Pentabufen^® (Tablets) Instructions for Use

Marketing Authorization Holder

Moscow Pharmaceutical Factory CJS (Russia)

ATC Code

N02BB72 (Metamizole sodium in combination with psycholeptics)

Dosage Form

Pentabufen®

Tablets 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Tablets from white with a yellowish tint to white with a yellow tint, round, flat-cylindrical, with a bevel and a score, with a weak specific odor.

* equivalent to 6 mg of codeine calculated as the anhydrous substance.

Excipients: crospovidone (kollidon CL) – 15 mg, ludipress (lactose monohydrate – 93%, povidone – 3.5%, crospovidone – 3.5%) – 154 mg, talc – 23 mg, calcium stearate monohydrate – 8 mg.

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

Combination analgesic-antipyretic

Pharmacotherapeutic Group

Combined analgesic agent (opioid analgesic agent + NSAID + non-narcotic analgesic agent + psychostimulant agent + barbiturate)

Pharmacological Action

A combined medicinal product that has analgesic, antipyretic, and anti-inflammatory effects.

Ibuprofen is an NSAID; it has analgesic, antipyretic, and anti-inflammatory effects due to non-selective blockade of COX-1 and COX-2 and exerts an inhibitory effect on the synthesis of prostaglandins. The analgesic effect is most pronounced in pain of an inflammatory nature.

Metamizole sodium is an NSAID, a pyrazolone derivative, its mechanism of action is practically the same as other NSAIDs (non-selectively blocks COX and reduces the formation of prostaglandin from arachidonic acid). A distinctive feature is the low severity of the anti-inflammatory effect, a weak influence on water-salt metabolism (sodium and water retention) and the gastrointestinal mucosa. It has analgesic, antipyretic, and some antispasmodic (regarding the smooth muscles of the urinary and biliary tracts) action.

Caffeine is a methylxanthine that has a psychostimulant and analeptic effect, increases mental and physical performance, stimulates mental activity, motor activity, shortens reaction time, temporarily reduces fatigue and drowsiness.

Codeine has a central antitussive effect (by suppressing the excitability of the cough center), as well as an analgesic effect due to the excitation of opiate receptors in various parts of the central nervous system and peripheral tissues, leading to the stimulation of the antinociceptive system and a change in the emotional perception of pain. In small doses, it does not cause depression of the respiratory center, does not impair the function of the ciliated epithelium, and does not reduce bronchial secretion.

Phenobarbital belongs to the group of barbiturates. It increases the sensitivity of GABA receptors to GABA, leading to the opening of chloride channels, which increases their entry into the cell and leads to hyperpolarization. It suppresses the sensory areas of the cerebral cortex, reduces motor activity, depresses cerebral functions, including the respiratory center. Reduces the tone of the smooth muscles of the gastrointestinal tract. In small doses, it has a sedative effect.

Pharmacokinetics

Ibuprofen is well absorbed after oral administration. C_max in blood plasma when taking the drug on an empty stomach is reached after 45 minutes, when taken with food – after 1-3 hours. Food intake has little effect on the bioavailability of ibuprofen. Binding to blood proteins is 90%. It slowly penetrates into the joint cavity, is retained in the synovial tissue, creating higher concentrations in it than in plasma. After absorption, about 60% of the pharmacologically inactive R-form is slowly transformed into the active S-form. It is metabolized in the liver. It is excreted by the kidneys, mainly in the form of metabolites and their conjugates (unchanged no more than 1%), to a lesser extent it is excreted with bile and eliminated through the intestines. T_1/2 is 2 hours. After oral administration, the elimination of ibuprofen ends after 24 hours. Ibuprofen penetrates the placental barrier and is excreted in breast milk in an amount of less than 1 µg/ml.

