Analgin-dibazol-papaverine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANALGIN-DIBAZOL-PAPAVERINE

Composition:

Active substances: metamizole sodium monohydrate, bendazole hydrochloride, papaverine hydrochloride;

One tablet contains: metamizole sodium monohydrate 250 mg, bendazole hydrochloride 20 mg, papaverine hydrochloride 20 mg;

Excipients: potato starch, talc, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or white with a yellowish tint color, flat cylindrical shape with a bevel; on one side of the tablet the company trademark is applied, on the other side – a score line.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Pyrazolones. Metamizole sodium, combinations without psychotropic agents.

ATC code N02BB52.

Pharmacological properties.

Pharmacodynamics.

A combined medicinal product with analgesic, spasmolytic, and vasodilatory effects determined by the specific action of its components. The medicinal product also exerts antihypertensive and antipyretic effects.

Metamizole sodium is a non-narcotic analgesic and antipyretic, a pyrazolone derivative, which produces a pronounced analgesic and antipyretic effect and a slight anti-inflammatory effect. The mechanism of action is due to inhibition of cyclooxygenase (COX) and blockade of prostaglandin synthesis from arachidonic acid, as well as interference with transmission of extra- and proprioceptive pain impulses along the fasciculi gracilis and cuneatus, increased excitability threshold of thalamic pain sensitivity centers, and enhanced heat dissipation. It exerts a pronounced spasmolytic effect on the smooth musculature of the urinary and biliary tracts.

Bendazole produces spasmolytic, vasodilatory, and hypotensive effects. It also stimulates spinal cord functions, promotes recovery of peripheral nerve function, and exerts moderate immunostimulatory activity.

Papaverine produces myotropic, spasmolytic, and hypotensive effects. It inhibits phosphodiesterase, leading to accumulation of cyclic adenosine monophosphate (cAMP) and reduction of intracellular calcium levels, resulting in relaxation of smooth muscles of blood vessels and internal organs (gastrointestinal tract, respiratory tract, urogenital system).

Pharmacokinetics.

After oral administration, it is rapidly and completely absorbed. It is hydrolyzed in the intestinal wall to form the active metabolite. The effect develops within 20–40 minutes and reaches its maximum within 2 hours. It is metabolized in the liver. Excreted by the kidneys.

Clinical characteristics.

Indications.

Pain syndrome associated with spasm of blood vessels or smooth muscles of internal organs.

Contraindications.

Known or suspected hypersensitivity to any component of the medicinal product, to pyrazolone derivatives (phenylbutazone, triazolone, antipyrine); suspected acute surgical pathology; conditions characterized by decreased muscle tone, seizure disorders; glaucoma, head trauma, severe heart failure, atrioventricular block, arterial hypotension, coma, diabetes mellitus, hypothyroidism, adrenal insufficiency, benign prostatic hyperplasia, glucose-6-phosphate dehydrogenase deficiency, leukopenia, agranulocytosis, cytotoxic or infectious neutropenia, anemia of any etiology, thrombocytopenia, hepatic porphyria, severe impairment of liver and/or kidney function, chronic nephritis with edema and impaired renal nitrogen excretion, respiratory depression, bronchial asthma, bronchoobstructive syndrome, gastric or duodenal ulcer with bleeding; hypotonic colitis, habitual constipation; concomitant use of monoamine oxidase inhibitors (MAOIs). Pregnancy or lactation period. Pediatric age. Age over 75 years (risk of hyperthermia).

Interaction with other medicinal products and other types of interactions.

The efficacy of the medicinal product is reduced by tobacco smoking.

Adsorbents, astringents, and coating agents: reduced absorption of the medicinal product from the gastrointestinal tract.

Spasmolytic and sedative medicinal products: enhanced hypotensive effect.

Caution is required when using this medicinal product concomitantly with salicylates.

Interactions related to sodium metamizole

Contrast media, colloidal plasma substitutes, penicillin: should not be used during treatment with sodium metamizole.

Oral hypoglycemic agents, indirect anticoagulants, glucocorticosteroids, phenytoin, indomethacin, ibuprofen: sodium metamizole enhances the effects of these drugs by displacing them from plasma protein binding.

