Andipal-forte

I N S T R U C T I O N for medical use of the medicinal product ANDIPAL-FORTE (ANDIPALUM-FORTE)

Composition:

Active substances: 1 tablet contains 500 mg (0.5 g) of sodium metamizole, 40 mg (0.04 g) of bendazole hydrochloride, 40 mg (0.04 g) of papaverine hydrochloride;

Excipients: potato starch, calcium stearate, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with a slight yellowish tint, with a flat surface, beveled edges and a score line.

Pharmacotherapeutic group. Analgesics and antipyretics. Metamizole sodium combinations without psychotropic agents. ATC code N02BB52.

Pharmacological properties.

Pharmacodynamics.

A combined agent with analgesic, spasmolytic, and vasodilatory effects due to the specific actions of its components. The medicinal product also exerts antihypertensive and antipyretic effects.

Metamizole sodium – a non-steroidal anti-inflammatory drug (NSAID) from the pyrazolone derivatives group, exhibits anti-inflammatory, analgesic, and antipyretic effects. The mechanism of action is mediated by inhibition of cyclooxygenase (COX) and blockade of prostaglandin synthesis from arachidonic acid, as well as interference with transmission of extra- and proprioceptive pain impulses, increased excitability threshold of thalamic pain sensitivity centers, and enhanced heat dissipation.

Bendazole hydrochloride – exerts vasodilatory, spasmolytic, and hypotensive effects; also stimulates spinal cord functions and promotes recovery of peripheral nerve functions; exerts moderate immunostimulatory activity.

Papaverine hydrochloride – has 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.

Pharmacokinetics.

After oral administration, it is rapidly and completely absorbed. It undergoes hydrolysis in the intestinal wall, forming an active metabolite. The effect begins 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 sodium metamizole, pyrazolone derivatives (phenylbutazone, tribuzone, antipyrine); suspicion of acute surgical pathology; anemia of any etiology, cytostatic or infectious neutropenia; leukopenia; agranulocytosis; thrombocytopenia; hepatic porphyria; glucose-6-phosphate dehydrogenase deficiency; bronchial asthma; respiratory depression; bronchoobstructive syndrome; conditions characterized by decreased muscle tone, seizure disorders; glaucoma.

Severe heart failure, atrioventricular (AV) block. Arterial hypotension. Severe impairment of liver and kidney function. Chronic nephritis with edema and impaired renal nitrogen excretory function. Gastric and duodenal ulcer with bleeding. Diabetes mellitus. Hypotonic colitis; habitual constipation; head trauma; hypothyroidism; adrenal insufficiency; benign prostatic hyperplasia; concomitant use of monoamine oxidase inhibitors (MAOIs). Agranulocytosis caused by metamizole, other pyrazolones or pyrazolidines in medical history. Impaired bone marrow function or diseases of the hematopoietic system. Patient age over 75 years (risk of hyperthermia).

Interaction with other medicinal products and other forms of interactions.

Radiographic contrast agents, colloidal plasma substitutes, penicillin: should not be used during treatment with sodium metamizole.

Chlorpromazine or other phenothiazine derivatives: may cause pronounced hypothermia. Oral hypoglycemic agents, indirect anticoagulants, phenytoin, glucocorticosteroids, indomethacin, ibuprofen: sodium metamizole increases the activity of these drugs by displacing them from protein binding.

Metamizole may induce metabolic enzymes, particularly CYP2B6 and CYP3A4.

Concomitant use of metamizole with bupropion, efavirenz, methadone, valproate, tacrolimus, or sertraline may lead to reduced plasma concentrations of these drugs, potentially reducing their clinical efficacy. Therefore, co-administration of these drugs with metamizole is recommended with caution; monitoring of clinical response and/or drug levels may be required.

Glutethimide: reduces the effectiveness of sodium metamizole.

Other nonsteroidal anti-inflammatory drugs (NSAIDs): potentiates their analgesic and antipyretic effects and increases the likelihood of additive adverse effects.

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

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

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

Diuretics (furosemide): possible reduction of diuretic effect.

Sulfonylurea hypoglycemic agents: enhanced hypoglycemic effect.

