Tricold mix®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRICOLD MIX® (TRICOLD MIX®)

Composition:

Active substances: paracetamol, phenylephrine hydrochloride, ascorbic acid;

1 sachet contains 750 mg of paracetamol, 10 mg of phenylephrine hydrochloride, and 60 mg of ascorbic acid (calculated as ascorbic acid);

Excipients: sucrose, sodium saccharin, povidone, anhydrous citric acid, sodium citrate, pregelatinized starch, quinoline yellow (E 104), lemon flavoring.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: Granular powder from light yellow to yellow in color with inclusion of white granules of various shapes, lemon-flavored.

Pharmacotherapeutic group. Analgesics and antipyretics. Paracetamol combinations without psychotropic agents. ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Trikold Mix**®** is a combined medicinal product, whose action is determined by the components included in its composition.

Paracetamol exerts analgesic and antipyretic effects. It can inhibit the synthesis of prostaglandins by suppressing cyclooxygenase of arachidonic acid in the central nervous system (CNS). As a result, the sensitivity of the CNS to the action of kinins and serotonin is reduced, leading to decreased pain perception. In addition, a reduction in prostaglandin concentration in the hypothalamus produces an antipyretic effect. Paracetamol does not affect platelet aggregation.

Phenylephrine hydrochloride belongs to sympathomimetic amines and primarily acts directly on adrenergic receptors, predominantly affecting α-adrenergic receptors, which leads to a reduction in nasal mucosal hyperemia.

Ascorbic acid (vitamin C) is an essential vitamin, deficiency of which may occur at the onset of acute viral infections.

The sedative effect of the active substances of the medicinal product has not been established.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed in the gastrointestinal tract and evenly distributed throughout all body fluids. The rate of absorption decreases when paracetamol is taken with food. At therapeutic doses, paracetamol is only minimally bound to plasma proteins. The drug is metabolized in the liver and is almost completely excreted in the urine, primarily as glucuronide and sulfate conjugates.

A potentially hepatotoxic intermediate metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is formed in small amounts (~5%), is eliminated after conjugation with glutathione as cysteine or mercapturic acid. When large doses of paracetamol are administered, glutathione stores in the liver become depleted, leading to the accumulation of toxic metabolites in the liver. This may result in hepatocyte damage, their death, and acute liver failure.

Less than 5% of the administered paracetamol dose is excreted unchanged.

The average elimination half-life of paracetamol ranges from 1 to 4 hours.

Patients with impaired liver function. The elimination half-life of paracetamol in individuals with compensated liver insufficiency is the same as in healthy individuals. In cases of severe liver failure, the elimination half-life of paracetamol may be prolonged. The clinical significance of prolonged paracetamol half-life in patients with liver disease is unknown. However, accumulation, hepatotoxicity, or impaired conjugation with glutathione have not been observed.

Patients with impaired kidney function. Over 90% of a therapeutic dose of paracetamol is usually excreted in the urine as metabolites within 24 hours. In patients with chronic renal failure, the ability to excrete polar metabolites is limited, which may lead to their accumulation. Patients with chronic renal failure are advised to increase the interval between doses of paracetamol.

Ascorbic acid (vitamin C) is rapidly absorbed in the gastrointestinal tract and delivered to all body tissues; 25% is bound to plasma proteins. Excess ascorbic acid exceeding the body's requirements is excreted in the urine as metabolites.

Phenylephrine hydrochloride is easily and rapidly absorbed in the gastrointestinal tract. It undergoes first-pass metabolism by monoamine oxidase in the intestine and liver, with a bioavailability of approximately 40%. Maximum plasma concentration is reached within 1–2 hours. The elimination half-life ranges from 2 to 3 hours. It is primarily excreted in the urine as sulfates.

Clinical characteristics.

Indications.

For short-term relief of symptoms of colds and influenza, including headache, fever, nasal congestion, sinusitis and associated pain, sore throat, and body aches.

Contraindications.