Metamizole sodium after oral administration is hydrolyzed to the pharmacologically active 4 N-methylaminoantipyrine (MAA). The bioavailability of MAA after oral administration is 90%, which is somewhat higher than with parenteral administration. Simultaneous food intake does not have a significant effect on the pharmacokinetics of metamizole sodium. Clinical efficacy is determined mainly by MAA, and to a lesser extent by the metabolites 4 N-aminoantipyrine (AA). Metamizole sodium penetrates the placental barrier. Metabolites of metamizole are excreted in breast milk. Plasma protein binding for MAA is 58%, for AA – 48%, for FAA – 18% and for AA – 14%. After a single oral dose, 85% of the dose is found in the urine as metabolites, of which 3±1% is MAA, 6±3% is AA, 26±8% is AAA and 23±4% is FAA. Renal clearance after a single oral dose of 1 g of metamizole sodium for MAA is 5±2 ml/min, for AA – 38±13 ml/min, for AAA – 61±8 ml/min and for FAA – 49±5 ml/min. The corresponding T_1/2 from plasma for MAA is 2.7±0.5 h, for AA – 3.7±1.3 h, for AAA – 9.5±1.5 h and for FAA – 11.2±1.5 h. According to a clinical study, the pharmacokinetic parameters of 4-MAA after oral administration of 1 g of metamizole sodium have the following values (mean values and standard deviation are given): C_max is 17.3±7.54 mg/l; T_max – 1.42±0.54 h; AUC – 80.9±34.1 mg x h/l. The absolute bioavailability of 4-MAA by AUC when taking tablets is 93%.

Caffeine. When taken orally, absorption is good and occurs throughout the intestine. Absorption occurs mainly due to lipophilicity, not water solubility. Time to reach C_max is 50-75 min. after oral administration, C_max 1.6-1.8 mg/l. It is rapidly distributed in all organs and tissues of the body; easily penetrates the blood-brain barrier and placental barrier. V_d in adults is 0.4-0.6 l/kg, in newborns – 0.78-0.92 l/kg. Binding to blood proteins (albumin) is 25-36%. More than 90% is metabolized in the liver, in children of the first years of life up to 10-15%. 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 monomethylxanthines and then to methylated uric acids. T_1/2 in adults is 3.9-5.3 hours. The excretion of caffeine and its metabolites is carried out by the kidneys (in adults, 1-2% is excreted unchanged).

Codeine is rapidly absorbed after oral administration. Plasma protein binding is 30%. Time to reach C_max is 2-4 hours. It is metabolized in the liver to active metabolites; the isoenzyme CYP2D6 is involved in the metabolism. 10% is converted to morphine by demethylation. It is excreted by the kidneys (5-15% as codeine and 10% as morphine and its metabolites) and with bile. T_1/2 is 2.5-4 hours.

Phenobarbital when taken orally is completely but relatively slowly absorbed. C_max in plasma is observed 1-2 hours after administration. About 50% is bound to plasma proteins. It is evenly distributed in various organs and tissues; lower concentrations are found in brain tissues. It penetrates well into breast milk and through the placental barrier. It is metabolized in the liver, induces liver microsomal enzymes: CYP3A4, CYP3A5, CYP3A7 (the rate of enzymatic reactions increases by 10-12 times), increases the detoxification function of the liver. It accumulates in the body. T_1/2 is 2-4 days. It is excreted by the kidneys in the form of a glucuronide, 25% is excreted unchanged.

Indications

Pain syndrome (mild to moderate intensity) of various origins: arthralgia; myalgia; radiculitis; neuralgia; headache; toothache; migraine; menstrual pain.

ICD codes

Dosage Regimen

Administer orally to adults and children over 12 years of age.

Take a single dose of one tablet.

Do not exceed three doses per day.

Maintain an interval of several hours between doses.

The maximum daily dose is four tablets.

Use for the shortest duration necessary to control symptoms.

Avoid use for more than five consecutive days without medical supervision.

Do not exceed the recommended dose or frequency of administration.

Discontinue use and consult a physician if pain persists or worsens.

Adverse Reactions

From the digestive system nausea, vomiting, heartburn, anorexia, epigastric discomfort, diarrhea, flatulence, impaired liver function.

From the nervous system: headache, dizziness, hearing loss, tinnitus, insomnia, agitation, drowsiness, depression.

From the cardiovascular system heart failure, tachycardia.

From the urinary system edematous syndrome, impaired renal function.

From the hematopoietic system anemia, thrombocytopenia, agranulocytosis, leukopenia.

Allergic reactions skin rash, itching, urticaria, angioedema.

Other bronchospasm, respiratory depression, sweating.

