Darfen®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Darfen® (Darfen)

Composition:

Active substance: ibuprofen in the form of sodium ibuprofen dihydrate;

1 tablet contains 200 mg or 400 mg of ibuprofen in the form of sodium ibuprofen dihydrate;

Excipients: microcrystalline cellulose, sodium croscarmellose, xylitol, colloidal anhydrous silicon dioxide, magnesium stearate, sucrose, talc, titanium dioxide (E 171), dried acacia dispersion, sodium carmellose, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), a derivative of propionic acid, which has demonstrated efficacy in inhibiting the synthesis of prostaglandins—mediators of pain and inflammation. Ibuprofen relieves pain, reduces inflammation, and lowers fever. In addition, ibuprofen reversibly inhibits platelet aggregation.

Clinical efficacy and safety

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid (ASA) 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 ASA (81 mg) was associated with reduced effects of ASA on thromboxane formation or platelet aggregation. Despite uncertainty regarding the extrapolation of these data to clinical settings, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose ASA cannot be excluded. However, clinically significant interaction is considered unlikely with occasional, short-term use of ibuprofen.

Clinical efficacy of ibuprofen has been demonstrated in the treatment of headache and dental pain, dysmenorrhea, fever associated with cold and influenza, as well as sore throat, muscle pain, and back pain.

Clinical studies have shown that the analgesic effect of ibuprofen may last up to 8 hours.

In a study evaluating treatment of dental pain, significant pain relief was observed as early as 15 minutes after administration of ibuprofen compared to placebo. In this study, significantly more patients reported substantial pain relief with ibuprofen compared to paracetamol. Patients treated with ibuprofen also experienced a significantly greater reduction in pain intensity and more pronounced pain relief over 6 hours compared to those receiving paracetamol.

Pharmacokinetics

Absorption.

Ibuprofen is rapidly absorbed in the gastrointestinal tract (GI tract), binds to plasma proteins, and is distributed throughout the body. It should be noted that the bioavailability of ibuprofen sodium salt is significantly higher, and onset of action occurs twice as fast compared to conventional ibuprofen tablets.

Distribution. Ibuprofen reaches the synovial fluid. Maximum serum concentration of ibuprofen sodium dihydrate is achieved within 35 minutes after administration. When ibuprofen acid is administered, maximum concentration is observed within 1–2 hours after intake. Absorption may be delayed by food intake.

Biotransformation. Following metabolism in the liver (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are completely excreted primarily in urine (90%), as well as in bile. Elimination half-life in healthy volunteers, as well as in patients with hepatic or renal disease, ranges from 1.8 to 3.5 hours. Plasma protein binding is approximately 99%.

Excretion. Ibuprofen is metabolized in the liver into two inactive metabolites, which are rapidly and completely eliminated by the kidneys. The elimination half-life of ibuprofen is approximately 2 hours.

No significant differences in pharmacokinetic profile have been observed in elderly patients.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origins, including headache and toothache, migraine, dysmenorrhea, neuralgia, back pain, muscle pain, rheumatic pain (except severe cases of arthritis), as well as sore throat, symptoms of cold and flu, and fever.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Patients with hypersensitivity reactions (e.g., bronchospasm, asthma, rhinitis, angioedema, or urticaria) previously experienced after taking ibuprofen or other NSAIDs (e.g., ASA).
• Gastrointestinal bleeding or perforation related to previous use of NSAIDs.
• Active or history of recurrent peptic ulcer disease/gastrointestinal bleeding (two or more documented episodes of confirmed ulceration or bleeding).
• Severe renal, hepatic, or cardiac [NYHA Class IV] insufficiency.
• Concomitant use with other NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, due to increased risk of adverse reactions.
• Active cerebrovascular or other bleeding.
• Disorders of hematopoiesis and/or blood coagulation.
• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Ibuprofen should not be used in combination with:

• Other NSAIDs, including selective COX-2 inhibitors, as concomitant use of multiple NSAIDs may increase the risk of adverse reactions.
• ASA (acetylsalicylic acid), as this increases the risk of adverse reactions.

Experimental data indicate that ibuprofen may inhibit the effect of low-dose ASA on platelet aggregation when used concomitantly. However, the limitations regarding extrapolation of these data to clinical practice do not allow definitive conclusions that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose ASA. Clinically significant effects are considered unlikely with occasional, short-term use of ibuprofen.

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

• Corticosteroids.*

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

Antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor antagonists) and diuretics.

NSAIDs may reduce the antihypertensive effects of drugs such as ACE inhibitors, angiotensin II receptor antagonists, and diuretics. 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 receptor antagonist with COX-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, especially in elderly patients. If long-term treatment is necessary, adequate hydration should be ensured and monitoring of renal function should be considered at the beginning of combination therapy and periodically thereafter. Diuretics may also increase the risk of NSAID-induced nephrotoxicity.

Anticoagulants.

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

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs).
Increased risk of gastrointestinal bleeding when taken with NSAIDs (see section "Special precautions for use").

