Amicitron® forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRON® FORTE

Composition:

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

1 sachet contains 650 mg of paracetamol, 10 mg of phenylephrine hydrochloride, 20 mg of pheniramine maleate, 50 mg of ascorbic acid;

Excipients: sucrose, colouring agent Yellow FCF (E 110), citric acid monohydrate, sodium citrate, natural lemon flavouring.

Pharmaceutical form. Powder for oral solution.

Main physicochemical characteristics: 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 transmission of pain impulses.

Phenylephrine is an α-adrenomimetic agent that produces vasoconstrictive action, reducing mucosal edema of the nasal cavity and paranasal sinuses.

Pheniramine is a histamine H1-receptor antagonist that reduces vascular permeability and relieves 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, and to a minor extent passes into breast milk. It 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, and excreted by the kidneys.

Pheniramine is well absorbed from the gastrointestinal tract, metabolized in the liver via the cytochrome P450 system, with a half-life of 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, rhinorrhea, 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 hyperbilirubinemias, 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, states of increased excitation, sleep disturbances, concomitant therapy with β-blockers, other sympathomimetics, appetite suppressants or 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 half-life of chloramphenicol; may induce hepatic metabolism of lamotrigine, thereby reducing its bioavailability and efficacy. Paracetamol may interfere with the determination of uric acid levels by the phosphotungstic acid method.

The risk of paracetamol hepatotoxicity increases with concomitant use of isoniazid and drugs that induce hepatic microsomal enzymes [barbiturates; anticonvulsants (phenytoin, phenobarbital, carbamazepine); rifampicin]. Hepatotoxic drugs 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 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 MAO inhibitors causes a hypertensive effect; with tricyclic antidepressants (including amitriptyline) increases the risk of cardiovascular adverse effects; with cardiac glycosides (including digoxin) may lead to arrhythmias and myocardial infarction; 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). Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methysergide) may increase the risk of ergotism.

Pheniramine potentiates the anticholinergic effects of atropine, antispasmodics, tricyclic antidepressants, and antiparkinsonian drugs; it inhibits the action of anticoagulants. Concurrent use of pheniramine with anesthetics, hypnotics and sedatives (including barbiturates), neuroleptics, tranquilizers, narcotic analgesics, and alcohol may significantly enhance its central nervous system depressant effects.

Ascorbic acid, when taken orally, enhances iron absorption, increases ethinylestradiol and penicillin and tetracycline levels, reduces blood levels of antipsychotic drugs (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 only 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, especially in the myocardium, potentially leading to cardiac decompensation. Prolonged high-dose use 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.

Amictron® forte contains sucrose; therefore, this medicinal product should not be used in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

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

The risk of hepatotoxicity is increased in patients with alcoholic liver disease or 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 Amictron® forte.

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. Immediate medical attention should be sought if these symptoms occur.

Cases of high anion gap metabolic acidosis caused by 5-oxoproline (pyroglutamic acidemia) have been reported in patients with severe conditions such as renal failure and sepsis, or in patients with malnutrition or other states associated with glutathione deficiency (e.g., alcoholism), who received paracetamol at therapeutic doses for prolonged periods 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 close 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 trigger angina attacks. Use with caution in patients with arterial hypertension, heart disease, arrhythmias, bradycardia (see section "Contraindications"), Raynaud's disease, benign prostatic hyperplasia (due to risk of urinary retention) (see section "Contraindications"), thyroid disorders (see section "Containdications"), liver disease (including acute hepatitis) and kidney disease (see section "Contraindications"), glaucoma (see section "Contraindications"), chronic lung diseases, hypercoagulability, chronic undernutrition, dehydration, stenosing peptic ulcer, and in elderly patients. Use with particular caution in patients with iron metabolism disorders (hemochromatosis, hemochromatosis, thalassemia), and in patients 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 Amictron® forte contains 3.5 mmol (80 mg) of sodium; therefore, patients on a sodium-restricted diet should use this product with caution. The 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. Occult blood testing in feces 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, medical advice should be sought, 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.

Ability to affect reaction speed when driving or operating machinery.

Driving vehicles or operating complex machinery is not recommended during treatment with Amictron® forte, as the 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 use 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 after paracetamol overdose, symptoms may include pallor, nausea, vomiting, loss of appetite, and abdominal pain. 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 also occur. With prolonged use of paracetamol in high doses, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, neutropenia, and thrombocytopenia may develop. In isolated cases, acute renal failure with tubular necrosis has been reported, even in the absence of severe liver damage; this condition is characterized by severe lumbar pain, hematuria, and proteinuria. Nephrotoxicity is possible: renal colic, interstitial nephritis, and capillary necrosis.

Ingestion of paracetamol by a child at a dose exceeding 150 mg/kg body weight, or ingestion of 10 g or more by an adult—especially with concomitant alcohol use—may lead to hepatocellular necrosis, resulting in encephalopathy, hemorrhages, hypoglycemia, hepatic coma, and potentially 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 result in liver damage.

In case of overdose, immediate medical assistance is required. The patient should be taken to hospital immediately, even if no early symptoms of overdose are present. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. If an excessive dose of paracetamol was taken less than 1 hour ago, activated charcoal should be administered. Paracetamol plasma concentration should be measured 4 hours or later 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 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.

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. For management of hypertensive effects, intravenous α-receptor blockers may be used; for seizures—diazepam.

Pheniramine overdose

Anticholinergic (atropine-like) symptoms occur: 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 parasympatholytic effect of pheniramine and the sympathomimetic effect of phenylephrine include drowsiness with possible subsequent development of excitation (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 cardiovascular and respiratory systems. CNS stimulants are contraindicated; vasoconstrictors may be used to treat arterial hypotension.

Ascorbic acid overdose

Symptoms include nausea, vomiting, or diarrhea (which resolve after discontinuation); abdominal distension and pain, pruritus, skin rashes, and increased excitability. Doses exceeding 3000 mg may cause transient osmotic diarrhea and gastrointestinal disturbances, disturbances in zinc and copper metabolism, and myocardial dystrophy. With prolonged high-dose use, suppression of pancreatic islet function and glucosuria may occur. Overdose may alter renal excretion of ascorbic and uric acids during urine acidification, leading to 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 exudativum, 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 development of jaundice), hepatonecrosis (with high-dose administration).

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

Endocrine disorders: hypoglycemia, up to hypoglycemic coma.

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

Cardiovascular 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 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 precautions"). Pyroglutamic acidemia may be caused by low glutathione levels in these patients.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Oral solution powder, 23 g in sachet, 1 sachet per pack.

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

Dispensing category. Over-the-counter.

Manufacturer.

Limited liability company "INTERCHEM".

Manufacturer's address and place of business.

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