Andifen ic

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANDIFEN IS

Composition:

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

Each tablet contains 250 mg of metamizole sodium monohydrate, 20 mg of phenobarbital, 20 mg of papaverine hydrochloride, and 20 mg of bendazole hydrochloride;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with a yellowish tint, cylindrical in shape with beveled edges and a bevel; the company trademark is imprinted on one side of the tablet, a score line on the other.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Pyrazolones. Metamizole sodium, combinations with psychotropic agents.

ATC code N02BB72.

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 – a non-narcotic analgesic and antipyretic, a derivative of pyrazolone, produces a pronounced analgesic and antipyretic effect, as well as 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 pain-related exteroceptive and proprioceptive impulses in the posterior spinal cord tracts (Goll and Burdach fasciculi), increased excitation threshold of thalamic pain centers, and enhanced heat dissipation. It exerts a pronounced spasmolytic effect on the smooth musculature of the urinary and biliary ducts.

Phenobarbital – a derivative of barbituric acid, exerts sedative and moderate spasmolytic effects. It increases the concentration of endogenous inhibitory neurotransmitter GABA in the central nervous system (CNS), reducing excitatory effects of amino acids (glutamate, aspartate) on the CNS.

Papaverine induces 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, genitourinary system).

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

Pharmacokinetics

Rapidly and completely absorbed after oral administration. It is hydrolyzed in the intestinal wall, forming an active metabolite. The effect begins within 20–40 minutes and reaches its maximum within 2 hours. Metabolized in the liver. Excreted by the kidneys.

Clinical characteristics.

Indications.

Pain syndrome associated with vascular or smooth muscle spasm of internal organs; arterial hypertension.

Contraindications.

Known or suspected hypersensitivity to any component of the medicinal product, to pyrazolone derivatives (phenylbutazone, tribenozide, antipyrine); suspicion of acute surgical pathology; conditions characterized by decreased muscle tone, seizure disorders; myasthenia gravis, glaucoma, head trauma, severe heart failure, acute myocardial infarction, atrioventricular block, arterial hypotension, comatose state, diabetes mellitus, hypothyroidism, adrenal insufficiency, benign prostatic hyperplasia, glucose-6-phosphate dehydrogenase deficiency, leukopenia, agranulocytosis, cytotoxic or infectious neutropenia, anemia of any etiology, thrombocytopenia, porphyria, severe impairment of liver and/or kidney function, severe liver disease, kidney damage with impaired function, respiratory diseases with dyspnea, obstructive syndrome; bronchial asthma, respiratory depression, gastric or duodenal ulcer with bleeding; hypotonic colitis, habitual constipation, depressive disorders with patient's tendency to suicidal behavior, alcoholism, drug or narcotic dependence (including in medical history); concomitant use of monoamine oxidase inhibitors (MAOIs). Pregnancy or breastfeeding. Age under 12 years. Age over 75 years (risk of hyperthermia).

Interaction with other medicinal products and other forms of interaction.

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 the medicinal product concomitantly with salicylates.

Interactions related to sodium metamizole

Contrast agents, 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 medicinal products by displacing them from protein binding sites in blood.

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 medicinal products, 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.

MTX (methotrexate): high-dose sodium metamizole may increase plasma methotrexate 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 of diuretic effect.

Myelotoxic medicinal products lead to enhanced hematotoxicity.

Sarcolysin, thiamazole, and medicinal products that suppress bone marrow activity, including gold preparations: increased risk of hematotoxicity, including development of leukopenia.

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

Chlorpromazine or other phenothiazine derivatives: risk of pronounced hypothermia.

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

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

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

Interactions related to phenobarbital

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain medicinal products metabolized by these enzymes, including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin, sulfonamides), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics (anticonvulsants), psychotropic agents (tricyclic antidepressants), hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticosteroids, cyclosporine, cytostatics), antiarrhythmics, antihypertensives (β-blockers, calcium channel blockers), oral hypoglycemic agents, etc.

Phenytoin, carbamazepine, clonazepam: possible influence of phenobarbital on blood concentrations of these medicinal products.

Oral contraceptives: phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of contraceptive effect.

Methotrexate: phenobarbital increases methotrexate toxicity.

Gold preparations: when used with phenobarbital, the risk of kidney damage increases.

Analgesics, anesthetics, neuroleptics, tranquilizers: phenobarbital enhances the effects of these medicinal products.

Other medicinal products that depress the CNS: possible mutual enhancement of action (sedative-hypnotic effect), which may be accompanied by respiratory depression.

NSAIDs: prolonged concomitant use of phenobarbital with NSAIDs carries a risk of gastric ulceration and bleeding.

Zidovudine: concomitant use of phenobarbital with zidovudine enhances the toxicity of both medicinal products.