Cardiac glycosides.

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

Lithium.

NSAIDs may reduce lithium excretion, leading to increased plasma lithium concentrations.

Methotrexate.

Use of NSAIDs may lead to increased methotrexate plasma concentrations.

Cyclosporine.

Increased risk of nephrotoxicity when used concomitantly with NSAIDs.

Mifepristone.

NSAIDs are not recommended within 8–12 days after mifepristone administration, as this may reduce mifepristone’s efficacy.

Tacrolimus.

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

Zidovudin.

Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics.

Animal experimental data suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Concomitant use with ibuprofen may increase the risk of seizures.

Sulfonylurea agents.

Possible potentiation of sulfonylurea effect.

Voriconazole and fluconazole.

Possible potentiation of ibuprofen's effect when used concomitantly with voriconazole and fluconazole.

Special precautions for use.

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

Elderly patients.

The incidence of adverse reactions to NSAIDs is higher in elderly patients, particularly gastrointestinal bleeding and perforations, which may be fatal (see section "Dosage and administration").

Systemic lupus erythematosus and mixed connective tissue diseases.

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

Severe skin reactions.

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 treatment with ibuprofen (see section "Adverse reactions"). Most such reactions occurred within the first month of treatment.

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

Renal function impairment.

Chronic use of analgesic agents, especially combinations of several analgesics, may lead to persistent impairment of renal function with a risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration. Ibuprofen should be used with caution in patients with impaired renal function, as renal function may worsen.

Hepatic effects.

Impairment of liver function may occur.

Children.

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

Gastrointestinal bleeding, ulcers, and perforations.

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

The risk of gastrointestinal bleeding, ulcers, or perforations is higher with increased NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients. Such patients should start treatment with the lowest doses. Concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, as well as for those receiving concomitant low-dose acetylsalicylic acid (ASA) or other drugs increasing the risk of gastrointestinal injury (see below and section "Interaction with other medicinal products and other forms of interaction").

Patients, especially elderly ones, with a history of gastrointestinal disorders should report any unusual abdominal symptoms (including gastrointestinal bleeding), particularly at the beginning 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), selective serotonin reuptake inhibitors, or antiplatelet agents such as ASA (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration is diagnosed in patients receiving Darfen®, treatment should be discontinued immediately.

NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated.

Respiratory effects.

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

Cardiovascular and cerebrovascular effects.

Patients with a history of hypertension and/or heart failure should start treatment with caution (medical consultation required), as fluid retention, 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), may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g., ≤1200 mg per day) increases the risk of arterial thrombotic complications.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg per day) should be avoided.

Careful clinical evaluation should also be performed before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., 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 Darfen®. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Masking symptoms of underlying infections.

Ibuprofen may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and worsening the course of illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When 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.

Important information on excipients.

Darfen® contains xylitol, which may have a laxative effect. The energy value of 1 g of xylitol is 2.4 kcal.

This medicinal product contains sucrose; therefore, if sugar intolerance is diagnosed, medical advice should be sought before taking this product.

Darfen® contains sodium; therefore, caution is advised when administering this medicinal product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

First and second trimesters of pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. In animal studies, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, has been observed.

From the 20th week of pregnancy, the use of Darfen® may cause oligohydramnios due to fetal renal dysfunction. This condition may occur early in treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, Darfen® should not be used during the first two trimesters of pregnancy unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus. If ibuprofen is used by a woman attempting to conceive or during the first or second trimester of pregnancy, the lowest possible dose should be used for the shortest duration.

Fetal monitoring for oligohydramnios and arterial duct constriction should be performed over several days following administration of Darfen®, starting from the 20th week of pregnancy. If oligohydramnios or arterial duct constriction is detected, the drug should be discontinued.

Third trimester of pregnancy

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

• to the fetus: cardio-pulmonary toxicity (characterized by premature constriction/closure of the arterial duct and pulmonary hypertension); renal dysfunction, which may progress to renal failure associated with oligohydramnios;
• to the mother and newborn near term: prolonged bleeding time, antiplatelet effect (which may occur even at very low doses); inhibition of uterine contractions leading to delayed or prolonged labor; possible increased risk of maternal edema.

Therefore, Darfen® is contraindicated during the third trimester of pregnancy.

Breastfeeding period

In limited studies, ibuprofen and its metabolites have been detected in breast milk at very low concentrations (0.0008% of the maternal dose), making it unlikely to adversely affect the breastfed infant. Darfen® is not recommended during breastfeeding.

Fertility

Limited data suggest that medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation when used long-term. This effect is reversible upon discontinuation of treatment.

Ability to influence reaction speed when driving or operating machinery.

When taken according to the recommended doses and duration of use, the medicinal product does not affect reaction speed when driving or operating machinery.

Dosage and Administration

For short-term use only.

Use the lowest effective dose necessary to relieve symptoms for the shortest possible duration.