• Hypersensitivity to any component of the medicinal product;
• arterial hypertension, severe cardiovascular insufficiency, severe forms of: atherosclerosis, ischemic heart disease;
• severe hepatic dysfunction, congenital hyperbilirubinemia;
• severe renal dysfunction, benign prostatic hyperplasia;
• blood disorders (including severe anemia, leukopenia), glucose-6-phosphate dehydrogenase deficiency, thrombosis, thrombophlebitis;
• sleep disorders, states of increased excitation, epilepsy;
• alcoholism;
• acute pancreatitis;
• diabetes mellitus, hyperthyroidism, pheochromocytoma;
• closed-angle glaucoma.
• Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs, tricyclic antidepressants, beta-blockers, other antihypertensive agents, or sympathomimetics.

Interaction with other medicinal products and other types of interactions.

Concomitant use with other medicinal products containing paracetamol or other active ingredients present in Trikold Mix® should be avoided.

Interactions of the medicinal product are determined by properties of its components.

Paracetamol.

The absorption rate of paracetamol may be increased when used concomitantly with metoclopramide and domperidone, and decreased with cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding, during long-term regular daily use of paracetamol. These interactions are not clinically significant when paracetamol is used short-term according to the recommended dosage regimen.

Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites.

Concomitant use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Paracetamol reduces the efficacy of diuretics. Do not use concomitantly with alcohol.

Phenylephrine hydrochloride.

Interaction of phenylephrine with monoamine oxidase inhibitors (MAOIs) causes a hypertensive effect; with tricyclic antidepressants (e.g., amitriptyline) — increases the risk of cardiovascular adverse effects; with digoxin and cardiac glycosides — may lead to arrhythmias or myocardial infarction. Phenylephrine combined with other sympathomimetics increases the risk of cardiovascular side effects. Phenylephrine may reduce the effectiveness of beta-blockers and other antihypertensive agents (including debrisoquin, guanethidine, reserpine, methyldopa), increasing the risk of arterial hypertension and other cardiovascular adverse reactions.

Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methysergide) increases the risk of ergotism. Alkaloids of Rauwolfia reduce the therapeutic effect of phenylephrine hydrochloride. Alpha-adrenergic blockers (phentolamine), phenothiazines, furosemide, and other diuretics counteract vasoconstriction.

Ascorbic acid (vitamin C).

Oral ascorbic acid enhances the absorption of penicillin and iron, reduces the effectiveness of heparin and indirect anticoagulants, and increases the risk of crystalluria during salicylate therapy. Antidepressants, antiparkinsonian and antipsychotic agents, phenothiazine derivatives increase the risk of urinary retention, dry mouth, constipation. Glucocorticoids increase the risk of glaucoma.

Absorption of vitamin C is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, and alkaline beverages. Concurrent intake of vitamin C and deferoxamine increases tissue toxicity of iron, especially in the myocardium, which may lead to circulatory decompensation. Ascorbic acid should be taken only 2 hours after deferoxamine injection. Prolonged use of high doses in patients treated with disulfiram inhibits the disulfiram-alcohol reaction. High doses of the drug reduce the effectiveness of tricyclic antidepressants. High doses of the medicinal product reduce the efficacy of neuroleptics — phenothiazine derivatives, tubular reabsorption of amphetamine, impair renal excretion of mexiletine, affect vitamin B12 resorption. Orally administered ascorbic acid promotes intestinal absorption of aluminum, which should be considered during concomitant treatment with aluminum-containing antacids.

Floxapen (flucloxacillin).

Caution is advised when using paracetamol and flucloxacillin concomitantly, as their combined use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients at risk (see "Special precautions").

Special precautions for use.

Before using the medicinal product, consult a physician.

Do not exceed the recommended doses.

Contains paracetamol. Avoid concomitant use with other medications for symptomatic treatment of cold and flu, vasoconstrictor agents for treatment of rhinitis, or medicinal products containing paracetamol. Concurrent use with other paracetamol-containing medications may lead to overdose. Paracetamol overdose may cause liver failure, which may necessitate liver transplantation or result in fatal outcome. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease. Avoid alcohol consumption during the treatment course.