Contraindications

Hypersensitivity; hepatic and/or renal failure; peptic ulcer of the stomach and duodenum in the acute stage; chronic constipation; bronchial asthma; urticaria; rhinitis against the background of the use of acetylsalicylic acid and other NSAIDs; diseases of the optic nerve; color vision impairment; amblyopia; scotoma; inhibition of hematopoiesis (agranulocytosis, cytostatic or infectious neutropenia); respiratory depression; intracranial hypertension; traumatic brain injury; hearing loss; pathology of the vestibular apparatus; arterial hypertension; pregnancy; lactation period; children’s age (up to 12 years).

With caution

Peptic ulcer of the stomach and duodenum in remission, gastritis, enteritis, colitis, concomitant liver and/or kidney diseases, chronic heart failure, blood diseases of unknown etiology, bronchial asthma, urticaria, rhinitis, polyps of the nasal mucosa, hyperbilirubinemia, hypothyroidism, old age.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated in hepatic insufficiency.

Use in Renal Impairment

The drug is contraindicated in renal insufficiency.

Pediatric Use

Contraindicated for use in children under 12 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

With long-term (more than 5 days) use, monitoring of the peripheral blood picture and the functional state of the liver is necessary. Prescribing the drug for acute abdominal pain syndrome may complicate the diagnosis. During productive cough, it can suppress the cough reflex, which can lead to the accumulation of sputum in the bronchial lumen and, as a result, to a deterioration in the patient’s condition.

Avoid prolonged use, as the codeine and Phenobarbital it contains can cause the development and formation of drug dependence.

The Metamizole sodium contained in the combination may color the urine red, but this has no clinical significance.
May change the results of doping control tests in athletes.

Influence on the ability to drive vehicles and mechanisms

It is necessary to refrain from performing potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Ibuprofen

Acetylsalicylic acid and other NSAIDs increase the risk of ulcerative lesions of the gastrointestinal tract. Ibuprofen may inhibit the anti-inflammatory and antiplatelet effects of acetylsalicylic acid in small doses when taken simultaneously.

Corticosteroids and mineralocorticosteroids: increased risk of ulcerative lesions of the gastrointestinal tract.

Antihypertensive drugs and diuretics NSAIDs may reduce the effects of diuretics and antihypertensive drugs. In some patients with impaired renal function (for example, in dehydrated patients, or in elderly patients with impaired renal function), the simultaneous use of ACE inhibitors, β-blockers and angiotensin II receptor antagonists with drugs that inhibit COX may lead to further deterioration of renal function, including the possibility of developing acute renal failure, which is usually reversible. Therefore, such a combination should be used with caution, especially in elderly patients. Potassium-sparing diuretics simultaneous use may lead to hyperkalemia (it is recommended to monitor the potassium content in the blood).

Indirect anticoagulants, antiplatelet agents, fibrinolytics NSAIDs may enhance the effects of indirect anticoagulants such as warfarin. Thrombolytics (alteplase, streptokinase, urokinase) the risk of bleeding increases. Selective serotonin reuptake inhibitors increased risk of gastrointestinal bleeding.

Lithium preparations, digoxin, phenytoin combination therapy may increase the serum concentrations of these drugs. Methotrexate the use of ibuprofen at a dose of 200 mg within 24 hours before or after the use of methotrexate may lead to an increase in the plasma concentration of methotrexate and an increase in its toxic effect. Baclofen NSAIDs may increase plasma concentrations of baclofen. Zidovudine the risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving zidovudine and Ibuprofen simultaneously increases. Quinolones may increase the risk of seizures associated with the use of quinolones. Cyclosporine, tacrolimus, gold preparations: an increased risk of nephrotoxicity due to a decrease in the synthesis of prostaglandins in the kidneys is possible. During combination therapy, renal function should be carefully monitored, especially in elderly patients. Ibuprofen increases the plasma concentration of cyclosporine and the likelihood of developing its hepatotoxic effects. Mifepristone: NSAIDs may reduce the effectiveness of mifepristone, NSAIDs should be started no earlier than 8-12 days after discontinuation of mifepristone. Drugs that block tubular secretion may increase the plasma concentration of ibuprofen. Oral hypoglycemic drugs, sulfonylurea derivatives as a precaution, it is recommended to monitor blood glucose concentration when used together. Sulfinpyrazone, probenecid when used together with ibuprofen, a slowdown in the excretion of ibuprofen is possible. Aminoglycosides Ibuprofen may reduce the clearance of aminoglycosides, which may increase the nephrotoxicity and hepatotoxicity of these drugs. Cefamandole, cefoperazone, cefotetan, valproic acid, plicamycin: may increase the incidence of hypoprothrombinemia when co-administered with ibuprofen. Inducers of microsomal oxidation (phenytoin, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) when used together, they increase the production of hydroxylated active metabolites, increasing the risk of severe intoxication. Uricosuric drugs Ibuprofen reduces the effectiveness of uricosuric drugs. Estrogens, ethanol with simultaneous use of ibuprofen, it is possible to enhance the side effects of estrogens, ethanol. Antacids and cholestyramine drugs reduce the absorption of ibuprofen. Caffeine enhances the analgesic effect of ibuprofen.

