Neophen belupo forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOFEN BELUPO FORTE

Composition:

Active substance: ibuprofen;

1 tablet contains 400 mg of ibuprofen;

Excipients: lactose monohydrate; pregelatinized starch; povidone; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; talc; magnesium stearate;

Coating composition: talc, polyethylene glycol (macrogol) 6000, titanium dioxide (E 171), hypromellose, 30% polyacrylate dispersion, carmoisine (E 122).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets of dark pink color.

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

Pharmacological Properties

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

Experimental data indicate that ibuprofen may competitively reduce the effect of low-dose acetylsalicylic acid on platelet aggregation when both 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 acetylsalicylic acid (81 mg) was associated with reduced effects of acetylsalicylic acid (aspirin) on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these findings to clinical settings, the possibility cannot be excluded 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 interaction is considered unlikely.

Pharmacokinetics
After oral administration, ibuprofen is rapidly absorbed, partially already in the stomach, and completely in the small intestine. Maximum plasma concentration is reached within 1–2 hours after administration. The elimination half-life is approximately 2 hours.

Following metabolism in the liver (via hydroxylation, carboxylation, and conjugation), pharmacologically inactive metabolites are excreted almost entirely via the urine (90%) and also via bile. Plasma protein binding is approximately 99%.

Clinical characteristics.

Indications. Symptomatic short-term treatment of mild to moderate pain of various origins (headache, migraine, back pain, muscle and joint pain, dental pain, neuralgia, rheumatic pain); treatment of symptoms of cold and influenza.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the medicinal product.
• Hypersensitivity reactions (e.g., asthma, rhinitis, urticaria, or angioedema) previously observed after administration of ibuprofen, acetylsalicylic acid, or other NSAIDs.
• Active peptic ulcer/gastrointestinal bleeding or history of recurrent episodes (two or more distinct episodes of peptic ulcer or bleeding).
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy.
• Patients with conditions associated with an increased tendency to bleeding.
• Severe hepatic impairment, severe renal impairment, severe heart failure (NYHA class IV).
• Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use with the following medicinal products requires caution due to potential drug interactions observed in some patients.

Antihypertensive agents, β-blockers, and diuretics. NSAIDs may reduce the effect of antihypertensive agents such as ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and diuretics. Diuretics may also increase the risk of nephrotoxicity associated with NSAIDs.

Cardiac glycosides. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.

Cholestyramine. Concomitant administration of ibuprofen and cholestyramine may reduce absorption of ibuprofen in the gastrointestinal tract (GI tract). However, the clinical significance of this interaction is unknown.

Lithium. NSAIDs may reduce lithium clearance.

Methotrexate. NSAIDs may inhibit tubular secretion of methotrexate and reduce methotrexate clearance.

Cyclosporine. Increased risk of nephrotoxicity when used concomitantly with NSAIDs.

Mifepristone. A reduction in efficacy is theoretically possible due to the anti-prostaglandin properties of NSAIDs, including acetylsalicylic acid. Limited data suggest that concomitant use of NSAIDs on the day of prostaglandin administration does not adversely affect the action of mifepristone or prostaglandin on cervical ripening or uterine contractility, and does not reduce the clinical efficacy of medical termination of pregnancy.

Other analgesics/NSAIDs, including selective COX-2 inhibitors. Concomitant administration of two or more NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided due to increased risk of adverse effects (see section "Special precautions for use**"**).

Acetylsalicylic acid/aspirin. As with other NSAID-containing medicinal products, concomitant use of ibuprofen and acetylsalicylic acid/aspirin is generally not recommended due to the risk of increased adverse reactions.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid/aspirin on platelet aggregation when used concomitantly. Although uncertainties exist regarding the extrapolation of these data to clinical practice, it cannot be excluded that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Clinically relevant effects are unlikely with occasional, non-regular use of ibuprofen (see section "Pharmacological properties. Pharmacodynamics").

Corticosteroids. Increased risk of gastrointestinal ulceration or bleeding when used concomitantly with NSAIDs (see section "Special precautions for use**"**).

Anticoagulants. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use**"**).

Quinolone antibiotics. Data from animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones concomitantly have an increased risk of developing seizures.

Sulfonylureas. NSAIDs may potentiate the effects of sulfonylurea agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas during ibuprofen therapy.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) (e.g., clopidogrel and ticlopidine). Increased risk of gastrointestinal bleeding when used concomitantly with NSAIDs (see section "Special precautions for use**"**).