Note that patients with alcoholic liver damage have an increased risk of hepatotoxic effects of paracetamol; the drug may affect laboratory test results for blood glucose and uric acid levels.

Consult a physician regarding the possibility of using the drug in patients with impaired kidney or liver function.

Cases of liver dysfunction/failure have been reported in patients with reduced glutathione levels, for example in patients who are severely malnourished, suffer from anorexia, have a low body mass index, or suffer from chronic alcohol dependence or sepsis.

Patients who take analgesics daily for mild forms of arthritis should consult a physician.

Before using the drug, individuals taking warfarin or similar anticoagulant agents, those with Raynaud's disease (which may manifest as pain in fingers and toes in response to cold or stress), hypertension, cardiovascular diseases, or impaired liver and kidney function should consult a physician.

Use the drug with caution in individuals predisposed to increased blood pressure and in patients with bronchial asthma.

This medicinal product contains phenylephrine, which may provoke angina attacks.

Do not use in patients taking other sympathomimetics (e.g., decongestants, appetite suppressants, or amphetamine-type psychostimulants). Use with caution in patients taking digoxin, cardiac glycosides, or ergot alkaloids (e.g., ergotamine, methysergide).

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

If the drug is used for a prolonged period as directed by a physician, monitoring of liver function and peripheral blood should be performed.

In patients with severe infections such as sepsis, which are accompanied by reduced glutathione levels, the risk of developing metabolic acidosis increases during paracetamol use. 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.

Patients should consult a physician if symptoms persist for more than 5 days, worsen, or are accompanied by high fever, skin rash, or persistent headache.

Keep the medicinal product out of sight and reach of children.

Excipients.

The medicinal product contains sucrose. If the patient has been diagnosed with intolerance to certain sugars, consult a physician before taking this medicinal product.

TriCold Mix**®** contains quinoline yellow (E 104), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The use of this medicinal product is contraindicated during pregnancy and breastfeeding.

Paracetamol and phenylephrine may be excreted in breast milk; therefore, if use of the drug is necessary, breastfeeding should be discontinued.

Effect on ability to drive or operate machinery.

The drug may affect the ability to drive or operate machinery if certain adverse effects, such as dizziness, occur.

Method of Administration and Dosage

The medicinal product is intended for oral administration. Empty the contents of 1 sachet into a glass and add hot water (but not boiling water). Stir until completely dissolved. If necessary, add cold water. Take while warm.

Adults and children aged 12 years and older: single dose — 1 sachet. The contents of 1 sachet should be taken every 4–6 hours as needed. The minimum interval between doses should be 4 hours. Maximum daily dose — 5 sachets. Do not use the medicinal product for more than 5 days without consulting a physician.

Do not exceed the recommended doses. Use the lowest effective dose for the shortest duration necessary to achieve the desired effect.

Children.

The medicinal product is not recommended for children under 12 years of age.

Overdose.

Symptoms related to paracetamol.

Overdose is generally caused by paracetamol and manifests as pallor, anorexia, nausea, vomiting, abdominal pain, hepatonecrosis, elevated liver transaminase activity, and increased prothrombin index.

Liver damage may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. 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 deficiency (digestive disorders, cystic fibrosis, HIV infection, malnutrition, cachexia)], liver damage may occur after ingestion of 5 g or more of paracetamol.

Symptoms of liver damage appear within 12–48 hours after overdose and may peak within 4–6 days. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress and lead to toxic encephalopathy with impaired consciousness, hemorrhages, hypoglycemia, coma, and in some cases, necessitate liver transplantation or result in death. Acute kidney injury with acute tubular necrosis may present as severe back pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have also been reported.

With prolonged use of the drug at high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. Ingestion of large doses may cause dizziness, psychomotor agitation, and disorientation due to central nervous system effects; nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis) may occur due to effects on the urinary system.

