Iprafeine Ultra (Tablets) Instructions for Use

Marketing Authorization Holder

Opella Healthcare France, SAS (France)

Manufactured By

Delpharm Reims (France)

ATC Code

M01AE51 (Ibuprofen in combination with other drugs)

Active Substances

Ibuprofen (Rec.INN WHO registered)

Caffeine (Ph.Eur. European Pharmacopoeia)

Dosage Form

Iprafeine Ultra

Film-coated tablets, 400 mg+100 mg: 6, 12, 18, or 24 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oblong.

Excipients: microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.

Film coating composition Aquapolish^® P 014.52 HS white, containing low-viscosity hypromellose (hydroxypropyl methylcellulose), hyprolose (hydroxypropyl cellulose), macrogol 6000, talc, titanium dioxide.

6 pcs. – blisters (1) – cardboard packs.
6 pcs. – blisters (2) – cardboard packs.
6 pcs. – blisters (3) – cardboard packs.
6 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

NSAIDs of combined composition

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic drugs; non-steroidal anti-inflammatory and antirheumatic drugs; propionic acid derivatives

Pharmacological Action

Combined medicinal product.

Ibuprofen – NSAID, a derivative of phenylpropionic acid. It has anti-inflammatory, analgesic, and antipyretic effects. The mechanism of action is associated with inhibition of COX activity – the main enzyme of arachidonic acid metabolism, which is a precursor of prostaglandins that play a major role in the pathogenesis of inflammation, pain, and fever. The analgesic effect is due to both peripheral (indirectly, through suppression of prostaglandin synthesis) and central mechanisms (inhibition of prostaglandin synthesis in the central and peripheral nervous system). Suppresses platelet aggregation.

Caffeine – psychostimulant and analeptic agent, a methylxanthine derivative. Competitively blocks central and peripheral A1 and A2 adenosine receptors. Inhibits PDE activity in the CNS, heart, smooth muscle organs, skeletal muscles, adipose tissue, promoting the accumulation of cAMP and cGMP in them (this effect is observed only when used in high doses). Stimulates the medullary centers (respiratory and vasomotor), as well as the n.vagus center, has a direct excitatory effect on the cerebral cortex. In high doses, it facilitates interneuronal conduction in the spinal cord, enhancing spinal reflexes. Increases mental and physical performance, stimulates mental activity, motor activity, shortens reaction time, temporarily reduces fatigue and drowsiness. In small doses, the stimulating effect predominates, while in large doses, the inhibitory effect on the nervous system predominates. Increases respiratory rate and depth. Usually has a positive inotropic, chronotropic, bathmotropic, and dromotropic effect (since the effect on the cardiovascular system consists of a direct stimulating effect on the myocardium and simultaneous excitatory influence on the n.vagus centers, the resulting effect depends on the predominance of one or the other action). Blood pressure changes under the influence of vascular and cardiac mechanisms of caffeine’s influence: with normal initial blood pressure, caffeine does not change or slightly increases it; with arterial hypotension, it normalizes it. It has an antispasmodic effect on smooth muscle (including a bronchodilator effect), and a stimulating effect on striated muscle. Increases the secretory activity of the stomach. It has a moderate diuretic effect, which is due to a decrease in the reabsorption of sodium and water ions in the proximal and distal renal tubules, as well as dilation of renal vessels and increased filtration in the renal glomeruli. Reduces platelet aggregation and histamine release from mast cells. Increases basal metabolism: increases glycogenolysis, increases lipolysis.

Pharmacokinetics

Ibuprofen when taken orally is almost completely absorbed from the gastrointestinal tract. Simultaneous food intake slows down the rate of absorption. Metabolized in the liver (90%). T_1/2 is 2-3 hours. 80% of the dose is excreted in the urine mainly as metabolites (70%), 10% – unchanged; 20% is excreted through the intestines as metabolites.

Caffeine after oral administration is well absorbed. C_max in blood plasma is reached after 50-75 minutes. Binding to plasma proteins is 15%. Caffeine is rapidly distributed to all organs and tissues of the body, penetrates the blood-brain barrier and placental barrier. In adults, about 80% of the caffeine dose is metabolized to paraxanthine, about 10% to theobromine, and about 4% to theophylline. These compounds are subsequently demethylated to monomethylxanthinates and then to methylated uric acids. T_1/2 is 3.9-5.3 hours (sometimes up to 10 hours). Excretion of caffeine and its metabolites is carried out by the kidneys.

Indications

Moderate intensity pain syndrome, including toothache, algodysmenorrhea, headache, migraine.

ICD codes

Dosage Regimen

Take one tablet orally with a sufficient amount of water.

Administer up to three times per day as needed for pain relief.

Maintain an interval of at least 6 hours between doses.

Do not exceed the maximum daily dose of three tablets (1200 mg ibuprofen / 300 mg caffeine).

