Amicitron® plus

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMITRON® PLUS

Composition:

Active substances: paracetamol, guaifenesin, phenylephrine hydrochloride;

One sachet contains 500 mg of paracetamol, 200 mg of guaifenesin, and 10 mg of phenylephrine hydrochloride;

Excipients: sucrose, citric acid monohydrate, sodium citrate, potassium acesulfame, aspartame (E 951), natural lemon flavor.

Pharmaceutical form. Oral powder for solution.

Main physicochemical characteristics: white or almost white powder.

Pharmacotherapeutic group.

Analgesics and antipyretics. Anilides. Paracetamol combinations without psychotropic agents.

ATC code N02B E51.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol exerts its analgesic effect primarily by inhibiting prostaglandin synthesis in the central nervous system and, to a lesser extent, through peripheral action by blocking the transmission of pain impulses. The antipyretic mechanism involves action on the thermoregulatory center in the hypothalamus.

Guaifenesin is an expectorant that acts by increasing the volume and reducing the viscosity of tracheobronchial secretions, thereby facilitating the expulsion of mucus during coughing.

Phenylephrine is a sympathomimetic agent that primarily stimulates α-adrenergic receptors, resulting in vasoconstriction and reduction of edema in the nasal mucosa and paranasal sinuses.

The active substances do not exhibit sedative effects.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract. After oral administration, maximum plasma concentration is reached within 10–60 minutes. Approximately 95% of paracetamol is metabolized in the liver via three pathways: sulfation, glucuronidation, and oxidation by the cytochrome P450 system. It is excreted by the kidneys, primarily as metabolites, with 3% excreted unchanged. The mean elimination half-life is approximately 2.3 hours. Paracetamol crosses the placental barrier, and a small amount is excreted into breast milk.

Guaifenesin is rapidly absorbed in the gastrointestinal tract. After oral administration, maximum plasma concentration is achieved within 15 minutes. Guaifenesin is metabolized via oxidation to β-(2-methoxyphenoxy)lactic acid—an inactive metabolite excreted in urine. The elimination half-life is 1 hour.

Phenylephrine is irregularly absorbed in the gastrointestinal tract and undergoes presystemic metabolism by monoamine oxidase in the intestine and liver. As a result, orally administered phenylephrine has reduced bioavailability. Maximum plasma concentration is reached within 1–2 hours. The elimination half-life ranges from 2 to 3 hours. It is excreted in urine almost entirely as a sulfate conjugate.

Clinical characteristics.

Indications.

Treatment of symptoms of cold and flu: headache, body aches and pains, sore throat, nasal congestion, elevated body temperature, productive cough with difficult expectoration of sputum.

Contraindications.

Hypersensitivity to the active substances or to any of the components of the medicinal product. Severe cardiovascular diseases, arterial hypertension, blood disorders (including severe anemia, leukopenia), closed-angle glaucoma, diabetes mellitus, hyperthyroidism, benign prostatic hyperplasia with urinary retention, pheochromocytoma, hepatic dysfunction, acute hepatitis, pancreatitis, severe renal impairment, alcoholism, porphyria, congenital hyperbilirubinemia (including Gilbert’s syndrome), glucose-6-phosphate dehydrogenase deficiency, phenylketonuria, hereditary fructose intolerance, glucose-galactose malabsorption syndrome, sucrase-isomaltase deficiency. Pregnancy or breastfeeding. Children under 12 years of age.

Do not use concurrently with paracetamol-containing medicinal products, other sympathomimetics [such as vasoconstrictors (by any route of administration), appetite suppressants, amphetamine-like psychostimulants], β-adrenoblockers, tricyclic antidepressants; do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of their use.

Interaction with other medicinal products and other types of interactions.

Interactions related to paracetamol

Pharmacological interactions between paracetamol and other medicinal products have been reported. These interactions are considered unlikely to be clinically significant when the medicinal product is used according to the recommended dosage regimen.

