Amicitron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRON®

Composition:

Active substances: paracetamol, phenylephrine hydrochloride, pheniramine maleate, ascorbic acid;

1 sachet contains 500 mg paracetamol, 10 mg phenylephrine hydrochloride, 20 mg pheniramine maleate, 50 mg ascorbic acid;

Excipients: sucrose, sunset yellow FCF dye (E 110), citric acid monohydrate, sodium citrate, natural lemon flavor.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: white powder, with pale yellow and/or orange specks permitted.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol, combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Paracetamol exerts antipyretic, analgesic, and weak anti-inflammatory effects. Paracetamol inhibits prostaglandin synthesis in the central nervous system (CNS) and blocks the transmission of pain impulses.

Phenylephrine is an α-adrenergic agonist that produces vasoconstrictive action, reducing swelling of the nasal mucosa and paranasal sinuses.

Pheniramine is a histamine H1-receptor blocker that reduces vascular permeability and relieves lacrimation, as well as itching of the eyes and nose.

Ascorbic acid enhances the body's nonspecific resistance.

Pharmacokinetics.

Paracetamol is well absorbed from the gastrointestinal tract, crosses the placental barrier, penetrates slightly into breast milk, is metabolized in the liver via the cytochrome P450 system, excreted by the kidneys, with a half-life of 1–4 hours. Duration of action is 3–4 hours.

Phenylephrine is metabolized in the intestine and liver, excreted by the kidneys.

Pheniramine is well absorbed from the gastrointestinal tract, metabolized in the liver via the cytochrome P450 system, has a half-life of 16–18 hours, and 70–83% is excreted by the kidneys.

Ascorbic acid is rapidly absorbed from the gastrointestinal tract, metabolized in the liver, and excreted by the kidneys.

Clinical characteristics.

Indications.

Symptomatic treatment of acute respiratory infections and influenza: elevated body temperature, headache, nasal congestion, rhinorrhea, muscle pain and aching.

Contraindications.

Hypersensitivity to the active substances or to any component of the medicinal product, pyloroduodenal obstruction, acute pancreatitis, severe impairment of liver and/or kidney function, congenital hyperbilirubinemias, glucose-6-phosphate dehydrogenase deficiency, phenylketonuria, diabetes mellitus, hyperthyroidism, prostatic hyperplasia with urinary retention, pheochromocytoma, bladder neck obstruction, severe forms of arrhythmia, arterial hypertension, atherosclerosis, ischemic heart disease; blood disorders, leukopenia, anemia, thrombosis, thrombophlebitis, bronchial asthma, closed-angle glaucoma, epilepsy, alcoholism, states of increased excitement, sleep disorders, concomitant therapy with β-blockers, other sympathomimetics, appetite-suppressing or appetite-enhancing agents, amphetamine-like psychostimulants, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and within 2 weeks following discontinuation of such agents.

Interaction with other medicinal products and other forms of interaction.

The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased when used with cholestyramine (this effect is negligible if cholestyramine is administered 1 hour apart). Barbiturates reduce the antipyretic effect of paracetamol. When probenecid is administered, the dose of paracetamol should be reduced, as probenecid affects paracetamol metabolism. Paracetamol reduces the efficacy of diuretics; may prolong the half-life of chloramphenicol; may induce hepatic metabolism of lamotrigine, thereby reducing its bioavailability and efficacy. Paracetamol may interfere with the determination of serum uric acid levels by the phosphotungstic acid method.

The risk of paracetamol hepatotoxicity increases with concomitant use of isoniazid and medicinal products that induce hepatic microsomal enzymes [barbiturates; anticonvulsants (phenytoin, phenobarbital, carbamazepine); rifampicin]. Hepatotoxic medicinal products increase the likelihood of paracetamol accumulation and overdose. Regular concomitant use of paracetamol and zidovudine may lead to neutropenia and increased risk of liver injury. Hepatotoxicity of paracetamol may be enhanced by prolonged or excessive alcohol consumption. Do not use concurrently with alcohol.