Tacrolimus. Possible increased risk of nephrotoxicity when NSAIDs are administered concomitantly with tacrolimus.

Zidovudine. NSAIDs increase the risk of hematological toxicity when administered concomitantly with zidovudine. Evidence suggests an increased risk of hemarthrosis and hematomas in HIV-positive patients with hemophilia receiving ibuprofen while on zidovudine therapy.

Aminoglycosides. NSAIDs may reduce the elimination of aminoglycosides.

Herbal extracts. Ginkgo biloba may potentiate the risk of bleeding associated with NSAID use.

CYP2C9 inhibitors. Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). One study demonstrated that voriconazole and fluconazole (CYP2C9 inhibitors) increased exposure to S(+)-ibuprofen by approximately 80–100%. Dose reduction of ibuprofen should be considered when co-administered with strong CYP2C9 inhibitors, particularly when high doses of ibuprofen are used concomitantly with voriconazole or fluconazole.

Special precautions for use

General warnings

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration", as well as information on gastrointestinal and cardiovascular risks and masking of symptoms of underlying infections below).

With prolonged use of any analgesic, headache may occur, which should not be treated with increased doses of the medicinal product.

Concomitant use of NSAIDs with alcohol may increase adverse effects related to the active substance, particularly those affecting the gastrointestinal tract or central nervous system.

Elderly patients

The incidence of adverse reactions during NSAID use is higher in elderly patients, especially gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Children

In children and adolescents with dehydration, there is a risk of impaired renal function.

Gastrointestinal bleeding, ulceration, and perforation

NSAIDs should be used with caution in patients with a history of peptic ulcer or other gastrointestinal disorders, as their condition may worsen (see section "Contraindications").

Gastrointestinal bleeding, ulceration, or perforation have been reported during treatment with all NSAIDs at any time. These adverse reactions may be fatal and may occur with or without warning symptoms or serious gastrointestinal disorders in history.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, particularly in patients with a history of ulcers, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest available dose. Consideration should be given to concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) in these patients, as well as in patients who are concurrently taking low-dose acetylsalicylic acid/aspirin or other drugs that increase the risk of gastrointestinal tract injury (see below, and section "Interaction with other medicinal products and other forms of interaction").

Ibuprofen should not be used concomitantly with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, due to increased risk of ulceration or bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Patients, especially elderly individuals, with a history of gastrointestinal disorders should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during initial stages of treatment.

Ibuprofen should be prescribed with caution to patients receiving concomitant therapy with drugs that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), SSRIs, or antiplatelet agents such as acetylsalicylic acid/aspirin (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in a patient receiving ibuprofen, treatment with the drug should be discontinued.

Respiratory disorders

Ibuprofen should be prescribed with caution to patients suffering from bronchial asthma, chronic rhinitis, allergic diseases, or with a history of such conditions, as NSAIDs have been reported to cause bronchospasm, urticaria, or angioedema in such patients.

Cardiac, renal, and hepatic function impairment

NSAID use may lead to dose-dependent reduction in prostaglandin synthesis and result in renal impairment. Concurrent regular use of similar analgesics further increases this risk. Patients at greatest risk of such reactions include those with impaired renal, cardiac, or hepatic function, those taking diuretics, and elderly patients. These patients should be treated with the lowest effective dose for the shortest possible duration, and renal function should be monitored, especially during long-term treatment (see section "Contraindications").

Ibuprofen should be used with caution in patients with a history of heart failure or arterial hypertension, as edema has been reported with ibuprofen use.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and supervision are required in patients with a history of hypertension and/or moderate to severe congestive heart failure, as fluid retention and edema have been reported during NSAID therapy.

Clinical studies indicate that ibuprofen use, particularly at high doses (2400 mg daily), may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest a clear association between low-dose ibuprofen use (i.e., ≤1200 mg daily) and increased risk of arterial thrombotic events.

Ibuprofen should be prescribed to patients with uncontrolled hypertension, congestive heart failure (NYHA functional class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration, and high doses (2400 mg daily) should be avoided.

Careful consideration is also required before initiating long-term ibuprofen therapy in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes, smoking), particularly if high-dose ibuprofen (2400 mg daily) is needed.

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

Ibuprofen treatment should be initiated with caution in patients with significant dehydration. There is a risk of impaired renal function, particularly in dehydrated children, adolescents, and elderly patients.