Ethanol: sodium metamizole enhances its sedative effect.

Sedatives and tranquilizers (sibazone, diazepam, trimethozine, trioxazine, valocardine, codeine, anaprilin, H2-receptor blockers, and propranolol): enhance the analgesic effect of sodium metamizole.

Tricyclic antidepressants (amitriptyline, amizole, doxepin), hormonal contraceptives, and allopurinol: concomitant use of sodium metamizole with these drugs may increase its toxicity.

Phentolamine, antihypertensive drugs (agents affecting the renin-angiotensin system), antidepressants, sedatives, diuretics, saluretics, procainamide, reserpine, quinidine: when used in combination with bendazole, hypotensive effect is enhanced.

Levodopa, methyldopa: reduced antihypertensive effect of methyldopa and reduced anti-Parkinsonian effect of levodopa.

Cyclosporine: concomitant use reduces cyclosporine blood concentration.

Nitrofurantoin: there are reports of hepatitis development when used concomitantly with the drug.

Cardiac glycosides: marked enhancement of myocardial contractile function due to decreased total peripheral vascular resistance.

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

Morphine: possible reduction of spasmolytic activity of papaverine hydrochloride.

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

There are reports of hepatitis development when used concomitantly with nitrofurantoin.

Drug efficacy is reduced by tobacco smoking.

Caution is required when using the drug concomitantly with salicylates.

Special precautions for use.

The recommended doses of the medicinal product should not be exceeded.

Since sodium metamizole has anti-inflammatory and analgesic properties, it may mask signs of infection, symptoms of non-infectious diseases, and complications associated with pain syndrome, which could complicate their diagnosis. The drug should not be used to relieve acute abdominal pain before the cause is determined.

The drug should be used with caution in patients:

• with existing allergic diseases (including pollinosis) or such conditions in medical history – the risk of allergic reactions is increased;
• with inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease;
• with cardiovascular insufficiency;
• with predisposition to arterial hypotension;
• with supraventricular tachycardia;
• with a history of kidney disease (pyelonephritis, glomerulonephritis);
• with impaired liver and/or kidney function;
• when used concomitantly with cytostatic medicinal agents (only under physician supervision).

The drug should be used with caution in patients with a history of chronic alcohol consumption, in debilitated patients, and in elderly individuals – due to the risk of hyperthermia and increased frequency of adverse reactions, particularly those affecting the gastrointestinal tract.

Patients should be warned prior to the start of treatment that if symptoms such as difficulty swallowing, gum bleeding, skin pallor, asthenia, or development of vaginitis or proctitis occur, the drug should be discontinued immediately.

Also, the drug intake should be stopped at the first signs of skin rashes or mucosal lesions. In case of these symptoms, patients should seek immediate medical advice.

The drug should not be used for longer than the recommended duration without consulting a physician. Regular long-term use of the drug is not recommended due to the myelotoxicity of sodium metamizole; in case of prolonged use (more than 7 days), kidney and liver function should be monitored.

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which were life-threatening or resulted in fatalities, have been reported during treatment with metamizole.

Patients should be informed about the signs and symptoms of skin reactions and should be closely monitored.

If symptoms indicating such reactions occur, metamizole treatment should be discontinued immediately and must never be restarted (see section "Contraindications").

Risk of drug-induced liver injury

Cases of acute hepatitis, predominantly of hepatocellular type, have been observed in patients treated with sodium metamizole. Symptoms appeared 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 rashes, blood dyscrasias, fever, and eosinophilia) or accompanied by features of autoimmune hepatitis. Most patients recovered after discontinuation of 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 fully understood, but available data suggest an immune-allergic mechanism.

Patients should be instructed to inform their physician if symptoms suggestive of liver injury occur. If liver injury is suspected, patients should discontinue sodium metamizole; liver function parameters should be assessed.

Cases of liver injury during treatment with metamizole are very rare, but the exact frequency of this adverse reaction cannot be determined. Liver injury recurrence has been observed in some patients upon re-administration of sodium metamizole. If a patient previously experienced liver injury during treatment with metamizole and other causes of liver injury have not been identified, medicinal products containing sodium metamizole should not be used again.