Alcohol: enhanced effect and toxic effects of phenobarbital.

Monoamine oxidase inhibitors (MAOIs): prolonged effect of phenobarbital.

Rifampicin: reduced effect of phenobarbital.

Medicinal products with acidic properties (ascorbic acid, ammonium chloride) and medicinal products containing valproic acid: enhanced barbiturate effects. Patients receiving concomitant treatment with valproates and phenobarbital should be monitored for signs of hyperammonemia. In half of reported cases, hyperammonemia was asymptomatic and did not necessarily lead to encephalopathy.

Interactions related to papaverine

Anticholinergic agents: papaverine enhances the anticholinergic (cholinolytic) effects of anticholinergic agents.

Anticholinesterase agents: possible reduction of the tonic effect of anticholinesterase drugs on smooth muscle under the influence of papaverine.

Cardiac glycosides: when used concomitantly with cardiac glycosides, a pronounced enhancement of myocardial contractile function occurs 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 with papaverine.

Morphine: possible reduction of papaverine's spasmolytic activity.

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

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

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

Interactions related to bendazole

Papaverine, theobromine, salsolin: when used with bendazole, the pharmacological activity spectrum of these medicinal products is expanded.

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

Antihypertensive medicinal products (those 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.

Special precautions for use.

Consult a physician before starting treatment with the medicinal product, especially if taking other medicinal products.

Do not use the medicinal product to relieve acute abdominal pain before determining its 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 may complicate their diagnosis.

Due to the presence of phenobarbital, the medicinal product is strictly contraindicated in depressive disorders with a tendency towards suicidal behavior.

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

The medicinal product should be used with caution in patients:

• with existing allergic diseases (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 kidney diseases in medical history (pyelonephritis, glomerulonephritis);
• with impaired hepatic function (see section "Contraindications");
• with hyperkinesia;
• with hyperthyroidism;
• when used concomitantly with cytostatic medicinal products (only under physician supervision).

The medicinal product should be used cautiously in patients with a history of chronic alcohol abuse, chronic pain, debilitated patients, elderly individuals – due to the risk of hyperthermia and increased frequency of adverse reactions, particularly gastrointestinal; in acute intoxication with medicinal products, decreased intestinal peristalsis, and following head injuries.

Risk of drug-induced liver injury

Cases of acute hepatitis, predominantly hepatocellular type, have been reported in patients receiving 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 medicinal products (e.g., skin rashes, 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 liver injury induced by sodium metamizole is not fully understood, 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 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. In some patients, recurrence of liver injury has been observed upon re-administration of sodium metamizole. If a previous episode of liver injury occurred during treatment with sodium metamizole and other causes of liver injury have not been established, medicinal products containing sodium metamizole should not be re-administered.

The medicinal product should be discontinued immediately and urgent medical advice sought if symptoms such as asthenia, unexplained chills, fever, sore throat, difficulty swallowing, bleeding gums, pallor of the skin, skin or mucosal rashes, vaginitis, or proctitis occur. If symptoms of impaired liver function develop, including gastrointestinal disturbances, jaundice, or elevated liver enzymes, the medicinal product must be discontinued. Patients should report symptoms such as hot flushes, excessive sweating, headache, increased fatigue, jaundice, nausea, epigastric discomfort, or constipation.

Severe skin adverse reactions

Life-threatening skin reactions, including Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome), have been reported during treatment with phenobarbital. Therefore, if characteristic symptoms occur (e.g., progressive skin rashes, often with blisters, and mucosal lesions), the medicinal product should be discontinued immediately and medicinal products containing phenobarbital should never be used again. The risk of developing Stevens-Johnson syndrome or Lyell’s syndrome is highest during the first weeks of treatment. Early diagnosis and immediate discontinuation of the suspected causative medicinal product offer the best chance for successful management.

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during treatment with sodium metamizole, which may be life-threatening or fatal (see section "Adverse reactions"). Before initiating treatment with Andifen IS, patients should be informed about the signs and symptoms of severe skin reactions. Patients should be closely monitored during treatment for the appearance of such symptoms. If symptoms suggestive of severe skin adverse reactions occur, the medicinal product should be discontinued immediately and must not be used again under any circumstances (see section "Contraindications").

During treatment with the medicinal product, urine may turn red due to excretion of a metabolite of sodium metamizole; this is clinically insignificant.

Orthostatic hypotension may occur during treatment.

Peripheral blood count (leukocyte formula) should be monitored during treatment.

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 the medicinal product is not recommended due to the myelotoxicity of sodium metamizole, potential accumulation of phenobarbital, and risk of drug dependence. Barbiturates are associated with withdrawal syndrome. If the medicinal product is used for more than 7 days, monitoring of peripheral blood count (due to myelotoxicity of metamizole), and renal and hepatic function is required.