Sodium metamizole may induce metabolic pathway enzymes, including CYP2B6 and CYP3A4. Concomitant use of sodium metamizole with bupropion, efavirenz, methadone, valproate, cyclosporine, tacrolimus, and sertraline may lead to decreased plasma concentrations of these drugs, potentially resulting in reduced therapeutic efficacy. Therefore, caution is recommended when co-administering sodium metamizole with other medicinal products; clinical response and/or drug levels should be monitored as necessary.

Methotrexate: high doses of sodium metamizole may increase methotrexate plasma concentration and enhance its toxic effects (primarily on the gastrointestinal tract and hematopoietic system).

Nonsteroidal anti-inflammatory drugs (NSAIDs): their analgesic and antipyretic effects are potentiated, and the risk of additive adverse effects increases.

Alcohol: sodium metamizole enhances the sedative effect of alcohol.

Diuretics (furosemide): possible reduction in diuretic effect.

Myelotoxic drugs: lead to enhanced hematotoxicity.

Sarcolysin, thiimazole (methimazole), drugs that suppress bone marrow activity, including gold compounds: increased risk of hematotoxicity, including development of leukopenia.

Non-narcotic analgesics, tricyclic antidepressants (amitriptyline, doxepin, etc.), hormonal contraceptives, allopurinol: concomitant use with sodium metamizole may increase the toxicity of sodium metamizole.

Chlorpromazine or other phenothiazine derivatives: risk of pronounced hypothermia.

Phenylbutazone, glutethimide, barbiturates, and other hepatic microsomal enzyme inducers: reduce the efficacy of sodium metamizole.

Sedatives, tranquilizers (diazepam, trimethoazine, etc.): enhance the analgesic effect of sodium metamizole.

Codeine, H2-histamine receptor blockers, propranolol: enhance the effects of sodium metamizole.

Interactions related to bendazole

Papaverine, theobromine, salsoline: when used with bendazole, the spectrum of pharmacological action of these drugs is broadened.

Barbiturates: when used with bendazole, the efficacy of long-acting barbiturates, particularly phenobarbital, is enhanced.

Antihypertensive drugs (agents affecting the renin-angiotensin system), phentolamine, diuretics (including saluretics): when used in combination with bendazole, the hypotensive effect is enhanced.

β-blockers: when used with bendazole, the hypotensive effect of the latter remains unchanged; however, with prolonged use, bendazole prevents the increase in total peripheral resistance caused by β-blockers.

Interactions related to papaverine

Anticholinergic agents: papaverine enhances the cholinolytic effects of anticholinergic drugs.

Anticholinesterase agents: possible reduction in the tonic effect of anticholinesterase drugs on smooth muscle due to papaverine.

Cardiac glycosides: when used concomitantly with cardiac glycosides, a pronounced enhancement of myocardial contractile function is observed due to decreased total peripheral vascular resistance.

Levodopa, methyldopa: papaverine reduces the hypotensive effect of methyldopa and the anti-parkinsonian effect of levodopa.

Alcohol: papaverine potentiates the effects of alcohol.

Nitrofurantoin: there are reports of hepatitis development with concomitant use of nitrofurantoin and papaverine.

Morphine: possible reduction in the spasmolytic activity of papaverine.

Barbiturates, diphenhydramine, sodium metamizole, diclofenac: enhanced spasmolytic effect of papaverine.

Phentolamine: potentiates the effect of papaverine on the corpora cavernosa of the penis.

Antihypertensive drugs, antidepressants (including tricyclics), procainamide, reserpine, quinidine: enhanced hypotensive effect.

Special precautions for use.

Consult a physician before starting treatment with this medicinal product, especially if taking other medications.

Do not use this medicinal product to relieve acute abdominal pain before determining the cause. Since sodium metamizole has analgesic and anti-inflammatory properties, it may mask signs of infection, symptoms of non-infectious diseases, and complications associated with pain syndrome, which could complicate their diagnosis.

During treatment with this medicinal product, alcohol consumption and use of medicinal products that depress the central nervous system (CNS) should be avoided.

This medicinal product should be used with caution in patients:

• with existing allergic conditions (including pollinosis) or such conditions in medical history — increased risk of allergic reactions;
• with inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease (see section "Contraindications");
• with cardiovascular insufficiency (see section "Contraindications");
• with supraventricular tachycardia (see section "Contraindications");
• with predisposition to arterial hypotension;
• with impaired renal function, chronic renal failure (see section "Contraindications"), or history of kidney diseases (pyelonephritis, glomerulonephritis);
• with impaired liver function (see section "Contraindications");
• when used concomitantly with cytostatic medicinal products (only under physician supervision).

