Dolorfen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOLORFEN

Composition:

Active ingredient: ibuprofen;

1 capsule contains 400 mg of ibuprofen;

Excipients: polyethylene glycol 600, potassium hydroxide, gelatin, sorbitol solution (E 420), purified water, printing inks (black ink) (deparaffinised bleached shellac resins, isopropyl alcohol, propylene glycol, iron oxide black, sodium lauryl sulfate).

Pharmaceutical form. Soft gelatin capsules.

Main physicochemical properties: transparent soft gelatin capsules of slightly yellowish color, oval-shaped, marked with "400" in black ink on one side; the capsule contents – a clear slightly yellowish liquid.

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 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 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) was associated with reduced effect of acetylsalicylic acid (aspirin) on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these data to the clinical setting, it cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, non-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

Inside the capsule, ibuprofen is dissolved in a hydrophilic solvent. After oral administration, the gelatin capsule disintegrates under the action of gastric juice, resulting in the release of pre-dissolved ibuprofen.

Pharmacokinetics.

After oral administration, ibuprofen is rapidly absorbed, partially already in the stomach and more completely in the small intestine.

Following hepatic metabolism (hydroxylation, carboxylation, conjugation), pharmacologically inactive metabolites are excreted predominantly in urine (90%), as well as in bile. The elimination half-life in healthy volunteers, as well as in patients with hepatic or renal disease, ranges from 1.8 to 3.5 hours. Protein binding in plasma is approximately 99%. After oral administration of the conventional release dosage form, maximum plasma concentration is reached within 1–2 hours. In a pharmacokinetic study, time to maximum plasma concentration (Tmax) under fasting conditions was 90 minutes for the tablet formulation and 40 minutes for the soft capsule formulation. Ibuprofen remains detectable in plasma for more than 8 hours after drug intake.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain of various origins (headache, toothache, painful menstruation), including pain associated with colds and fever.

Contraindications.

• Hypersensitivity to ibuprofen or to any component of the drug.
• Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid, 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 related to previous NSAID therapy.
• Severe hepatic impairment, severe renal impairment, severe heart failure (NYHA class IV).
• Third trimester of pregnancy.
• Active cerebrovascular or other bleeding.
• Hemorrhagic diathesis or coagulation disorders.
• Blood dyscrasias of unknown etiology.
• Severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake).

Interaction with other medicinal products and other forms of interaction.

Ibuprofen, like other NSAIDs, should not be used in combination with:

• 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 use of ibuprofen may inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. However, limitations in extrapolating these data to clinical settings prevent definitive conclusions regarding whether regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, short-term use of ibuprofen, such clinically significant effects are considered unlikely.

• Other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors:

Concomitant use of multiple NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect. Therefore, concomitant use of ibuprofen with other NSAIDs should be avoided.

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

Anticoagulants: Ibuprofen may enhance the effects of anticoagulants such as warfarin; when anticoagulants are used, it should be noted that prolonged use of ibuprofen may increase the risk of bleeding.

Antihypertensive agents and diuretics: Ibuprofen may attenuate the effect of thiazide diuretics and other antihypertensive drugs. Diuretics may increase the risk of nephrotoxic effects of ibuprofen.

Corticosteroids: Increased risk of gastrointestinal ulcers and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): May increase the risk of gastrointestinal bleeding.

Cardiac glycosides: Ibuprofen may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Lithium: Evidence suggests a potential increase in plasma lithium levels.

MTX (Methotrexate): Concurrent use of ibuprofen with moderate or high doses of methotrexate may result in severe and potentially fatal methotrexate toxicity. Patients with impaired renal function may be at additional risk of toxicity from this combination, even when low-dose methotrexate (20 mg/week) is used.

Cyclosporine: Increased risk of nephrotoxicity.

Mifepristone: Ibuprofen should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when used concomitantly with ibuprofen.

Zidovudine: Increased risk of hematologic toxicity is known with concomitant use of zidovudine and NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Concomitant administration with ibuprofen may increase the risk of seizures. Patients receiving NSAIDs and quinolones may have an increased risk of developing seizures.

Phenytoin: Concomitant use with phenytoin may increase its serum levels. Patients on long-term ibuprofen therapy should be monitored.

Antacids: Some antacids may increase the absorption of ibuprofen in the gastrointestinal tract (GI tract). This is considered clinically relevant, particularly during prolonged use of ibuprofen.

Special precautions for use.

Adverse reactions associated with ibuprofen and NSAIDs in general can be minimized by using the lowest effective dose required to treat symptoms, for the shortest possible duration.

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

Respiratory system effects

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

Other NSAIDs

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

Systemic lupus erythematosus and mixed connective tissue disorders

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

Porphyrin metabolism

Caution should be exercised in patients with congenital disorders of porphyrin metabolism (e.g., acute intermittent porphyria).