As with other NSAIDs, prolonged use of ibuprofen may lead to renal papillary necrosis and other pathological renal changes. Toxic effects on the kidneys may also occur in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. Administration of NSAIDs to such patients may cause dose-dependent reduction in prostaglandin synthesis and, consequently, reduced renal blood flow, potentially leading to renal failure. Patients at high risk of such reactions include those with impaired renal, cardiac, or hepatic function, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors, and elderly patients. Discontinuation of NSAIDs is usually followed by return to the pre-treatment state.

Systemic lupus erythematosus and mixed connective tissue disorders

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

Cutaneous effects

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 therapy considered (if necessary).

In rare cases, serious skin and soft tissue infections may occur during chickenpox. The role of NSAIDs in worsening these infections has not been established. Therefore, it is recommended to avoid ibuprofen use in patients with active chickenpox.

Hematological effects

Ibuprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time in healthy volunteers.

Aseptic meningitis

Aseptic meningitis has been rarely observed in patients during ibuprofen treatment. Although aseptic meningitis is more likely to occur in patients with systemic lupus erythematosus and related connective tissue disorders, cases have also been reported in patients without these chronic conditions.

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious disease, potentially delaying initiation of appropriate treatment and thereby complicating the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox. If ibuprofen is used for fever or pain relief during infection, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding

Fertility

Ibuprofen use may impair female fertility and is not recommended for women attempting to conceive. Women experiencing fertility problems or undergoing infertility evaluation should consider discontinuing ibuprofen.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. This risk is considered to increase with dose and duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryonic/fetal mortality. Furthermore, increased incidences of various developmental abnormalities, including cardiovascular malformations, have been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, ibuprofen use may cause oligohydramnios (low amniotic fluid) due to impaired fetal renal function. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of ductus arteriosus constriction have been reported after second-trimester treatment, most of which resolved after treatment cessation. Therefore, ibuprofen should not be prescribed during the first and second trimesters unless clearly necessary. If ibuprofen is used by women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and treatment duration as short as possible. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ibuprofen for several days starting from the 20th week of pregnancy. Ibuprofen should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

In the third trimester of pregnancy, ibuprofen is contraindicated, as inhibition of prostaglandin synthesis in the fetus may lead to:

Fetal risks:

• Cardio-pulmonary toxicity syndrome (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function, which may progress to renal failure with development of oligohydramnios;

Risks at the end of pregnancy for mother and child:

• Prolonged bleeding time (due to inhibition of platelet aggregation), which may occur even with low-dose use;
• Delayed uterine contractions, leading to delayed labor and prolonged delivery.

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

Breastfeeding

Limited available studies show that NSAIDs pass into breast milk in very low concentrations. NSAIDs should be avoided in breastfeeding women if possible.

Ability to affect reaction speed when driving or operating machinery

Ibuprofen may impair patients' reaction speed, which should be considered when engaging in activities requiring heightened attention, such as driving or operating machinery. This effect is significantly enhanced when combined with alcohol.

Undesirable effects such as dizziness, drowsiness, malaise/fatigue, and visual disturbances may occur after taking NSAIDs. If such effects occur, patients should refrain from driving and operating machinery.

Dosage and Administration

For oral use. The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section "Special Warnings and Precautions for Use"). To reduce the risk of gastrointestinal disturbances, the drug should be taken during meals with sufficient amount of liquid.

Adults and children aged 12 years and older: initial dose – 1 tablet. If necessary, the dose may be repeated every 4–6 hours.

The daily dose of ibuprofen should not exceed 1200 mg.

If symptoms persist or worsen after using the medication for more than 3 days, the patient should consult a physician.

Elderly patients do not require special dosage adjustments.

Patients with mild to moderate renal or hepatic impairment do not require dose adjustment; however, the drug should be used with caution in these patients.

Children

Use in children under 12 years of age is not recommended.

Overdose

Symptoms of overdose depend on the amount of drug ingested and the time elapsed since ingestion. Initial symptoms may include: nausea, vomiting, headache, dizziness, epigastric pain, somnolence, diarrhea, tinnitus, nystagmus, visual disturbances, excitement, disorientation, seizures, acute renal failure, liver damage, respiratory depression, cyanosis, and prolonged prothrombin time. In cases of overdose, coma, arterial hypotension, hyperkalemia with cardiac arrhythmias, metabolic acidosis, elevated body temperature, respiratory complications, and impaired kidney function may occur. Prolonged use may lead to hemolytic anemia, granulocytopenia, and thrombocytopenia.