Use the shortest duration necessary to control symptoms.

Limit continuous use to a maximum of three days for pain or a maximum of one day for fever.

Discontinue use and consult a physician if symptoms persist or worsen.

Avoid taking this medication on an empty stomach to minimize gastrointestinal irritation.

Do not use with other products containing ibuprofen, caffeine, or other NSAIDs.

This product is not intended for preventive use or for chronic conditions without medical supervision.

Adverse Reactions

From the hematopoietic system: very rarely – hematopoiesis disorders (anemia, leukopenia, aplastic anemia, hemolytic anemia, thrombocytopenia, pancytopenia, agranulocytosis).

From the immune system infrequently – hypersensitivity reactions – nonspecific allergic reactions and anaphylactic reactions, respiratory tract reactions (bronchial asthma, including its exacerbation, bronchospasm, dyspnea, shortness of breath), skin reactions (itching, urticaria, purpura, angioedema, exfoliative and bullous dermatoses, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, erythema multiforme), allergic rhinitis, eosinophilia; very rarely – severe hypersensitivity reactions, including facial, tongue and laryngeal edema, dyspnea, tachycardia, arterial hypotension (anaphylaxis, angioedema or severe anaphylactic shock).

From the digestive system infrequently – abdominal pain, nausea, dyspepsia (including heartburn, bloating); rarely – diarrhea, flatulence, constipation, vomiting; very rarely – peptic ulcer, perforation or gastrointestinal bleeding, melena, hematemesis, in some cases fatal, especially in elderly patients, ulcerative stomatitis, gastritis; frequency unknown – exacerbation of colitis and Crohn’s disease.

From the liver and biliary tract: very rarely – liver function disorders, increased activity of liver transaminases, hepatitis and jaundice.

From the urinary system: very rarely – acute renal failure (compensated and decompensated), especially with prolonged use, in combination with an increase in plasma urea concentration and the appearance of edema, hematuria and proteinuria; nephritic syndrome, nephrotic syndrome, papillary necrosis, interstitial nephritis, cystitis.

From the nervous system infrequently – headache; very rarely – aseptic meningitis.

From the cardiovascular system: frequency unknown – heart failure, peripheral edema; with prolonged use, increased risk of thrombotic complications (e.g., myocardial infarction, stroke), increased blood pressure.

From the respiratory system: frequency unknown – bronchial asthma; bronchospasm; dyspnea.

From laboratory parameters: possible – decrease in hematocrit or hemoglobin, increased bleeding time, decrease in plasma glucose concentration, decrease in creatinine clearance, increase in plasma creatinine concentration, increase in liver transaminase activity.

Contraindications

Hypersensitivity to ibuprofen, caffeine; erosive and ulcerative lesions of the gastrointestinal tract in the acute phase or ulcer bleeding in the active phase or in history (2 or more confirmed episodes of peptic ulcer or ulcer bleeding); bleeding or perforation of gastrointestinal organs in history, provoked by the use of NSAIDs; severe heart failure (functional class IV according to NYHA classification); severe renal and/or hepatic impairment; optic nerve diseases, “aspirin triad”, hematopoiesis disorders; period after coronary artery bypass surgery; intracranial or other bleeding; hemophilia and other coagulation disorders (including hypocoagulation), hemorrhagic diatheses; III trimester of pregnancy; children and adolescents under 18 years of age.

With caution

Simultaneous use of other NSAIDs; history of a single episode of gastric and duodenal ulcer or gastrointestinal ulcer bleeding; gastritis, enteritis, colitis, presence of Helicobacter pylori infection, ulcerative colitis; bronchial asthma or allergic diseases in the acute phase or in history; systemic lupus erythematosus or mixed connective tissue disease (Sharp’s syndrome) – increased risk of aseptic meningitis; chickenpox; renal failure, including with dehydration (creatinine clearance less than 30-60 ml/min), nephrotic syndrome, hepatic failure, liver cirrhosis with portal hypertension; hyperbilirubinemia; arterial hypertension and/or heart failure; cerebrovascular diseases; blood diseases of unclear etiology (leukopenia and anemia); severe somatic diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; peripheral artery diseases; with glaucoma, increased excitability, with epilepsy and a tendency to convulsive seizures; smoking, frequent alcohol consumption; simultaneous use of drugs that may increase the risk of ulcers or bleeding, in particular, oral corticosteroids (including prednisolone), anticoagulants (including warfarin), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline) or antiplatelet agents (including acetylsalicylic acid, clopidogrel); I-II trimester of pregnancy; breastfeeding period; elderly age.

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment. Use with caution in concomitant liver diseases.

Use in Renal Impairment

Contraindicated in severe renal impairment. Use with caution in concomitant kidney diseases.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients to avoid worsening of concomitant diseases.