During treatment, red discoloration of urine may occur (due to metabolite excretion), which is not clinically significant.

Use with caution in debilitated patients and in patients with reduced intestinal peristalsis. Orthostatic hypotension may develop during drug intake.

If symptoms of liver dysfunction occur, such as gastrointestinal disturbances, jaundice, or elevated liver enzymes, the drug should be discontinued.

Patients should inform their physician if the following symptoms occur: flushing, sweating, headache, increased fatigue, jaundice, skin rash, nausea, epigastric discomfort, or constipation.

When used in children, continuous medical supervision is required.

Smoking reduces the effectiveness of the drug.

During treatment, alcohol consumption and use of central nervous system depressants should be avoided.

If disease symptoms do not begin to subside, or if the patient's condition worsens, or if adverse effects occur, drug use should be discontinued and medical advice should be sought.

Use during pregnancy or breastfeeding.

Use during pregnancy or breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this drug, driving and operating complex machinery should be avoided.

Dosage and Administration

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

The recommended dose for adults is 1 tablet 1–2 times daily.

The maximum daily dose is 2 tablets.

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

Children

This medicinal product in the given dosage is not intended for use in children.

Overdose

Symptoms: hypothermia, pronounced decrease in arterial blood pressure, arrhythmia, tachycardia, partial or complete atrioventricular block, acute agranulocytosis, excessive sweating, headache, sensation of heat, dizziness, dysphagia, delirium, possible development of acute agranulocytosis, acute renal or hepatic failure, respiratory muscle paralysis, reduced tissue perfusion, restlessness, lethargy, visual disturbances, ataxia, nystagmus, diplopia, central nervous system depression, convulsive syndrome, collapse, coma, cyanosis, metabolic acidosis, hyperventilation, hyperglycemia, hyperkalemia, oliguria, anuria, constipation, gastrointestinal disturbances, gastralgia, gastritis, nausea, vomiting, diarrhea, skin rash, dyspnea, moderate bronchospasm, tinnitus, drowsiness, skin flushing, general weakness, palpitations. With prolonged use in high doses: liver function disorders, neutropenia, hemorrhagic syndrome, possible seizures and impaired consciousness.

Treatment: discontinue the drug, induce vomiting, gastric lavage, maintain arterial blood pressure, administer enterosorbents and saline laxatives, perform forced diuresis, and provide symptomatic therapy aimed at supporting vital functions. In severe cases, hemodialysis, hemoperfusion, or peritoneal dialysis may be considered. In case of seizures, seek immediate medical attention.

In the event of the first symptoms of overdose, seek immediate medical help.

Adverse Reactions

Skin and subcutaneous tissue disorders: severe skin reactions have been reported with metamizole use, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions"); the frequency of these reactions is unknown;

Gastrointestinal disorders: nausea, constipation, increased liver transaminase activity, jaundice, hepatitis, gastric discomfort, dry mouth;

Immune system disorders: hypersensitivity reactions may occur, including skin and mucosal rashes, skin hyperemia, conjunctivitis, itching, urticaria, dry cough, rhinitis, dyspnea, throat burning, facial flushing, angioneurotic edema, bronchospastic syndrome, anaphylactic shock, Stevens-Johnson syndrome, Lyell's syndrome;

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, granulocytopenia, anemia, eosinophilia, agranulocytosis;

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

Cardiovascular system disorders: A-V block, ventricular extrasystoles, reduced cardiac output, decreased arterial pressure, weakness, numbness, tremor, loss of consciousness, palpitations, arrhythmias, chest pain; with prolonged use – worsening ECG parameters, orthostatic hypotension, ventricular fibrillation, asystole, ventricular flutter, collapse, apnea;

Central nervous system disorders: drowsiness, increased sweating, dizziness, headache, hot flushes, flushing, anorexia;

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

If any adverse events occur, patients should consult their physician.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in blisters;

10 tablets per blister; 2 or 10 blisters per cardboard pack.

Prescription status.

Over-the-counter.

Manufacturer.

JSC "Monfarm".

Manufacturer's address and location of business activity.

8, Zavodska St., Avramivka, Uman district, Cherkasy region, 19161, Ukraine.