In severe poisoning, metabolic acidosis and prolonged prothrombin time may develop, likely due to inhibition of circulating blood coagulation factors.

In patients with bronchial asthma, an exacerbation of asthma symptoms may occur.

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

If less than 1 hour has passed since overdose, induction of emesis, gastric lavage, or administration of activated charcoal is recommended. In case of frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be prescribed for patients with asthma.

There is no specific antidote or specific treatment for ibuprofen overdose. Symptomatic and supportive therapy is indicated, including correction of fluid and electrolyte imbalances and continuous monitoring and support of vital functions until the patient's condition normalizes.

Side effects.

Ibuprofen may cause hypersensitivity reactions: non-specific allergic reactions, anaphylactic shock and respiratory tract reactions, such as asthma, exacerbation of asthma, bronchospasm, dyspnea, various skin reactions, for example pruritus, urticaria, Quincke's edema; very rarely exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme) have been reported.

Adverse reactions associated with the use of ibuprofen are classified by organ systems and frequency of occurrence: very common: ≥ 1/10; common: ≥ 1/100 – < 1/10; uncommon: ≥ 1/1000 – < 1/100; rare: ≥ 1/10000 – < 1/1000; very rare: < 1/10000; and unknown (frequency cannot be estimated due to limited available data).

Gastrointestinal system:

uncommon – abdominal pain, dyspepsia, nausea;

rare – diarrhea, flatulence, constipation, vomiting;

very rare – melena, vomiting blood, sometimes fatal outcomes (especially in elderly patients), ulcerative stomatitis, gastritis, pancreatitis, peptic ulcer, perforation or gastrointestinal bleeding, which in some cases may lead to fatal outcomes, particularly in elderly patients, exacerbation of ulcerative colitis and Crohn's disease;
unknown – heartburn, formation of oral ulcers, esophagitis, development of diaphragmatic intestinal strictures.

Nervous system:

uncommon – headache;

rare – aseptic meningitis (in patients with autoimmune disorders, specifically systemic lupus erythematosus, connective tissue diseases – during ibuprofen treatment isolated cases of aseptic meningitis symptoms have been observed: neck muscle rigidity, headache, nausea, vomiting, high fever, or disorientation);

unknown – paresthesia, drowsiness.

Respiratory system:

unknown – respiratory distress.

Cardiovascular system:

unknown – increased heart rate, palpitations, development of edema, hypertension, heart failure (prolonged use and high doses increase the risk of arterial thrombotic complications, such as myocardial infarction and/or stroke), Cozzarelli syndrome.

Urinary system:

very rare – acute renal function impairment, papillary necrosis, especially with prolonged use, associated with increased serum urea levels and edema;
unknown – renal failure, nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Hepatobiliary system:

very rare – liver disorders;

unknown – liver failure, acute hepatitis; with prolonged treatment, hepatitis and jaundice may occur.

Blood and lymphatic system:

very rare – blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs include: fever, sore throat, oral ulcers, flu-like symptoms, increased fatigue, severe exhaustion, unexplained bleeding and bruising, ecchymoses, purpura, epistaxis. Blood parameters should be monitored regularly during long-term therapy.

Skin and subcutaneous tissue:

uncommon – skin rashes;

very rare – severe skin adverse reactions (SSARs) may occur (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis);

unknown – photosensitivity, drug-induced eosinophilia with systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP).

Immune system:

uncommon – hypersensitivity reactions such as urticaria and pruritus;

very rare – severe hypersensitivity reactions presenting as facial, tongue, and laryngeal swelling, dyspnea, shortness of breath, tachycardia, hypotension, anaphylactic shock, Quincke's edema. Exacerbation of asthma and bronchospasm.

Psychiatric disorders:

unknown – with prolonged use, depression, hallucinations, confusion, psychotic reactions, vertigo, insomnia, irritability, and agitation may occur.

Visual organs:

unknown – with prolonged treatment, visual disturbances and optic neuritis may occur.

Auditory organs:

unknown – with prolonged treatment, tinnitus and dizziness may occur.

General disorders:

malaise and increased fatigue.

Laboratory findings:
very rare – decreased hemoglobin levels.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per blister, 1 blister per cardboard pack.

Supply category.

Over-the-counter.

Manufacturer.

Belupo, Pharmaceuticals and Cosmetics, d.d.

Manufacturer's address and place of business.

Danicica 5, 48000 Koprivnica, Croatia.