therefore, such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured if long-term treatment is necessary, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter. Patients should maintain sufficient fluid intake, and liver function should be monitored after initiation of concomitant therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs;
Methotrexate and lithium preparations: there is evidence of potential increase in plasma levels of these drugs;
Cyclosporines and tacrolimus: increased risk of nephrotoxicity;
Corticosteroids: increased risk of gastrointestinal bleeding or ulceration;
Antiplatelet agents and selective serotonin reuptake inhibitors: may increase the risk of gastrointestinal bleeding;
Potassium-sparing diuretics: may lead to hyperkalemia (plasma potassium level monitoring is recommended);
Hydantoins and sulfonamides: possible increase in toxic effects of these agents;
Ticlopidine: risk of additive effect in platelet function inhibition when used in combination with NSAIDs;
Digoxin: NSAIDs may increase digoxin plasma concentration, potentially leading to digoxin toxicity;
Cardiac glycosides: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides;
Pentoxifylline and thrombolytics: increased risk of bleeding;
Phenytoin: concomitant use of ibuprofen may increase plasma phenytoin levels;
Probenecid and sulfinpyrazone: possible increase in ibuprofen plasma concentration;
Quinolones: isolated cases of seizures have been reported, possibly associated with concomitant use of quinolones and certain NSAIDs;
Sulfonylurea derivatives: possible reduction in blood glucose levels;
Zidovudine: possible increased risk of erythrocyte toxicity. Evidence suggests increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen therapy;
CYP2C9 inhibitors: concomitant use of ibuprofen with CYP2C9 inhibitors may enhance the effect of ibuprofen (a CYP2C9 substrate). Studies using voriconazole and fluconazole (CYP2C9 inhibitors) demonstrated an approximately 80–100% increase in the effect of S(+)-ibuprofen. When ibuprofen is used concomitantly with strong CYP2C9 inhibitors, dose reduction of ibuprofen is recommended, especially when high doses of ibuprofen are used with voriconazole or fluconazole;
Food: administration of ORAFEN with food reduces the rate of absorption.

Special precautions for use.

The drug should be discontinued immediately at the first signs of skin rash, mucosal lesions, or any other manifestations of hypersensitivity.

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 connective tissue diseases and systemic lupus erythematosus due to an increased risk of aseptic meningitis;
arterial hypertension and/or history of heart failure associated with fluid retention and edema during NSAID therapy;
congenital porphyrin metabolism disorders (acute intermittent porphyria);
impaired renal and/or hepatic function;
hay fever, nasal polyps, or chronic obstructive respiratory diseases due to an increased risk of allergic reactions, including asthma attacks (so-called analgesic-induced asthma), Quincke's edema (angioedema), or urticaria;
pronounced dehydration due to diarrhea, following surgical procedures, or in cases of cardiac, hepatic, or renal insufficiency, or during diuretic therapy. In such cases, careful monitoring of diuresis and renal function is required.

In case of gastrointestinal bleeding or ulceration, the drug should be discontinued immediately.

Patients with acute porphyria should not take ORAFEN without medical prescription.

In patients with pronounced dehydration, adequate fluid intake should be ensured.

Patients with arterial hypertension and/or a history of moderate to severe congestive heart failure should begin long-term treatment cautiously (medical consultation required), as fluid retention, arterial hypertension, and edema have been reported during therapy with ibuprofen and other NSAIDs. Long-term treatment may be prescribed by a physician only after careful evaluation in patients with uncontrolled arterial hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen. 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.

Long-term NSAID therapy should be prescribed only after careful consideration in patients with significant risk factors for cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Caution is recommended when treating patients who are concurrently taking medications such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., aspirin), as these may increase the risk of ulceration or bleeding. For patients on long-term therapy, as well as those requiring concomitant low-dose acetylsalicylic acid (aspirin) or other drugs that may increase gastrointestinal risk, combined therapy with misoprostol or proton pump inhibitors should be considered by the physician.

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

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been observed with all NSAIDs, regardless of treatment duration and with or without serious gastrointestinal complications in medical history.

Higher NSAID doses, advanced age, and history of peptic ulcer disease increase the risk of gastrointestinal adverse reactions. In such cases, the use of the lowest effective dose is recommended.

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

Severe 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 occur within the first month of treatment.

If signs or symptoms indicating these reactions appear, ibuprofen should be discontinued immediately and alternative treatment options considered (if necessary).

Bronchospasm may occur in patients with or with a history of bronchial asthma or allergic diseases.