Treatment: in case of paracetamol overdose, prompt medical attention is required, even if no symptoms are apparent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Gastric lavage should be performed, activated charcoal administered (within 1 hour of overdose), and symptomatic therapy provided. Administration of paracetamol antidotes — intravenous N-acetylcysteine and oral methionine — may be effective within 24 hours after overdose.

Symptoms related to phenylephrine hydrochloride.

Overdose due to phenylephrine may cause effects similar to those listed in the section "Adverse Reactions." Other symptoms may include irritability, restlessness, hypertension, and reflex bradycardia. In severe cases, confusion, hallucinations, seizures, and arrhythmias may occur. However, the amount of drug required to cause serious phenylephrine toxicity is greater than the amount that would cause hepatotoxic effects from paracetamol.

Treatment: in case of overdose, gastric lavage, administration of activated charcoal, symptomatic therapy, and use of alpha-blockers such as phentolamine in cases of severe hypertension are indicated.

Symptoms related to ascorbic acid.

Overdose due to ascorbic acid may manifest as nausea, vomiting, bloating and abdominal pain, itching, skin rash, and increased excitability. High doses of ascorbic acid (over 3000 mg) may cause transient osmotic diarrhea and gastrointestinal disturbances, disturbances in zinc and copper metabolism, glucosuria, crystalluria, and kidney stone formation. The consequences of ascorbic acid overdose may be mistaken for those caused by severe liver damage due to paracetamol overdose.

Side effects.

Skin and subcutaneous tissue disorders: skin and mucosal rashes (usually erythematous, urticaria), pruritus, allergic dermatitis, erythema multiforme including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), purpura, hemorrhages.

Immune system disorders: hypersensitivity reactions, allergic reactions (including angioneurotic edema), anaphylaxis, anaphylactic shock.

Psychiatric disorders: psychomotor agitation and disorientation, restlessness, nervousness, fear, irritability, anxiety, sleep disturbances, insomnia, drowsiness, sedative state, confusion, depression, hallucinations, impaired concentration the following day, especially with insufficient sleep after taking the medication.

Nervous system disorders: headache, dizziness, tremor, paresthesia, nervous excitement, general weakness.

Ear and labyrinth disorders: tinnitus, vertigo.

Eye disorders: mydriasis, visual disturbances and accommodation disorders, increased intraocular pressure, acute angle-closure glaucoma (more common in patients with glaucoma).

Gastrointestinal disorders: nausea, vomiting, abdominal discomfort and pain, heartburn, decreased appetite, constipation, diarrhea, flatulence, dry mouth, oral mucosal ulcers, hypersalivation, hemorrhages.

Metabolism and nutrition disorders: frequency unknown – metabolic acidosis with high anion gap.

Hepatobiliary disorders: increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), liver function impairment, hepatic failure.

Endocrine disorders: hypoglycemia, up to hypoglycemic coma.

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

Renal and urinary disorders: (with high-dose use) urinary disorders, urinary retention (more likely in patients with prostatic hyperplasia), nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), oliguria, aseptic pyuria.

Cardiac disorders: arterial hypertension, chest pain, tachycardia, sinus tachycardia, dyspnea, edema, reflex bradycardia.

Respiratory, thoracic and mediastinal disorders: bronchospasm in patients sensitive to aspirin and other nonsteroidal anti-inflammatory drugs.

Other: general weakness, fever, glucosuria, disturbances in zinc and copper metabolism.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap, resulting from pyroglutamic acidosis, have been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Reporting of suspected adverse reactions.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

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.

5 g per sachet. Packs of 5, 10, or 20 sachets in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

Kusum Healthcare Pvt Ltd /
Kusum Healthcare Pvt Ltd.

Manufacturer's address.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India /
Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.

Marketing Authorization Holder.

Amaxa Ltd /
Amaxa Ltd.

Address of the Marketing Authorization Holder.

31 John Islip Street, London SW1P 4FE, United Kingdom /
31 John Islip Street, London SW1P 4FE, United Kingdom.