Use with caution in patients with a history of chronic alcohol abuse, debilitated patients, and elderly individuals — due to the risk of hyperthermia and increased frequency of adverse reactions, especially those affecting the gastrointestinal tract. Use cautiously in cases of reduced intestinal peristalsis and following head injuries.

Risk of drug-induced liver injury

Cases of acute hepatitis, predominantly hepatocellular in nature, have been reported in patients taking sodium metamizole, with symptoms appearing from several days to several months after initiation of treatment. Manifestations included elevated serum liver enzymes, with or without jaundice, often in the context of hypersensitivity reactions to other drugs (e.g., skin rash, blood dyscrasias, fever, and eosinophilia) or accompanied by features of autoimmune hepatitis. Most patients recovered after discontinuation of sodium metamizole; however, in isolated cases, progression to liver failure requiring liver transplantation has been reported.

The mechanism of sodium metamizole-induced liver injury is not clearly established, but available data suggest an immune-allergic mechanism.

Patients should be instructed to promptly inform their physician if symptoms indicating liver injury occur. If liver injury is suspected, sodium metamizole should be discontinued immediately, and liver function tests should be performed.

Cases of liver injury during treatment with sodium metamizole are very rare, but the exact frequency of this adverse reaction cannot be determined. Recurrent liver injury has been observed in some patients upon re-exposure to sodium metamizole. If a previous episode of liver injury occurred during treatment with sodium metamizole and other causes of liver injury have not been identified, medicinal products containing sodium metamizole should not be re-administered.

Immediately discontinue the medicinal product and urgently consult a physician if symptoms such as asthenia, unexplained chills, fever, sore throat, difficulty swallowing, gum bleeding, pallor of the skin, skin or mucosal rashes, vaginitis, or proctitis occur. Discontinue the medicinal product if symptoms of liver dysfunction appear, including gastrointestinal disturbances, jaundice, or elevated liver enzymes. Inform the physician if any of the following symptoms occur: hot flashes, excessive sweating, headache, increased fatigue, jaundice, nausea, stomach discomfort, or constipation.

Severe skin adverse reactions

Severe skin adverse reactions have been reported during treatment with sodium metamizole, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal (see section "Adverse reactions"). Before initiating therapy with Analgin-Dibazol-Papaverine, patients should be informed about the signs and symptoms of severe skin reactions. Close monitoring for such symptoms is required during treatment. If symptoms suggestive of severe skin adverse reactions occur, the medicinal product should be immediately discontinued, and medicinal products containing sodium metamizole must not be used again (see section "Contraindications").

During treatment with this medicinal product, red discoloration of urine may occur due to excretion of a metabolite of sodium metamizole; this is not clinically significant.

Orthostatic hypotension may occur during treatment with this medicinal product.

During treatment, peripheral blood composition (leukocyte formula) should be monitored.

Do not exceed the recommended doses of the medicinal product.

Do not use the medicinal product for longer than the recommended duration without consulting a physician.

Regular long-term use of this medicinal product is not recommended due to the myelotoxic potential of sodium metamizole. If prolonged use (more than 7 days) is necessary, monitoring of peripheral blood composition (due to myelotoxicity of metamizole), renal and liver function is required.

Smoking reduces the effectiveness of the medicinal product.

If signs of illness do not begin to improve, or if the patient's condition worsens, or if adverse effects occur, discontinue use of the medicinal product and consult a physician for further management.

Use during pregnancy or breastfeeding.

Use of this medicinal product during pregnancy or breastfeeding is contraindicated.

If use of the medicinal product is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when operating vehicles or machinery.

During treatment with this medicinal product, driving vehicles and operating complex machinery should be avoided.

Method of Administration and Dosage

Take orally after meals, swallowing with a small amount of water.

Adults

1–2 tablets 1–2 times daily. Maximum daily dose – 4 tablets.

The duration of treatment depends on the nature and course of the disease, the therapeutic effect achieved, and the characteristics of concomitant pharmacotherapy, but treatment duration should not exceed 3 days.

Children

Do not use (see section "Contraindications").

Overdose

In case of first symptoms of overdose, seek immediate medical attention.