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

Prolonged use of high-dose analgesics may lead to medication-overuse headache, which 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 a risk of renal failure (analgesic nephropathy).

There is some evidence that drugs inhibiting cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of the drug.

Use during pregnancy or breastfeeding.

The drug should not be used in children under 12 years of age.

Pregnancy.

The drug is contraindicated in women during the third trimester of pregnancy (see section "Contraindications").

Prostaglandin synthesis inhibitors may negatively affect pregnant women and/or embryonic/fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects following exposure to prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with higher doses and longer duration of treatment. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. 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 conception 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.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitor may affect the fetus by causing cardiopulmonary toxicity (premature constriction/closure of the fetal ductus arteriosus and pulmonary hypertension) and impaired renal function, which may progress to renal failure with oligohydramnios. Ibuprofen is contraindicated in the third trimester of pregnancy due to possible inhibition of uterine contractility, which may lead to delayed or prolonged labor with a tendency toward increased bleeding in both mother and child, as well as due to its antiplatelet effect, which may occur even at very low doses. Increased risk of maternal edema is also possible.

Starting from the 20th week of pregnancy, use of ORAFEN may cause oligohydramnios due to fetal renal dysfunction. Additionally, there are reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after discontinuation of therapy. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after several days of ibuprofen exposure starting from the 20th gestational week. Use of ORAFEN should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

Breastfeeding. Ibuprofen and its metabolites may pass into breast milk in low concentrations. There is currently no evidence of adverse effects on the infant; therefore, interruption of breastfeeding is usually not required during short-term treatment of pain and fever at recommended doses.

Fertility.

Limited data suggest that cyclooxygenase/prostaglandin synthesis inhibitors may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of therapy.

Therefore, the use of ibuprofen is not recommended in women experiencing difficulty conceiving.

Ability to affect reaction speed when driving or operating machinery.

The drug should not be used in children under 12 years of age.

Ibuprofen does not affect or has negligible effects on the ability to drive or operate machinery when used short-term. However, during prolonged use, adverse effects such as increased fatigue and dizziness may occur. Patients experiencing dizziness, drowsiness, disorientation, or visual disturbances while taking NSAIDs should refrain from driving or operating machinery.

Method of Administration and Dosage

The medication is intended for oral use only.

The dose for children depends on age and body weight.

The single dose should be 5–10 mg/kg.

For children aged 6 months to 12 years, the maximum daily dose should not exceed 30 mg/kg. The interval between doses should depend on symptom changes but must be at least 4 hours.

Children aged 6 months: 2.5 ml of suspension (50 mg) every 8 hours, but not more than 7.5 ml (150 mg) per day.
Children aged 6 to 12 months: 2.5 ml of suspension (50 mg) 3–4 times daily (every 6 hours), but not more than 10 ml (200 mg) per day.
Children aged 1 to 3 years: 5 ml of suspension (100 mg) every 8 hours, but not more than 15 ml (300 mg) per day.
Children aged 4 to 6 years: 7.5 ml of suspension (150 mg) 3 times daily (450 mg per day).
Children aged 7 to 9 years: 10 ml of suspension (200 mg) 3 times daily (600 mg per day).
Children aged 10 to 12 years: 15 ml of suspension (300 mg) 3 times daily (900 mg per day).

For fever after vaccination: 2.5 ml, and if necessary, another 2.5 ml after 6 hours, but not more than 5 ml within 24 hours.

Adults and children aged 12 years and older are advised to use ibuprofen in another pharmaceutical form.

The lowest effective dose should be used. The duration of treatment is determined by the physician, depends on the course of the disease, and usually lasts 3 days.

Patients with gastrointestinal disorders are advised to take the medication during meals.

Elderly patients: dose adjustment is generally not required. However, ORAFEN should be used with caution in this population, as elderly patients are more susceptible to adverse effects.

For dosing, use the 5 ml graduated syringe with 0.2 ml increments provided in the package.

Children

ORAFEN should not be used in children under 6 months of age.

Overdose

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

In acute overdose, symptoms depend on the amount ingested and the time elapsed since ingestion. Initial symptoms typically observed include nausea, vomiting, headache, dizziness, epigastric pain, and somnolence.

In more severe poisoning, toxic effects on the central nervous system may occur, such as vertigo, sometimes excitement, disorientation, or coma. Seizures may occasionally develop in patients. Severe intoxication may lead to hyperkalemia and metabolic acidosis, as well as prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors). Acute renal failure, liver damage, hypotension, respiratory depression, and cyanosis may occur. In patients with bronchial asthma, asthma exacerbation is possible. Nystagmus, visual disturbances, and loss of consciousness may also occur.