Long-term use of paracetamol may enhance the anticoagulant effect of warfarin and other coumarin derivatives, increasing the risk of bleeding. This effect is not pronounced with occasional paracetamol use.

Paracetamol should be used with caution in combination with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidemia, particularly in patients with risk factors (see section "Special precautions").

Interaction of phenylephrine with monoamine oxidase inhibitors (MAOIs) may cause a hypertensive effect. Combined use with tricyclic antidepressants (including amitriptyline) increases the risk of cardiovascular adverse effects. Concomitant use with cardiac glycosides (including digoxin) may lead to arrhythmias and infarction. Combined use with other sympathomimetics increases the risk of cardiovascular adverse reactions (including arterial hypertension). Phenylephrine may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa, debrisoquin, guanethidine), increasing the risk of cardiovascular adverse reactions (including arterial hypertension). Concurrent use of phenylephrine with ergot alkaloids (ergotamine, methysergide) may increase the risk of ergotism.

Pheniramine potentiates the anticholinergic effects of atropine, antispasmodics, tricyclic antidepressants, and antiparkinsonian agents, and may inhibit the action of anticoagulants. Concomitant use of pheniramine with anesthetics, hypnotics, sedatives (including barbiturates), neuroleptics, tranquilizers, narcotic analgesics, and alcohol may significantly enhance its CNS depressant effects.

Ascorbic acid enhances the absorption of iron when administered orally, increases serum levels of ethinylestradiol, penicillins, and tetracyclines, and reduces blood levels of antipsychotic agents (including phenothiazine derivatives). It decreases the efficacy of heparin and indirect anticoagulants, increases the risk of crystalluria during salicylate therapy, and increases the risk of glaucoma during glucocorticoid therapy. High doses reduce the efficacy of tricyclic antidepressants. Ascorbic acid should be taken no earlier than 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, particularly in the myocardium, potentially leading to cardiac decompensation. Prolonged use of high doses during disulfiram therapy inhibits the disulfiram–alcohol reaction. Absorption of ascorbic acid is reduced by oral contraceptives, fruit or vegetable juices, and alkaline beverages.

Special precautions for use.

Amitsitron® contains sucrose; therefore, this medicinal product should not be taken by patients with rare hereditary problems associated with fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Due to the risk of overdose, Amitsitron® should not be used concurrently with other medicinal products intended for symptomatic treatment of cold and flu (vasoconstrictors, paracetamol-containing preparations), or with other products containing vitamin C.

The risk of hepatotoxicity is increased in patients with alcoholic liver disease and in those who abuse alcohol. Patients with liver or kidney disorders, bronchopulmonary diseases (chronic obstructive pulmonary disease, see section "Contraindications"), established intolerance to certain sugars, patients with mild arthritis who take analgesics daily, and patients taking warfarin or similar anticoagulants should consult a physician before using Amitsitron®.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases the risk of metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Medical attention should be sought immediately if these symptoms occur.

Cases of high anion gap metabolic acidosis caused by 5-oxoprolinuria (pyroglutamic acidemia) have been reported in patients with severe underlying conditions such as renal failure and sepsis, or in patients with malnutrition or other states associated with glutathione deficiency (e.g., alcoholism), who received prolonged therapeutic doses of paracetamol or combination therapy with paracetamol and flucloxacillin. In suspected cases of high anion gap metabolic acidosis due to pyroglutamic acidemia, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Monitoring urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidemia as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

The medicinal product contains phenylephrine, which may provoke angina attacks. Use with caution in patients with arterial hypertension, heart disease, arrhythmia, bradycardia (see section "Contraindications"); Raynaud's disease, benign prostatic hyperplasia (due to the risk of urinary retention) (see section "Contraindications"), thyroid disorders (see section "Contraindications"), liver (including acute hepatitis) and kidney diseases (see section "Contraindications), glaucoma (see section "Contraindications"), chronic lung diseases, hypercoagulability, chronic malnutrition, dehydration, stenosing peptic ulcer, and elderly patients. Use with particular caution in patients with iron metabolism disorders (hemochromatosis, hemosiderosis, thalassemia), and in those with a history of nephrolithiasis (risk of hyperoxaluria and oxalate precipitation in the urinary tract after high-dose ascorbic acid intake). Absorption of ascorbic acid may be altered in intestinal motility disorders, enteritis, or reduced gastric secretion.