Overdose may result in restlessness, lethargy, central nervous system (CNS) depression, coma, moderate dyspnea, skin rash, decreased tissue perfusion, cyanosis, metabolic acidosis, hyperglycemia, hyperkalemia.

Prolonged use of the drug in high doses may lead to impaired liver function and development of neutropenia.

Symptoms of sodium metamizole overdose: hypothermia, palpitations, marked decrease in arterial blood pressure, tachycardia, dysphagia, dyspnea, tinnitus, nausea, vomiting, gastralgia/gastritis, weakness, drowsiness, delirium, impaired consciousness, convulsive syndrome; acute agranulocytosis, hemorrhagic syndrome, oliguria, anuria, acute renal and hepatic failure, and paralysis of respiratory muscles may develop.

Treatment: discontinue the drug, induce vomiting, gastric lavage, administration of enterosorbents, saline laxatives, forced diuresis, and symptomatic therapy aimed at supporting vital functions. In severe cases, hemodialysis, hemoperfusion, or peritoneal dialysis may be performed. In case of convulsive syndrome, intravenous diazepam and fast-acting barbiturates should be administered.

Symptoms of bendazole overdose: hypotension, increased sweating, sensation of warmth, dizziness, nausea, mild headache, which rapidly resolve upon dose reduction or discontinuation of the drug.

Treatment: induce vomiting, perform gastric lavage with activated charcoal, administer saline laxatives. In case of arterial hypotension, transfusion therapy and symptomatic treatment (vasoconstrictors, cardiac glycosides) are recommended. No specific antidote is available.

Symptoms of papaverine overdose: visual disturbances, diplopia, nystagmus, tachycardia, asystole, ventricular flutter, collapse, arterial hypotension, redness of the skin of the upper body, hyperventilation, ataxia, drowsiness, headache, dry mouth, nausea, constipation, gastrointestinal functional disorders, increased sweating, weakness, allergic reactions. After ingestion of very high doses of papaverine, moderate sedative effects and toxic effects in the form of arrhythmias, complete or partial atrioventricular block may occur.

Treatment: discontinue the drug, symptomatic therapy, gastric lavage, administration of enterosorbents. No specific antidote is available. Papaverine is completely removed from the blood during hemodialysis.

Adverse Reactions

Nervous system disorders: drowsiness, dizziness, headache.

Eye disorders: visual disturbances, diplopia, conjunctivitis.

Respiratory, thoracic and mediastinal disorders: dry cough, rhinitis, dyspnea, apnea; in patients predisposed to bronchospasm, bronchospasm attacks may be provoked, bronchospastic syndrome, shortness of breath.

Cardiac disorders: facial flushing, atrioventricular block, arrhythmias, tachycardia, ventricular extrasystoles, reduced cardiac output, arterial hypotension, collapse, chest pain, palpitations, hot flushes, sensation of heat, numbness, tremor, loss of consciousness; with prolonged use – worsening of electrocardiogram (ECG) parameters due to reduced cardiac output, ventricular fibrillation, asystole, ventricular flutter, orthostatic hypotension.

Blood and lymphatic system disorders: eosinophilia; with prolonged use – leukopenia, granulocytopenia, agranulocytosis, anemia, thrombocytopenia.

Gastrointestinal disorders: anorexia, dry mouth, sore throat, nausea, epigastric discomfort, constipation, diarrhea.

Hepatobiliary disorders: increased liver transaminase activity, impaired liver function, hepatitis, jaundice; drug-induced liver injury, including acute hepatitis (see section "Special precautions").

Renal and urinary disorders: usually in patients with impaired renal function and/or when excessive doses are used – transient oliguria, anuria, proteinuria, interstitial nephritis, red discoloration of urine.

Skin and subcutaneous tissue disorders: possible hypersensitivity reactions, including skin and mucosal rashes (e.g. urticaria), pruritus, skin hyperemia, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Immune system disorders: angioedema, anaphylactic shock.

General disorders: hyperthermia, weakness, malaise, increased sweating.

If any adverse reactions occur, discontinue use of the medicinal product immediately and consult a physician without delay.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

10 tablets in a blister; 1 blister per carton.

10 tablets in a blister.

Prescription status

Over-the-counter.

Manufacturer

Limited liability company "INTERCHEM".

Manufacturer's address and location of business activity

40-A, 21st km of Starokyivska Road, Odesa, 65025, Ukraine.