If less than 1 hour has passed since acute overdose, induce vomiting, perform gastric lavage, or administer activated charcoal. If ibuprofen has already been absorbed, alkaline substances may be administered to enhance urinary excretion of the acidic ibuprofen.

There is no specific antidote or targeted treatment for ibuprofen overdose. Symptomatic treatment includes monitoring of vital functions, measuring arterial blood pressure, performing ECG, and interpreting symptoms indicating possible gastrointestinal bleeding, metabolic acidosis, or central nervous system disturbances.

In cases of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. In case of bronchial asthma exacerbation, bronchodilators should be administered. Seek immediate medical assistance.

Adverse Reactions.

The most common adverse reactions are gastrointestinal in nature and mostly dose-dependent. Adverse reactions are least likely when the maximum daily dose is 1200 mg.

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 reports.
Not known (cannot be estimated due to limited available data).

If signs of infection occur or worsen during ibuprofen use, patients are advised to seek immediate medical advice. The need for antimicrobial/antibiotic therapy should be evaluated.

Regular blood tests are required during long-term therapy.

Patients should immediately consult a physician and discontinue ibuprofen if any symptoms of hypersensitivity reactions occur, which may develop even after the first dose of the drug. In such cases, immediate medical attention is required.

If severe epigastric pain, melena, or bloody vomiting occurs, the drug should be discontinued and immediate medical advice sought.

Infections and infestations.
Very rare: Exacerbation of infection-related inflammation (e.g., development of necrotizing fasciitis). In exceptional cases, varicella may lead to severe skin and soft tissue infections.

General disorders:
Malaise and fatigue.

Gastrointestinal disorders:
Uncommon: abdominal pain, dyspepsia, nausea;
Rare: diarrhea, flatulence, constipation, vomiting;
Very rare: heartburn, ulcerative stomatitis, gastritis, gastrointestinal perforation or hemorrhage, melena, hematemesis, which may in some cases be fatal, especially in elderly patients, formation of diaphragm-like intestinal strictures;
Not known: exacerbation of ulcerative colitis and Crohn’s disease. Irritation or dryness of the oral mucosa, oral mucosal ulcers of the gums, aphthous stomatitis, pancreatitis.

Nervous system disorders:
Uncommon: headache, dizziness, insomnia, anxiety, depression, nervousness, irritability, psychomotor agitation, confusion, hallucinations;
Very rare: aseptic meningitis, with individual symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) possibly occurring in patients with pre-existing autoimmune diseases such as systemic lupus erythematosus or mixed connective tissue disease;
Not known: paresthesia, somnolence.

Cardiovascular disorders:
Very rare: vasculitis;
Not known: heart failure, edema, tachycardia, increased blood pressure, arterial thrombosis (myocardial infarction or stroke), Kounis syndrome.

Renal and urinary disorders:
Very rare: acute renal impairment, papillary necrosis, particularly with prolonged use, associated with increased plasma urea levels and edema;
Not known: renal failure, nephrotoxicity including interstitial nephritis and nephrotic syndrome, allergic nephritis, glomerulonephritis, oliguria, polyuria, cystitis, hematuria.

Hepatobiliary disorders:
Very rare: liver function abnormalities;
Not known: hepatitis, pancreatitis, duodenitis, esophagitis with prolonged use.

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, unexplained bleeding or bruising.

Skin and subcutaneous tissue disorders:
Rare: various skin rashes;
Very rare: severe cutaneous adverse reactions (SCARs) (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis);
Not known: photosensitivity; drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); acute generalized exanthematous pustulosis (AGEP).

Immune system disorders:
Rare: hypersensitivity reactions including urticaria and pruritus;
Very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension, anaphylactic reactions, angioedema, or severe shock;
Not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm.

Ear and labyrinth disorders:
Not known: tinnitus and dizziness may occur with prolonged treatment.

Eye disorders:
Not known: visual disturbances, optic neuritis may occur with prolonged treatment.

Laboratory investigations:
Very rare: decreased hemoglobin levels.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25°C in the original packaging. Keep out of the reach of children.

Packaging.

200 ml in a bottle; 1 bottle with a dosing syringe in a cardboard box.

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

LABORATORIO ALDO-UNION, S.L.

Manufacturer's address and place of business.

Baronesa de Maldà, 73, 08950 Esplugues de Llobregat, Barcelona, Spain.

Orafen