One sachet of Amitsitron® contains 3.5 mmol (80 mg) of sodium; therefore, patients on a sodium-restricted diet should use this preparation with caution.

The medicinal product contains the colorant Yellow West FCF (E 110), which may cause allergic reactions.

The medicinal product may interfere with laboratory tests for blood glucose, uric acid, creatinine, and inorganic phosphates. Fecal occult blood testing may yield false-negative results.

Recommended doses must not be exceeded.

If symptoms do not improve within 5 days, or are accompanied by high fever, chills lasting more than 3 days, rash, or persistent headache, a physician should be consulted, as these may be signs of a more serious condition.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy or breastfeeding.

The effect of the medicinal product on fertility has not been specifically studied. Preclinical studies have not shown any specific effect of paracetamol on fertility when used at therapeutic doses. Adequate studies on the reproductive toxicity of phenylephrine and pheniramine in animals have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Driving and operating complex machinery are not recommended during treatment with Amitsitron® because the medicinal product may cause drowsiness and other adverse reactions affecting the nervous system and visual function.

Dosage and Administration

The medicinal product is intended for use in adults and children aged 14 years and older. The contents of the sachet should be dissolved in a glass of hot water (not boiling water) and taken orally. The dose may be repeated every 3–4 hours, but no more than 3 sachets should be taken per day. The maximum duration of treatment is 5 days.

Children

The use of this medicinal product is contraindicated in children under 14 years of age.

Overdose

Paracetamol overdose:
Within the first 24 hours, symptoms may include pallor, nausea, vomiting, loss of appetite, and abdominal pain. Following ingestion of high doses, disturbances in orientation, psychomotor agitation, dizziness, sleep disturbances, cardiac arrhythmias, pancreatitis, and hepatonecrosis may occur. The first sign of liver injury may be abdominal pain, which does not always appear within the first 12–48 hours and may develop later, up to 4–6 days after drug administration. Liver damage typically occurs within 72–96 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may develop, along with bleeding tendencies. With prolonged high-dose use of paracetamol, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, neutropenia, and thrombocytopenia may occur. In rare cases, acute renal failure with tubular necrosis has been reported, even in the absence of severe liver damage. This condition may present with severe lumbar pain, hematuria, and proteinuria. Nephrotoxicity is possible, including renal colic, interstitial nephritis, and capillary necrosis.

Ingestion of more than 150 mg/kg of paracetamol in children or ingestion of 10 g or more in adults, particularly with alcohol, may lead to hepatocellular necrosis, resulting in encephalopathy, hemorrhage, hypoglycemia, hepatic coma, and potentially fatal outcomes. In patients with risk factors [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs that induce liver enzymes; chronic alcohol abuse; glutathione system deficiency (eating disorders, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may result in liver injury.

In case of overdose, prompt medical attention is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of the overdose or risk of organ damage. If an excessive dose of paracetamol was taken less than 1 hour ago, activated charcoal should be administered. Plasma paracetamol concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine can be initiated within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within the first 8 hours. The efficacy of the antidote declines sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. As an alternative, in the absence of vomiting and when medical care is not immediately accessible, oral methionine may be used.

Phenylephrine overdose:
Symptoms include hyperhidrosis, psychomotor agitation or CNS depression, headache, dizziness, drowsiness, impaired consciousness, tremor, hyperreflexia, seizures, nausea, vomiting, irritability, restlessness, arrhythmias, and arterial hypertension. In severe cases, coma may occur. To counteract hypertensive effects, intravenous α-receptor blockers may be used; for seizures, diazepam is indicated.