Cardiovascular and cerebrovascular effects

Patients with a history of arterial hypertension and/or heart failure should begin treatment cautiously (medical consultation is required), as fluid retention, arterial hypertension, and edema have been reported during treatment 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 arterial hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful assessment of the clinical condition. High doses of the drug (2400 mg per day) should be avoided.

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

Renal effects

Ibuprofen should be used with caution in patients with impaired renal function, as renal function may deteriorate.

Hepatic effects

Impairment of liver function may occur.

Surgical procedures

Caution should be exercised immediately after major surgical procedures.

Effects on female fertility

Limited data suggest that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis, when used long-term (doses of 2400 mg per day and treatment duration exceeding 10 days), may impair female fertility by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal effects

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated. Cases of gastrointestinal bleeding, perforation, and ulcers, possibly 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, and ulcers increases with higher NSAID doses, in patients with a history of peptic ulcer (especially complicated by bleeding or perforation), and in elderly patients. Such patients should start treatment with the lowest possible doses. For these patients, as well as for individuals requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, consideration should be given to combined therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors).

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

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

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued immediately.

Skin effects

Rare but serious skin reactions, which may be fatal, have been reported with NSAIDs, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see section "Adverse reactions").

The risk of these reactions is highest at the beginning of therapy, with most cases occurring within the first month of treatment. Cases of acute generalized exanthematous pustulosis have also been reported after administration of ibuprofen-containing medicinal products.

Ibuprofen should be discontinued at the first signs or symptoms of skin involvement, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Allergy

Caution should be exercised in patients with allergic reactions to other substances, as such patients have an increased risk of hypersensitivity reactions when using ibuprofen.

Patients with hay fever, nasal polyps, chronic obstructive respiratory diseases, or a history of allergic conditions have an increased risk of allergic reactions, which may manifest as asthma attacks (so-called analgesic-induced asthma), angioedema (Quincke’s edema), or urticaria.

Masking symptoms of underlying infections

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

Other

Severe acute hypersensitivity reactions (e.g., anaphylactic shock) are very rare. If the first signs of hypersensitivity occur after administration of the drug, treatment must be discontinued immediately. Symptomatic and specialized therapy should be initiated in such cases.

Ibuprofen may temporarily inhibit platelet function (affect platelet aggregation). Therefore, careful monitoring is recommended in patients with coagulation disorders during treatment.

With prolonged use of the drug, regular monitoring of liver and kidney function tests, as well as blood parameters, is necessary.

Long-term use of any analgesic for headache treatment may worsen the condition. If this situation is suspected or confirmed, medical advice should be sought and treatment discontinued. Medication-overuse headache should be considered in patients with frequent or daily headaches despite (or because of) regular use of headache medications.

Chronic use of analgesics, particularly combinations of multiple analgesics, may lead to persistent impairment of kidney function with risk of renal failure (analgesic nephropathy). This risk may be increased by salt loss and dehydration.

Concomitant use of NSAIDs with alcohol may increase the risk of adverse reactions related to the active substance, particularly affecting the gastrointestinal tract or CNS.

Excipients

This medicinal product contains sorbitol. In case of diagnosed intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.

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 in early pregnancy. The absolute risk of cardiovascular malformations increases from 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

From the 20th week of pregnancy, the use of this drug may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester. Most of these adverse reactions resolved after stopping treatment.

During the first and second trimesters of pregnancy, the drug should not be prescribed unless clearly necessary. If used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Fetal monitoring for oligohydramnios and arterial duct constriction should be considered after several days of drug exposure, starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

Risks to the fetus:

• Cardio-pulmonary toxicity (characterized by premature constriction/closure of the arterial duct and pulmonary hypertension);
• Renal dysfunction (see above).

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

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

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to adversely affect the breastfed infant. However, the medicinal product Dolophen is not recommended during breastfeeding.

Fertility

Ibuprofen use may affect female fertility. This effect is reversible upon discontinuation of treatment. Therefore, ibuprofen use is not recommended in women experiencing difficulty conceiving.

Ability to influence reaction speed when driving or operating machinery

Patients who experience dizziness, drowsiness, or visual disturbances while taking ibuprofen should avoid driving or operating machinery. Single or short-term use of ibuprofen generally does not require special precautions. This is particularly relevant when the drug is used concomitantly with alcohol.

When used according to recommended dosage and treatment duration, the drug does not affect reaction speed during driving or operating machinery.

Method of Administration and Dosage

Administer orally to adults and children aged 12 years and older with body weight > 40 kg. For short-term use only.

Capsules should be taken preferably during or after meals, without chewing, and swallowed with water.

The single dose for children aged 12 years and older with body weight > 40 kg and for adults is 400 mg of ibuprofen (1 capsule). The interval between doses should be at least 6 hours. The maximum daily dose is 1200 mg (3 capsules per day).