The absorption rate of paracetamol may be increased when used with metoclopramide or domperidone, leading to an increase in the maximum plasma concentration of paracetamol. Absorption of paracetamol may be reduced when used concomitantly with cholestyramine, but this reduction is insignificant if cholestyramine is administered one hour after paracetamol. Antacids and food reduce paracetamol absorption. Probenecid inhibits the conjugation of paracetamol with glucuronic acid, resulting in a nearly twofold reduction in paracetamol clearance; therefore, the dose of paracetamol should be reduced when used concomitantly. Salicylates / acetylsalicylic acid may prolong the elimination half-life of paracetamol. Medicinal products that induce hepatic microsomal enzyme activity, such as anticonvulsants (including phenytoin, barbiturates, carbamazepine) and antituberculosis agents (including rifampicin), may enhance the hepatotoxic effects of paracetamol due to increased formation of hepatotoxic metabolites. Barbiturates reduce the antipyretic effect of paracetamol and may enhance its nephrotoxicity. Tetracycline increases the risk of anemia and methemoglobinemia induced by paracetamol. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs and increases the risk of paracetamol accumulation and overdose. Concurrent use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Concomitant use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of renal dysfunction. Hepato- and nephrotoxicity of paracetamol may be enhanced by prolonged or excessive alcohol consumption. Paracetamol may reduce the bioavailability of lamotrigine by inducing its hepatic metabolism, thereby reducing its efficacy. Paracetamol may prolong the elimination half-life of antibiotics, particularly chloramphenicol. Regular use of paracetamol may reduce zidovudine metabolism and increase the risk of neutropenia. The anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding, with long-term, regular daily use of paracetamol; occasional use does not show a significant effect. Paracetamol reduces the effectiveness of diuretics. Caution is recommended when using paracetamol in combination with flucloxacillin, as this combination has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidemia, especially in patients with risk factors (see section "Special precautions").

Interactions related to guaifenesin

Guaifenesin potentiates the effects of sedatives and muscle relaxants.

Guaifenesin may affect the results of urine laboratory tests (determination of 5-hydroxyindoleacetic acid, vanillylmandelic acid) for up to 24 hours after administration.

Interactions related to phenylephrine

The use of the medicinal product is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) (including moclobemide) and in patients who have received MAOIs within the previous 2 weeks. Phenylephrine may potentiate the effects of MAOIs and provoke a hypertensive crisis. Phenylephrine should not be used with theophylline, glucocorticoids, phenothiazine derivatives (e.g., promethazine), appetite suppressants, amphetamine-like psychostimulants, other central nervous system stimulants, α-adrenoblockers, and other antihypertensive agents, tricyclic antidepressants, or ergot alkaloids. Phenylephrine may reduce the effectiveness of β-adrenoblockers and other antihypertensive drugs (including debrisoquin, guanethidine, reserpine, methyldopa), increasing the risk of arterial hypertension and other cardiovascular side effects. In particular, concurrent use of phenylephrine with β-adrenoblockers may cause arterial hypertension and excessive bradycardia, possibly leading to cardiac block. Concurrent use of phenylephrine and other sympathomimetics may lead to additive stimulation of the central nervous system to an extremely high level, resulting in nervousness, irritability, and insomnia. Seizure attacks are also possible. In addition, concurrent use of other sympathomimetics with phenylephrine may enhance the cardiovascular effects (particularly vasoconstrictive effects) of either drug, potentially leading to hypertensive crisis or arrhythmias. The medicinal product Amicitron® Plus should not be used together with other vasoconstrictors (by any route of administration). The vasoconstrictive effect of phenylephrine may be enhanced when used concomitantly with labor stimulants. Concurrent use with halogenated anesthetics such as chloroform, cyclopropane, halothane, enflurane, or isoflurane may induce or worsen ventricular arrhythmias. Phenylephrine may cause severe arterial hypertension when combined with indomethacin or bromocriptine. Concurrent use of phenylephrine with tricyclic antidepressants (e.g., amitriptyline) increases the risk of cardiovascular side effects. Antidepressants, antiparkinsonian, and antipsychotic medicinal products, phenothiazine derivatives, increase the risk of urinary retention, dry mouth, and constipation. Concurrent use of phenylephrine and ergot alkaloids (ergotamine and methysergide) increases the risk of ergotism. Significant elevation of arterial pressure may occur with concurrent intravenous administration of ergot alkaloids. Phenylephrine should be used with caution with thyroid hormones. Concurrent use with medicinal products affecting cardiac conduction [cardiac glycosides (e.g., digoxin), antiarrhythmic agents] increases the risk of cardiac rhythm disturbances or myocardial infarction. There is a possibility that digitalis preparations may sensitize the myocardium to the effects of sympathomimetic agents. Conditions for which these drugs are prescribed are contraindications for the use of the medicinal product Amicitron® Plus. Concurrent use with medicinal products that promote potassium excretion, such as certain diuretics like furosemide, may enhance hypokalemia and reduce arterial sensitivity to vasopressor agents such as phenylephrine. Atropine sulfate blocks the reflex bradycardia caused by phenylephrine and increases the vasopressor response to phenylephrine. Rauwolfia alkaloids reduce the therapeutic effect of phenylephrine. Concurrent use of phenylephrine with linezolid is not recommended.