Pheniramine overdose:
Anticholinergic (atropine-like) symptoms occur, including mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, and intestinal atony. CNS depression may lead to respiratory and cardiovascular system dysfunction (bradycardia, arterial hypotension, collapse).

Symptoms resulting from mutual potentiation of the anticholinergic effect of pheniramine and the sympathomimetic effect of phenylephrine include drowsiness, possibly followed by excitation (especially in children) or CNS depression, visual disturbances, persistent headache, nervousness, insomnia, hyperreflexia, irritability, circulatory disturbances, bradycardia, and skin rash. There is no specific antidote for antihistamine overdose. Standard emergency measures should be implemented, including administration of activated charcoal, a saline laxative, and supportive care for the cardiovascular and respiratory systems. Stimulants must not be used; vasoconstrictors may be administered to treat arterial hypotension.

Ascorbic acid (vitamin C) overdose:
Symptoms include nausea, vomiting, or diarrhea (which resolve after discontinuation), abdominal bloating and pain, itching, skin rashes, and increased excitability. Doses exceeding 3000 mg may cause transient osmotic diarrhea, gastrointestinal disturbances, disturbances in zinc and copper metabolism, and myocardial dystrophy. With prolonged high-dose use, possible suppression of pancreatic islet function and glucosuria may occur. Overdose may alter renal excretion of ascorbic acid and uric acid, leading to precipitation of oxalate stones during urine acidification.

Treatment: Symptomatic management is recommended. Gastric lavage should be performed within the first 6 hours after overdose. Within the first 8 hours, oral methionine or intravenous cysteamine or N-acetylcysteine should be administered.

Adverse reactions.

Skin and subcutaneous tissue disorders: dermatitis, rash, pruritus, urticaria, erythema multiforme, Stevens–Johnson syndrome, Lyell’s syndrome.

Immune system disorders: hypersensitivity reactions, including anaphylactic shock, angioneurotic edema.

Nervous system disorders: headache, dizziness, tremor, psychomotor agitation, disorientation, anxiety, nervousness, fear, irritability, insomnia, somnolence, confusion, hallucinations, depression, paresthesia, tinnitus; in individual cases – coma, seizures, dyskinesia, behavioral changes.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs).

Gastrointestinal disorders: nausea, vomiting, heartburn, dry mouth, abdominal discomfort and pain, constipation, diarrhea, flatulence, anorexia, aphthae, hypersalivation, hemorrhages, mucosal irritation.

Hepatobiliary disorders: liver function abnormalities, hypertransaminasemia (usually without jaundice), hepatonecrosis (with high-dose administration).

Metabolic and nutritional disorders: frequency unknown (cannot be estimated from available data) – metabolic acidosis with high anion gap.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Renal and urinary disorders: nephrotoxicity, interstitial nephritis, capillary necrosis, dysuria, urinary retention and difficulty in urination, renal colic, renal failure.

Cardiovascular disorders: arterial hypertension, arrhythmia, tachycardia, bradycardia, palpitations, dyspnea, chest pain, angina attacks.

In contrast to second-generation antihistamines, the use of pheniramine is not associated with QT interval prolongation or cardiac arrhythmias.

Blood and lymphatic system disorders: anemia (including hemolytic anemia), sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), pancytopenia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, bleeding, bruising.

Other: general weakness, malaise.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap caused by pyroglutamic acidemia have been observed in patients with risk factors who used paracetamol (see section "Special instructions"). Pyroglutamic acidemia may be caused by low glutathione levels in these patients.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Oral solution powder, 23 g in sachet № 1.

Oral solution powder, 23 g in sachet; 10 sachets in a cardboard pack.

Prescription status. Over-the-counter.

Manufacturer.

Limited liability company "INTERKHIM".

Manufacturer's address and location of business activity.

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