Elderly patients do not require special dose adjustment, except in cases of severe renal or hepatic impairment.

If symptoms worsen or persist for more than 3 days, medical advice should be sought to confirm diagnosis and adjust treatment. The duration of treatment is determined individually by a physician, depending on the course of the disease and the patient's condition.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Children.

Do not use in children under 12 years of age or with body weight < 40 kg.

Overdose.

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

Symptoms. In most patients who have ingested clinically significant amounts of NSAIDs, only nausea, vomiting, epigastric pain, and very rarely diarrhea occur. Tinnitus, headache, and gastrointestinal bleeding may also develop. In more severe poisoning, toxic CNS effects may occur, manifesting as vertigo, drowsiness, occasionally agitation, disorientation, or coma. Seizures may sometimes be observed in patients. In severe poisoning, hyperkalemia and metabolic acidosis may develop; prolongation of prothrombin time/increased prothrombin index may be observed, possibly due to effects on circulating blood coagulation factors. Acute kidney injury, liver damage, arterial hypotension, respiratory failure, and cyanosis may also occur. In patients with bronchial asthma, exacerbation of the disease may occur.

Treatment. Treatment should be symptomatic and supportive, including ensuring airway patency and monitoring cardiac parameters and vital functions until stabilization. Oral administration of activated charcoal or gastric lavage 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. For frequent or prolonged seizures, intravenous diazepam or lorazepam should be administered. Bronchodilators should be used to treat exacerbations of bronchial asthma.

Side effects

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

Adverse reactions occur less frequently when the maximum daily dose does not exceed 1200 mg.

The adverse reactions associated with ibuprofen use are listed by organ systems and frequency of occurrence. The frequency of adverse reactions is defined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Laboratory investigations

Very rare: decreased hemoglobin levels and hematocrit.

Cardiac disorders

Frequency not known: heart failure, edema, arterial hypertension, angina pectoris. Clinical studies indicate that the use of ibuprofen, especially at high doses (2400 mg per day), may lead to a slight increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Blood and lymphatic system disorders

Very rare: blood disorders (anemia, hemolytic anemia, aplastic anemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis). Initial signs include fever, sore throat, oral ulcers, flu-like symptoms, severe fatigue, unexplained bleeding, and bruising.

Nervous system disorders

Uncommon: headache, dizziness, cerebral circulation disorders.

Very rare: aseptic meningitis (isolated cases reported very rarely).

Eye disorders

Very rare: visual disturbances.

Ear and labyrinth disorders

Very rare: tinnitus and vertigo.

Respiratory, thoracic and mediastinal disorders

Very rare: asthma, bronchospasm, dyspnea, and wheezing.

Gastrointestinal disorders

Adverse reactions observed are most commonly related to the gastrointestinal tract (GIT).

Uncommon: abdominal pain, bloating, nausea, and dyspepsia.

Rare: diarrhea, flatulence, constipation, and vomiting.

Very rare: peptic ulcer, perforations, or gastrointestinal hemorrhage, melena, hematemesis, sometimes fatal (especially in elderly patients), ulcerative stomatitis, gastritis, oral ulcers.

Frequency not known: exacerbation of colitis and Crohn's disease.

Renal and urinary system disorders

Very rare: acute renal failure, papillary necrosis (particularly with prolonged use), associated with elevated serum urea levels, edema, interstitial nephritis, nephrotic syndrome, hematuria, and proteinuria.

Skin and subcutaneous tissue disorders

Uncommon: various skin rashes.

Very rare: severe skin reactions such as bullous reactions, including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis.

Frequency not known: acute generalized exanthematous pustulosis; drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity reactions.

Infections and infestations

Frequency not known: meningitis, aseptic meningitis.

Vascular disorders

Very rare: arterial hypertension.

General disorders

Very rare: edema, swelling, and peripheral edema.

Immune system disorders

Uncommon: 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.

Frequency not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm. Various skin reactions, including exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

In patients with pre-existing autoimmune disorders (such as systemic lupus erythematosus, mixed connective tissue disease), isolated cases of aseptic meningitis symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation have been observed during ibuprofen treatment.

Hepatic disorders

Very rare: liver function abnormalities, hepatitis, and jaundice.

Psychiatric disorders

Very rare: restlessness.

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

Shelf life. 3 years.

Storage conditions.

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

Packaging.

10 capsules per blister; 2 blisters per cardboard box.

Dispensing category.

Over-the-counter.

Manufacturer.

Softgel HealthCare Pvt. Ltd.

Manufacturer's address and location of business activity.

Survey No. 20/1, Vandalur, Kelambakkam Road, Puduppakkam Village, Kancheepuram District, Tamil Nadu, 603103, India.