Special precautions for use.

Before using the medicinal product Amicitron® plus, consult a physician if cold and flu symptoms are accompanied by fever, rash, or prolonged headache. The medicinal product is recommended for use when all symptoms are present (pain and/or elevated temperature, nasal congestion, and chesty cough).

Due to the risk of overdose, the product should not be used concurrently with other cold remedies, decongestants, or paracetamol-containing medications. Prior to initiating treatment, ensure that medicinal products containing sympathomimetics are not being administered simultaneously via multiple routes (i.e., orally and locally, such as nasal, ear, or eye preparations). Do not use together with other antitussive medicinal products, particularly those that suppress cough reflex.

Consult a physician before using the medicinal product in patients with mild forms of arthritis who take analgesics daily, and in patients taking warfarin or similar anticoagulant agents. Concurrent use of paracetamol and zidovudine should be performed under medical supervision. The medicinal product should be used with caution in patients taking hepatotoxic medicinal products or cardiac glycosides (including digitalis preparations) (see section "Interaction with other medicinal products and other forms of interaction").

Consult a physician regarding the potential use of the medicinal product in patients with liver disorders, particularly non-cirrhotic alcoholic liver disease, and in patients who abuse alcohol, due to the increased risk of paracetamol-induced hepatotoxicity. Consult a physician before using the medicinal product in patients with cardiovascular disorders, occlusive vascular diseases (including Raynaud's phenomenon), kidney disorders (see section "Contraindications"), benign prostatic hyperplasia (due to possible urinary retention), persistent or chronic cough (caused by smoking, asthma, chronic bronchitis, or emphysema), bronchial asthma, chronic lung diseases, myasthenia gravis, severe gastrointestinal disorders, or glutathione system deficiency due to metabolic disturbances. Cases of hepatic dysfunction/failure have been reported in patients with reduced glutathione levels, such as those suffering from severe malnutrition, anorexia, low body mass index, alcohol dependence, or sepsis. 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. Seek immediate medical attention if these symptoms occur. Cases of high anion gap metabolic acidosis caused by 5-oxoproline (pyroglutamic acidemia) have been reported in critically ill patients, such as those with renal failure or sepsis, or in patients with malnutrition or other conditions associated with glutathione deficiency (e.g., alcoholism), who received paracetamol at therapeutic doses over a prolonged period or in combination with flucloxacillin. In suspected cases of high anion gap metabolic acidosis due to pyroglutamic acidemia, immediate discontinuation of paracetamol and close monitoring of the patient are recommended. 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.

Medicinal products containing sympathomimetics should be used with particular caution in patients with angina pectoris. These products may stimulate the central nervous system, leading to insomnia, nervousness, hyperpyrexia, tremor, and epileptiform seizures.

Paracetamol may affect laboratory test results for blood glucose and uric acid levels.

Do not take the medicinal product with alcohol.

Prolonged use of the medicinal product is not recommended.

If headache becomes persistent, consult a physician.

In case of overdose, seek immediate medical attention due to the risk of liver damage, even if the patient feels well.

Amicitron® plus contains sucrose. Patients with diagnosed intolerance to certain sugars should consult a physician before taking this medicinal product. The medicinal product must not be used in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency (see section "Contraindications").

One sachet of Amicitron® plus contains 5.1 mmol (or 117 mg) of sodium. Therefore, patients on a controlled-sodium diet should use this medicinal product with caution.

The medicinal product contains aspartame (E 951), a source of phenylalanine, which may be harmful to patients with phenylketonuria (see section "Contraindications").

Use during pregnancy or breastfeeding.

