Amicitron® sugar-free

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRON® SUGAR-FREE

Composition:

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

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

Excipients: isomalt (E 953), yellow azo dye FCF (E 110), citric acid monohydrate, sodium citrate, potassium acesulfame, natural lemon flavor.

Pharmaceutical form. Oral powder for solution.

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

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Anilides. Paracetamol combinations without psycholeptics.

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 transmission of pain impulses.

Phenylephrine is an α-adrenomimetic agent that produces vasoconstriction, reduces swelling of the nasal mucosa and paranasal sinuses.

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

Ascorbic acid enhances non-specific resistance of the body.

Pharmacokinetics.

Paracetamol is well absorbed from the gastrointestinal tract, penetrates the placental barrier, passes into breast milk to a minor extent, is metabolized in the liver via the cytochrome P450 system, excreted by the kidneys; elimination half-life is 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, elimination half-life is 16–18 hours; 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, runny nose, muscle pain and aching.

Contraindications.

Hypersensitivity to the active substances or to any component of the medicinal product, pyloroduodenal obstruction, acute pancreatitis, severe hepatic and/or renal dysfunction, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, phenylketonuria, diabetes mellitus, hyperthyroidism, prostate 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, conditions of increased excitation, sleep disturbances, concomitant therapy with β-blockers, other sympathomimetics, appetite suppressants or appetite stimulants, 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. The dose of paracetamol should be reduced when administered with probenecid, as it affects paracetamol metabolism. Paracetamol reduces the efficacy of diuretics; may prolong the elimination 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 damage. Hepatotoxicity of paracetamol may be enhanced by chronic 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 use of paracetamol.

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

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

Ascorbic acid, when taken orally, enhances iron absorption, increases ethinylestradiol and plasma levels of penicillins and tetracyclines, reduces blood levels of antipsychotic agents (including phenothiazine derivatives), reduces 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 high-dose ascorbic acid intake during disulfiram therapy inhibits the disulfiram–alcohol reaction. Absorption of ascorbic acid is reduced when taken with oral contraceptives, fruit or vegetable juices, or alkaline beverages.

Special precautions for use.

Due to the presence of isomalt (E 953), this medicinal product should not be taken by patients with rare hereditary fructose intolerance. One sachet of the sugar-free medicinal product Amictron® contains 10.4 g of isomalt and therefore may have a mild laxative effect. The energy value of 1 g of isomalt is 2.3 kcal.

Because of the risk of overdose, Amictron® sugar-free should not be used simultaneously with other medicinal products intended for symptomatic treatment of cold and rhinitis (vasoconstrictors, paracetamol-containing products), or with other medicinal 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"), known 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 Amictron® sugar-free.

In patients with severe infections such as sepsis, 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 have been reported in patients with severe conditions such as renal failure and sepsis, or in patients with malnutrition or other conditions associated with glutathione deficiency (e.g., alcoholism), who were treated with paracetamol at therapeutic doses for prolonged periods or received combination therapy with paracetamol and flucloxacillin. In suspected cases of high anion gap metabolic acidosis due to 5-oxoprolinuria, immediate discontinuation of paracetamol is recommended, along with close monitoring of the patient. Monitoring urinary 5-oxoproline levels may be helpful in identifying 5-oxoprolinuria 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 risk of urinary retention) (see section "Contraindications"), thyroid disorders (see section "Contraindications"), liver (including acute hepatitis) and kidney disorders (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 deposition in the urinary tract after high-dose ascorbic acid intake). Absorption of ascorbic acid may be altered in patients with intestinal motility disorders, enteritis, or reduced gastric secretion.

One sachet of the sugar-free medicinal product Amictron® contains 3.5 mmol (80 mg) of sodium; therefore, patients on a sodium-restricted diet should use this product with caution.

The medicinal product contains the colorant sunset yellow 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 if symptoms are accompanied by high fever, chills lasting more than 3 days, skin rash, or persistent headache, consult a physician, as these may be signs of a more serious condition.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

The effect of the medicinal product on fertility has not been specifically studied. Preclinical studies have not revealed 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.

Effect on ability to drive and use machines.

Driving vehicles or operating complex machinery is not recommended during treatment with Amictron® sugar-free, as the medicinal product may cause drowsiness and other adverse reactions affecting the nervous system and vision.

Method of Administration and Dosage.

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 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.

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

Ingestion of paracetamol by a child at doses exceeding 150 mg/kg body weight, or ingestion of 10 g or more by an adult, especially with alcohol, may lead to hepatocellular necrosis, resulting in encephalopathy, hemorrhages, hypoglycemia, hepatic coma, and fatal outcome. In patients with risk factors [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing 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 cause liver damage.

In case of overdose, immediate medical assistance is required. The patient must be taken to hospital immediately, 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 the 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 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine can be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within the first 8 hours. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to current guidelines. As an alternative, in the absence of vomiting and when far from medical care, oral methionine may be used.

In case of phenylephrine overdose, symptoms include hyperhidrosis, psychomotor agitation or CNS depression, headache, dizziness, drowsiness, impaired consciousness, tremor, hyperreflexia, seizures, nausea, vomiting, irritability, restlessness, arrhythmia, and arterial hypertension; in severe cases – coma. To counteract hypertensive effects, intravenous α-receptor blockers may be used; for seizure management – diazepam.

In case of pheniramine overdose, anticholinergic-like symptoms occur: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, and intestinal atony. CNS depression leads to respiratory and cardiovascular system dysfunction (bradycardia, arterial hypotension, collapse).

Symptoms caused by mutual potentiation of the parasympatholytic effect of pheniramine and the sympathomimetic effect of phenylephrine: drowsiness with possible subsequent development of agitation (especially in children) or CNS depression, visual disturbances, persistent headache, nervousness, insomnia, hyperreflexia, irritability, circulatory disturbances, bradycardia, and skin rashes. There is no specific antidote for antihistamine overdose. Standard emergency measures should be provided, including administration of activated charcoal, a saline laxative, and standard supportive measures for the cardiopulmonary system. Stimulants must not be used. For treatment of arterial hypotension, vasoconstrictors may be administered.

In case of ascorbic acid 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 temporary osmotic diarrhea and gastrointestinal disturbances, disturbances in zinc and copper metabolism, and myocardial dystrophy; with prolonged high-dose use, possible suppression of pancreatic islet function and glucosuria. Overdose may lead to altered renal excretion of ascorbic and uric acids during urine acidification, resulting in precipitation of oxalate stones.

Treatment is symptomatic: 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 and angioneurotic edema.

Nervous system disorders: headache, dizziness, tremor, psychomotor agitation, disorientation, restlessness, 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 system disorders: nephrotoxicity, interstitial nephritis, capillary necrosis, dysuria, urinary retention and difficulty in urination, renal colic, renal failure.

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

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

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 precautions for use"). Pyroglutamic acidemia may be triggered 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, 13 g per sachet, 1 sachet.

Oral solution powder, 13 g per 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.