Tricolde mix®

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

Composition:

Active substances: paracetamol, phenylephrine hydrochloride, ascorbic acid;

One sachet contains: paracetamol 750 mg, phenylephrine hydrochloride 10 mg, ascorbic acid (coated, calculated as ascorbic acid) 60 mg;

Excipients: sucrose, sodium saccharin, povidone, anhydrous citric acid, sodium citrate, pregelatinized starch, Ponceau 4R (E 124), strawberry flavoring.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: Granular powder ranging from light pink to pink in color, containing white granules of various shapes, with a strawberry taste.

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

Pharmacological properties.

Pharmacodynamics.

Trikold Mix**®** is a combined medicinal product, whose action is determined by its constituent components.

Paracetamol exerts analgesic and antipyretic effects. It inhibits 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. Additionally, reduced prostaglandin concentrations in the hypothalamus produce an antipyretic effect. Paracetamol does not affect platelet aggregation.

Phenylephrine hydrochloride belongs to sympathomimetic amines and primarily acts directly on adrenergic receptors, predominantly α-adrenergic receptors, resulting in reduced 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 from the gastrointestinal tract and evenly distributed throughout all body fluids. The rate of absorption is reduced 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), formed in small amounts (~5%), is eliminated after conjugation with glutathione via cysteine or mercapturic acid. When large doses of paracetamol are administered, glutathione reserves in the liver become depleted, leading to accumulation of toxic metabolites in the liver. This may result in hepatocyte damage, cell 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 hepatic impairment. The elimination half-life of paracetamol in individuals with compensated liver insufficiency is similar to that in healthy individuals. In cases of severe hepatic impairment, 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, no accumulation, hepatotoxicity, or impaired conjugation with glutathione has been observed.

Patients with renal impairment. 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, potentially leading 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 readily and rapidly absorbed in the gastrointestinal tract. It undergoes first-pass metabolism by monoamine oxidase in the intestine and liver, resulting in a bioavailability of approximately 40%. Maximum plasma concentration is reached within 1–2 hours. The elimination half-life is 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 flu, including headache, fever, nasal congestion, sinusitis and associated pain, sore throat, and body aches.

Contraindications.

• Hypersensitivity to any component of the drug;
• arterial hypertension, severe cardiovascular insufficiency, severe forms of atherosclerosis, ischemic heart disease;
• severe impairment of liver function, congenital hyperbilirubinemia;
• severe impairment of kidney function, prostatic hypertrophy;
• 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 drugs, or sympathomimetics.

Interaction with other medicinal products and other forms of interaction.

Avoid concomitant use with other medicinal products containing paracetamol or other active ingredients present in TriCold Mix®.

Interactions of the drug are determined by the 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 formation of hepatotoxic metabolites.

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

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

Phenylephrine hydrochloride.

Interaction of phenylephrine with monoamine oxidase inhibitors (MAOIs) may cause a hypertensive effect; with tricyclic antidepressants (e.g., amitriptyline) — increases the risk of cardiovascular adverse effects; with digoxin and cardiac glycosides — may lead to arrhythmia or myocardial infarction. Phenylephrine combined with other sympathomimetics increases the risk of cardiovascular adverse reactions. 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 side effects.

Concomitant use of phenylephrine with ergot alkaloids (ergotamine, 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, and 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 drinks. Concurrent intake of vitamin C and deferoxamine increases tissue iron toxicity, especially in the myocardium, potentially leading 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 drug reduce the effectiveness of phenothiazine-derived neuroleptics, amphetamine tubular reabsorption, impair renal excretion of mexiletine, affect vitamin B12 resorption. Orally administered ascorbic acid promotes intestinal absorption of aluminum, which should be considered when treating concomitantly with aluminum-containing antacids.

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

Note that patients with alcoholic liver disease 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, such as those suffering from severe malnutrition, anorexia, low body mass index, 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 this medicinal product with caution in individuals predisposed to increased blood pressure or suffering from 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) treated with paracetamol at therapeutic doses over a prolonged period 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 long-term as directed by a physician, monitoring of liver function and peripheral blood counts is necessary.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the risk of developing metabolic acidosis is increased during paracetamol use. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention 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 a patient has been diagnosed with intolerance to certain sugars, consult a physician before taking this medicinal product.

TriCold Mix**®** contains Ponceau 4R (E 124), 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 medicinal product is necessary, breastfeeding should be discontinued.

Effect on ability to drive and use machinery.

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

Dosage and Administration.

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 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 at least 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. The lowest effective dose should be used 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 due to 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 depletion (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 typically appear 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, leading to toxic encephalopathy with impaired consciousness, hemorrhage, hypoglycemia, coma, and in some cases, the need for liver transplantation or 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 in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. High-dose intake may cause dizziness, psychomotor agitation, and disorientation in the central nervous system. In the urinary system, nephrotoxicity may occur (renal colic, interstitial nephritis, capillary necrosis).

Treatment: Immediate medical attention is required in case of paracetamol overdose, even if no symptoms are present. Symptoms such as nausea and vomiting may be mild and do not necessarily reflect the severity of overdose or risk of organ damage. Gastric lavage should be performed, activated charcoal should be administered (within 1 hour of overdose), and symptomatic therapy initiated. Antidotes for paracetamol—N-acetylcysteine (intravenous) and methionine (oral)—are effective if administered within 24 hours of overdose.

Symptoms related to phenylephrine hydrochloride.

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

Treatment: In case of overdose, gastric lavage, activated charcoal, symptomatic therapy, and 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.

Adverse Reactions

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, somnolence, 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 and accommodation disturbances, increased intraocular pressure, acute angle-closure glaucoma (more frequently 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 intake) impaired urination, urinary retention (more likely in patients with prostatic hyperplasia), nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), oliguria, aseptic pyuria.

Cardiovascular disorders: Arterial hypertension, chest pain, tachycardia, palpitations, 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 specific adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors taking 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 suspected adverse reactions after a medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via 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 in sachets. 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 and location.

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 Marketing Authorization Holder.

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