Continuous medical supervision is required when used in children.

Smoking reduces the effectiveness of the medicinal product.

If disease symptoms do not begin to subside, if the patient's condition worsens, or if adverse effects occur, discontinue use of the medicinal product and consult a physician regarding further management.

Use during pregnancy or breastfeeding.

The use of the 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 driving or operating machinery.

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

Method of Administration and Dosage

Take orally after meals, with a sufficient amount of water.

Adults and children aged 14 years and older

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

Children aged 12 to 14 years

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

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

Children

Do not administer the drug to children under 12 years of age.

Overdose

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

Overdose of the drug may lead to restlessness, lethargy, moderate dyspnea, reduced tissue perfusion, cyanosis, metabolic acidosis, hyperglycemia, hyperkalemia.

Prolonged use of the drug in high doses may result in liver function disorders and development of neutropenia.

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

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

Symptoms of mild or moderate acute barbiturate poisoning: dizziness, increased fatigue, even deep sleep from which the patient cannot be awakened. Hypersensitivity reactions may occur: angioedema, pruritus, skin rashes (including urticaria).

Symptoms of severe acute barbiturate poisoning: central nervous system depression up to deep coma, accompanied by tissue hypoxia; shallow breathing, initially rapid, then slowed breathing, respiratory depression up to respiratory arrest; depression of cardiovascular activity, including arrhythmias, decreased arterial blood pressure up to collapse-like state; tachycardia or bradycardia, diminished or absent reflexes, decreased body temperature, reduced diuresis, nystagmus, headache, nausea, weakness.

If not treated, fatal outcome may occur due to circulatory failure, respiratory paralysis, or pulmonary edema.

Treatment: symptomatic therapy (primarily monitoring of vital functions: respiration, pulse, arterial blood pressure). Patients may require intensive care. It is necessary to stabilize and normalize respiration and circulation. Respiratory failure is managed by artificial ventilation; shock should be treated with plasma and plasma substitutes. If a short time has passed since drug intake (not more than 6 hours), gastric lavage should be performed, followed by administration of a sorbent (activated charcoal) and sodium sulfate. To accelerate barbiturate elimination from the body, forced alkaline diuresis, hemodialysis, and/or hemoperfusion may be performed.

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

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

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

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

Adverse Reactions

Nervous system disorders: asthenia, weakness, increased fatigue, drowsiness, cognitive disturbances, decreased attention concentration, dizziness, headache, hallucinations, confusion, slowed reaction time, movement coordination disorders, ataxia, hyperkinesia (in children), nystagmus, paradoxical excitation, insomnia (mainly in children and elderly patients), depression.

Eye disorders: visual disturbances, diplopia, conjunctivitis.

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

Cardiovascular disorders: facial flushing, atrioventricular block, arrhythmias, tachycardia, bradycardia, 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 decreased cardiac output, ventricular fibrillation, asystole, ventricular flutter, orthostatic hypotension.

Blood and lymphatic system disorders: leukocytosis, leukopenia, agranulocytosis, lymphocytosis, eosinophilia, thrombocytopenia, anemia, megaloblastic anemia, enlarged lymph nodes; with prolonged use – granulocytopenia.

Gastrointestinal disorders: anorexia, dry mouth, burning sensation in throat, nausea, vomiting, stomach discomfort, constipation, diarrhea.

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

Renal and urinary disorders: usually in patients with impaired renal function and/or following overdose – transient oliguria, anuria, proteinuria, interstitial nephritis, red discoloration of urine.

Musculoskeletal and connective tissue disorders: with prolonged use, there is a risk of impaired osteogenesis and rickets development. Cases of decreased bone mineral density, osteopenia, osteoporosis, and fractures have been reported in patients receiving long-term phenobarbital therapy. The mechanism of phenobarbital’s effect on bone tissue metabolism has not been established.

Skin and subcutaneous tissue disorders: possible manifestations of hypersensitivity reactions, including skin and mucous membrane rashes (e.g., urticaria), pruritus, skin hyperemia, severe skin reactions such as polymorphic exudative erythema, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), drug-induced hypersensitivity reaction with eosinophilia and systemic symptoms (DRESS syndrome); increased photosensitivity (photosensitization), exfoliative dermatitis.

Immune system disorders: angioneurotic edema, anaphylactic shock.

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

With prolonged use of phenobarbital, folate deficiency, impotence, drug dependence, and withdrawal syndrome may develop, typically occurring after abrupt discontinuation of the drug and accompanied by nightmares and nervousness.

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.

Availability category

Over-the-counter.

Manufacturer

Limited liability company “INTERKHIM”.

Manufacturer’s address and location of business activity

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