Do not use during pregnancy or breastfeeding due to insufficient data on the safety of the medicinal product.

Women should discontinue breastfeeding while using this medicinal product.

According to some data, fertility impairment in women may occur due to the effect of drugs that inhibit cyclooxygenase activity and prostaglandin synthesis, which is reversible and resolves after discontinuation of treatment. Since paracetamol inhibits prostaglandin synthesis, it may potentially affect fertility, although such cases have not been reported. Data on the effects of guaifenesin and phenylephrine on fertility are lacking or limited.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product may cause dizziness and slightly affect reaction speed. This should be taken into account when driving or operating machinery.

Dosage and Administration

The medicinal product should be taken orally as a solution.

Dissolve the contents of 1 sachet in 250 ml of hot water, but not boiling water. The prepared solution should be taken while warm.

Adults, elderly patients, children aged 12 years and older

1 sachet every 4–6 hours as needed. The minimum interval between doses should be 4 hours. Do not use more than 4 sachets within 24 hours.

Do not exceed the recommended doses.

The duration of treatment should be determined by a physician. The maximum duration of use without medical consultation is 3 days. If symptoms persist, medical advice should be sought.

Children.

The use of this medicinal product is contraindicated in children under 12 years of age.

Overdose.

In case of overdose, symptoms caused by paracetamol will be the most prominent. The risk of overdose is higher in elderly patients, children, patients with liver disease, alcoholics, and those with chronic malnutrition.

Paracetamol overdose

Paracetamol overdose may cause liver damage, which could lead to the need for liver transplantation or result in death.

If a patient has taken a dose exceeding the recommended amount, immediate medical attention is required due to the risk of liver damage. It is believed that an excess amount of the toxic metabolite of paracetamol (normally neutralized by glutathione when standard doses are used) irreversibly binds to liver tissue. Liver damage is possible in adults who have ingested 10 g or more of paracetamol and in children who have ingested more than 150 mg/kg body weight. Ingestion of 5 g or more of paracetamol may lead to liver damage in patients with risk factors such as long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs that induce liver enzymes; chronic excessive alcohol consumption; glutathione system deficiency, e.g., eating disorders, HIV infection, fasting, cystic fibrosis, cachexia.

Symptoms within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain. Clinical signs of overdose may not be apparent. Liver damage may become evident 12–48 hours after ingestion of an excessive dose. Glucose metabolism disturbances and metabolic acidosis may occur. Increased levels of liver transaminases (aspartate aminotransferase, alanine aminotransferase), lactate dehydrogenase, and bilirubin may be observed, along with decreased prothrombin levels. Paracetamol overdose may cause hepatocellular necrosis. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage, presenting as severe back pain, hematuria, and proteinuria. Cases of cardiac arrhythmia and pancreatitis have been reported.

After ingestion of large doses, central nervous system effects may include dizziness, psychomotor agitation, disorientation, and sleep disturbances; urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis); gastrointestinal tract effects may include hepatonecrosis. With prolonged use of high-dose paracetamol, hematological effects may include aplastic anemia, pancytopenia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia. Paracetamol overdose, including high cumulative doses taken over prolonged therapy, may lead to analgesic-induced nephropathy with irreversible liver function impairment.

Treatment. Immediate treatment of paracetamol overdose is essential, even if no symptoms are present. Despite the absence of severe early symptoms, the patient should be immediately hospitalized for emergency medical care. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be considered within 1 hour of paracetamol overdose. Plasma paracetamol concentration should be measured 4 hours or later after overdose (earlier concentrations are unreliable). Administration of SH-group donors and glutathione synthesis precursors (such as methionine, N-acetylcysteine) intravenously is recommended, with doses determined based on blood paracetamol concentration and time elapsed since ingestion. N-acetylcysteine treatment may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases sharply after this time. If necessary, N-acetylcysteine should be administered intravenously according to current guidelines. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings. Symptomatic treatment is also required.

Guaifenesin overdose

Mild or moderate overdose may cause dizziness, gastrointestinal disturbances (including nausea, vomiting), and reduced muscle tone. Very high doses may cause symptoms such as agitation, confusion, and respiratory depression.

Treatment: symptomatic measures, including gastric lavage, and general supportive care.

Phenylephrine overdose

The dose of the medicinal product that may cause serious toxic effects of phenylephrine is higher than the dose causing toxic effects of paracetamol.