Special Precautions

It is recommended to use the shortest possible course and the minimum effective dose necessary to relieve symptoms.

Effect on ability to drive vehicles and mechanisms

Patients who experience dizziness, drowsiness, lethargy, or visual disturbances when taking ibuprofen should avoid driving vehicles and other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use, Ibuprofen reduces the effect of antihypertensive agents (ACE inhibitors, beta-blockers), diuretics (furosemide, hydrochlorothiazide).

With simultaneous use with anticoagulants, their effect may be enhanced.

With simultaneous use with corticosteroids, the risk of adverse effects from the gastrointestinal tract increases.

With simultaneous use, Ibuprofen may displace from plasma protein binding indirect anticoagulants (acenocoumarol), hydantoin derivatives (phenytoin), oral hypoglycemic drugs sulfonylurea derivatives.

With simultaneous use with amlodipine, a slight decrease in the antihypertensive effect of amlodipine is possible; with acetylsalicylic acid – the concentration of ibuprofen in plasma decreases; with baclofen – a case of increased toxic effect of baclofen has been described.

With simultaneous use with warfarin, an increase in bleeding time is possible, microhematuria, hematomas have also been observed; with captopril – a decrease in the antihypertensive effect of captopril is possible; with cholestyramine – a moderately pronounced decrease in the absorption of ibuprofen.

With simultaneous use with lithium carbonate, the concentration of lithium in plasma increases.

With simultaneous use with magnesium hydroxide, the initial absorption of ibuprofen increases; with methotrexate – the toxicity of methotrexate increases.

Simultaneous use of NSAIDs and cardiac glycosides may lead to worsening of heart failure, decreased glomerular filtration rate, and increased concentration of cardiac glycosides in plasma.

There is evidence of the likelihood of an increase in methotrexate plasma concentration against the background of NSAID use.

With simultaneous use of NSAIDs and cyclosporine, the risk of nephrotoxicity increases.

NSAIDs may reduce the effectiveness of mifepristone, so NSAID use should be started no earlier than 8-12 days after the end of mifepristone use.

With simultaneous use of NSAIDs and tacrolimus, an increased risk of nephrotoxicity is possible.

Simultaneous use of NSAIDs and zidovudine may lead to increased hematotoxicity. There is evidence of an increased risk of hemarthrosis and hematomas in HIV-positive patients with hemophilia receiving combined treatment with zidovudine and ibuprofen.

In patients receiving combined treatment with NSAIDs and quinolone antibiotics, the risk of seizures may increase.

In patients receiving NSAIDs and myelotoxic drugs simultaneously, hematotoxicity is enhanced.

With simultaneous use of ibuprofen and cefamandole, cefoperazone, cefotetan, valproic acid, plicamycin, the frequency of hypoprothrombinemia development increases.

With simultaneous use of ibuprofen and drugs that block tubular secretion, a decrease in excretion and an increase in plasma concentration of ibuprofen are noted.

With simultaneous use of ibuprofen and inducers of microsomal oxidation (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants), the production of hydroxylated active metabolites increases, increasing the risk of severe intoxications.

When used concomitantly, the effect of hypnotic drugs and anesthetic agents is reduced.

When used concomitantly, the effect of analgesic-antipyretics, salicylamide, and naproxen may be enhanced.

Concomitant use with estrogens ( hormonal contraceptives, hormone replacement therapy agents) may increase the intensity and duration of caffeine‘s action due to inhibition of the CYP1A2 isoenzyme by estrogens.

Concomitant use with adenosine: Caffeine reduces the increased heart rate and blood pressure changes caused by adenosine infusion; it reduces vasodilation induced by adenosine.

Concomitant use may increase the bioavailability, absorption rate, and plasma concentration of acetylsalicylic acid.

Concomitant use with mexiletine reduces the clearance of caffeine and increases its plasma concentrations, apparently due to inhibition of caffeine metabolism in the liver by mexiletine.

Methoxsalen reduces the elimination of caffeine from the body, which may lead to an enhancement of its effect and the development of toxic action.

Concomitant use of caffeine with beta-blockers may lead to mutual suppression of therapeutic effects.

Caffeine accelerates the absorption and enhances the effect of cardiac glycosides, increasing their toxicity.

Due to the induction of hepatic microsomal enzymes under the influence of phenytoin, its concomitant use leads to an acceleration of caffeine metabolism and elimination.

Fluconazole and terbinafine cause a moderate increase in caffeine plasma concentration; ketoconazole causes a less pronounced increase.

The most pronounced increase in AUC and decrease in clearance are observed with the concomitant use of caffeine with enoxacin, ciprofloxacin, and pipemidic acid; less pronounced changes are observed with pefloxacin, norfloxacin, and fleroxacin.

When used concomitantly, Caffeine accelerates the absorption of ergotamine.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Over-the-Counter

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.