The single dose for adults and children aged 12 years and older is 1–2 tablets (200 mg–400 mg). The interval between doses should be at least 4 hours. Do not exceed 6 tablets of 200 mg or 3 tablets of 400 mg per day. The maximum daily dose of 1200 mg must not be exceeded.

If symptoms in adolescents aged 12 years and older worsen or persist beyond 3 days, consult a physician for diagnosis clarification and treatment adjustment.

If prolonged use beyond 10 days is required, consult a physician.

Geriatric patients.

No special dose adjustment is necessary.

Administration method.

Administer orally. Patients with gastric problems are advised to take Darfen**®** during or after meals.

Children.

Darfen® must not be used in children under 12 years of age.

Overdose.

In children, ibuprofen doses exceeding 400 mg/kg body weight may cause intoxication symptoms. In adults, the effects of overdose are less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. Nausea, vomiting, epigastric pain, and rarely diarrhea. Tinnitus, blurred vision, headache, dizziness, nystagmus, blurred vision, loss of consciousness, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, presenting as dizziness, vertigo, drowsiness, occasionally agitation, disorientation, or coma. Seizures may sometimes occur. In severe poisoning, hyperkalemia and metabolic acidosis may develop, along with prolonged prothrombin time/international normalized ratio (likely due to interaction with circulating blood coagulation factors). Acute renal failure, hepatic injury, arterial hypotension, respiratory depression, and cyanosis may also occur. In patients with bronchial asthma, asthma exacerbation is possible.

Treatment. Management should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac and vital functions until stabilization. Oral activated charcoal or gastric lavage is recommended within 1 hour after ingestion of a potentially toxic dose. If ibuprofen has already been absorbed, administration of alkalizing agents may enhance renal excretion of acidic ibuprofen. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used to treat bronchial asthma exacerbation. There is no specific antidote.

Side effects.

The adverse reactions listed below were observed during short-term use of ibuprofen doses not exceeding 1200 mg per day. When treating chronic diseases or with prolonged use, additional adverse reactions may occur.

Gastrointestinal adverse reactions are the most common and are mostly dose-dependent; in particular, the risk of gastrointestinal bleeding depends on the dose and duration of treatment. Adverse reactions are least likely when the maximum daily dose is 1200 mg.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg per day), increases the risk of arterial thrombotic complications (e.g., myocardial infarction or stroke).

All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Eye disorders: frequency not known – visual disturbances, optic neuritis may occur with prolonged treatment.

Ear and labyrinth disorders: rare – tinnitus and dizziness may occur with prolonged treatment.

Gastrointestinal disorders: uncommon – abdominal pain, nausea, dyspepsia; rare – diarrhea, flatulence, constipation, vomiting; very rare – peptic ulcer, gastrointestinal perforation or gastrointestinal bleeding, melena, hematemesis, sometimes fatal, especially in elderly patients; ulcerative stomatitis, pancreatitis, exacerbation of colitis and Crohn's disease.

Hepatobiliary disorders: very rare – liver function abnormalities (especially with prolonged treatment); frequency not known – hepatitis and jaundice may occur with prolonged treatment.

Renal and urinary disorders: very rare – acute renal failure, papillary necrosis, especially with prolonged use, associated with increased serum urea levels and edema; frequency not known – nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Nervous system disorders: uncommon – headache; very rare – aseptic meningitis².

Psychiatric disorders: rare – psychiatric disorders, depression, insomnia, excitement, hallucinations, confusion.

Cardiovascular disorders: very rare – heart failure, edema, arterial hypertension; frequency not known – Quincke's edema (angioneurotic edema).

Blood and lymphatic system disorders: very rare – blood disorders (anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs of such disorders include fever, sore throat, superficial oral ulcers, flu-like symptoms, severe exhaustion, bleeding and unexplained hematomas.

Immune system disorders: uncommon – hypersensitivity reactions manifesting as urticaria and pruritus¹; very rare – severe hypersensitivity reactions, symptoms of which may include facial, tongue and laryngeal edema, dyspnea, tachycardia, hypotension (anaphylaxis, angioneurotic edema or severe shock); frequency not known – respiratory tract reactivity, including asthma, bronchospasm or dyspnea.

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

Investigations: very rare – decreased hemoglobin levels, decreased renal clearance of urea.

General disorders: malaise and fatigue, irritability.

Description of selected adverse reactions

1 Hypersensitivity reactions may include: non-specific allergic reactions and anaphylaxis; respiratory tract reactivity, including asthma, exacerbation of asthma, bronchospasm and dyspnea; various 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 NSAIDs suggest a hypersensitivity reaction (based on temporal association with drug intake and symptom resolution after drug discontinuation). Isolated cases of aseptic meningitis symptoms (nuchal rigidity, headache, nausea, vomiting, fever, or disorientation) have been observed in patients with autoimmune diseases (systemic lupus erythematosus and mixed connective tissue disease).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and/or lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Packaging. 7 tablets in a blister; 1 or 2 blisters per carton.

Pharmaceutical category. Over-the-counter.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13 Borispilska Street, Kyiv, 02093, Ukraine.