Overdose may intensify adverse reactions, especially with prolonged use. Possible effects include increased blood pressure and associated reflex bradycardia and arrhythmia; arterial hypotension, chest pain and discomfort, palpitations, dyspnea, non-cardiogenic pulmonary edema; drowsiness followed by excitation (especially in children), sleep disturbances (including insomnia), seizures, headache, tremor, visual disturbances, dizziness, weakness, restlessness, anxiety, nervousness, irritability, inappropriate behavior, psychosis with hallucinations, confusion, anorexia, nausea, vomiting, oliguria, urinary retention, painful or difficult urination, hyperpyrexia, facial flushing, cold sensation in extremities, paresthesia, pallor, skin rash, piloerection, increased sweating, hyperglycemia, hypokalemia, pancytopenia, thrombocytopenia, agranulocytosis, leukopenia, peripheral vasoconstriction, reduced blood flow to vital organs, potentially worsening renal perfusion, metabolic acidosis, and increased cardiac workload due to elevated systemic vascular resistance; coma is possible. Severe overdose symptoms include severe peripheral and visceral vasoconstriction with cardiovascular collapse. Severe consequences of vasoconstriction are more likely in patients with hypovolemia and severe bradycardia.

Treatment: early gastric lavage, symptomatic and supportive measures, use of α-adrenergic blockers such as phentolamine in cases of severe arterial hypertension; atropine may be used in case of bradycardia (preferably after blood pressure control); diazepam may be used in case of seizures.

Side effects

Nervous system disorders (usually occur with high-dose administration): headache, tremor, insomnia, dizziness, disorientation, impaired consciousness, psychomotor agitation, nervousness, irritability, anxiety, restlessness.

Eye disorders: photophobia, mydriasis, acute angle-closure glaucoma (most commonly occurring in patients with pre-existing angle-closure glaucoma).

Cardiovascular system disorders: tachycardia, bradycardia, chest pain, dyspnea, arrhythmia, increased blood pressure, palpitations.

Blood and lymphatic system disorders: anemia, hemolytic anemia, sulfhemoglobinemia, and methemoglobinemia (manifested as cyanosis, dyspnea, chest pain). With prolonged use at doses exceeding therapeutic levels: aplastic anemia, pancytopenia, leukopenia, neutropenia, agranulocytosis; thrombocytopenia, which may lead to nosebleeds and/or gum bleeding, bruising, or hemorrhages.

Gastrointestinal disorders: gastrointestinal discomfort, loss of appetite, epigastric pain, nausea, vomiting, diarrhea, acute pancreatitis.

Hepatobiliary disorders: liver function abnormalities, increased serum liver enzyme activity, usually without development of jaundice; hepatonecrosis (a dose-dependent effect).

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

Endocrine system disorders: hypoglycemia; hypoglycemic coma may develop.

Renal and urinary disorders: dysuria, urinary retention or difficulty in urination (most commonly in patients with bladder outlet obstruction, particularly with prostate hyperplasia), renal colic, sterile pyuria. Rare cases of bladder or kidney stones have been reported in patients who have taken high doses of guaifenesin for prolonged periods. Isolated cases of interstitial nephritis have been reported following prolonged use of high-dose paracetamol.

Respiratory system disorders: dyspnea, bronchospasm. Cases of bronchospasm with paracetamol use have been reported, occurring more frequently in patients with bronchial asthma sensitive to acetylsalicylic acid and other NSAIDs.

Skin and subcutaneous tissue disorders: hypersensitivity reactions, including pruritus, skin and mucosal rashes (typically generalized rash, erythematous rash, urticaria, allergic dermatitis), angioneurotic edema, multiform exudative erythema (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome); cross-reactivity with other sympathomimetics is possible.

Immune system disorders: anaphylaxis.

Description of selected side effects

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap, caused by 5-oxoproline (pyroglutamic acid) accumulation, have been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidemia may result from low glutathione levels in these patients.

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:

5 g powder in sachets; 10 sachets per pack.

Pharmaceutical category: Over-the-counter (without prescription).

Manufacturer:

Interkhim Limited Liability Company.

Manufacturer's address and location of business activity:

40-A, 21st km of Staryokyivska Road, Odessa, 65025, Ukraine.