Metamizole sodium

Enhances the effects of ethanol. It is not recommended to use simultaneously X-ray contrast agents, colloidal blood substitutes and penicillin. With simultaneous use of cyclosporine, the concentration of the latter in the blood decreases, therefore, when used simultaneously, the concentration of cyclosporine should be monitored. Metamizole sodium increases the activity of oral hypoglycemic drugs, indirect anticoagulants, glucocorticoids and indomethacin. Phenylbutazone, barbiturates and other inducers of liver microsomal enzymes, when used simultaneously, reduce the effectiveness of metamizole sodium. Simultaneous use with other non-narcotic analgesics, tricyclic antidepressants, contraceptive hormonal drugs and allopurinol may lead to an increase in their toxicity. Sedative and anxiolytic drugs (tranquilizers) enhance the analgesic effect of metamizole sodium. Thiamazole and cytostatics increase the risk of leukopenia. The effect is enhanced by codeine, histamine H₂-receptor blockers and propranolol (slows down inactivation). Simultaneous use of metamizole sodium and methotrexate may enhance the hematotoxicity of the latter, especially in elderly patients. With simultaneous use of metamizole sodium and chlorpromazine, severe hypothermia may develop.

Caffeine

Concomitant use with cimetidine, oral contraceptives, disulfiram, ciprofloxacin, norfloxacin leads to a decrease in the hepatic metabolism of caffeine, a slowdown in its elimination, and an increase in blood concentration.

When used with caffeine-containing beverages and other drugs that stimulate the CNS, excessive stimulation of the central nervous system is possible.

Caffeine reduces the absorption of calcium preparations in the gastrointestinal tract.

It reduces the effectiveness of narcotic and hypnotic drugs, increases the excretion of lithium preparations in the urine; accelerates the absorption and enhances the effect of cardiac glycosides, increasing their toxicity.

Concomitant use of caffeine with β-blockers may lead to mutual suppression of therapeutic effects; with β-agonists – to additional stimulation of the central nervous system and other additive toxic effects.

Caffeine may reduce the clearance of theophylline and possibly other xanthines, increasing the possibility of additive pharmacodynamic and toxic effects.

Codeine

With the simultaneous use of drugs that depress the CNS (hypnotics, antipsychotics, etc.), an enhancement of the sedative effect and a depressant effect on the respiratory center are possible.

Codeine enhances the effect of ethanol on psychomotor function.

When codeine is used in large doses, the effect of cardiac glycosides may be enhanced due to reduced absorption resulting from weakened peristalsis.

Adsorbents, astringents, and coating agents may reduce the absorption of codeine from the gastrointestinal tract.

Phenobarbital

It reduces the antibacterial activity of antibiotics and sulfonamides, and the antifungal activity of griseofulvin (reduces absorption).

It reduces the effectiveness of indirect anticoagulants, glucocorticoids, doxycycline, estrogens, and other drugs metabolized by hepatic microsomal enzymes.

The hypnotic effect is reduced with the simultaneous use of atropine, belladonna extract, dextrose, thiamine, nicotinic acid, analgesics, and psychostimulants.

When combined with reserpine, the anticonvulsant effect is reduced; under the influence of amitriptyline, nialamide, diazepam, chlordiazepoxide – it is enhanced.

Acetazolamide, by alkalinizing the urine, reduces the renal reabsorption of phenobarbital and weakens its effect.

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

Rx Only

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.