Flucold® sachet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCOLD® SACHET (FLUCOLD® SACHET)

Composition:

Active substances: paracetamol, ascorbic acid, phenylephrine hydrochloride;

One 5 g sachet contains: paracetamol 750 mg, phenylephrine hydrochloride 10 mg,
ascorbic acid coated granules 60 mg;

Excipients: mannitol (E 421), anhydrous lactose, aspartame (E 951), starch, anhydrous citric acid, sodium citrate, lemon flavor, quinoline yellow (E 104), calcium gluconate.

Pharmaceutical form. Oral soluble powder with lemon flavor.

Main physicochemical properties: pale yellow powder.

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

Pharmacological properties.

Pharmacodynamics.

Paracetamol exerts analgesic and antipyretic effects. It has the ability to inhibit the synthesis of prostaglandins by suppressing cyclooxygenase of arachidonic acid in the central nervous system (CNS). As a result, 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 may occur at the onset of acute viral infections.

Sedative effects of the active ingredients of the drug have 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 is reduced when paracetamol is taken with food. At therapeutic doses, paracetamol binds only slightly to plasma proteins. The drug is metabolized in the liver and is almost completely excreted in urine, mainly as glucuronide and sulfate conjugates.

A potentially hepatotoxic intermediate metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is formed in small amounts (~5%), is eliminated via conjugation with glutathione and excreted as cysteine or mercapturic acid conjugates. 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 dose of paracetamol 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 patients with compensated liver insufficiency is similar to that in healthy individuals. In cases of severe liver failure, the elimination half-life of paracetamol may be prolonged. The clinical significance of prolonged half-life in patients with liver disease is unknown. However, no accumulation, hepatotoxicity, or impaired conjugation with glutathione has been observed.

Patients with impaired renal function. Over 90% of a therapeutic dose of paracetamol is usually excreted in urine as metabolites within 24 hours. In patients with chronic renal failure, the ability to eliminate polar metabolites is limited, which may lead to their accumulation. Patients with chronic renal failure should have extended intervals between doses of paracetamol.

Ascorbic acid (vitamin C) is rapidly absorbed in the gastrointestinal tract and delivered to all body tissues; 25% binds to plasma proteins. Excess ascorbic acid exceeding the body's requirements is excreted in 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 ranges from 2 to 3 hours. It is excreted in urine primarily as sulfate conjugates.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to any component of the drug, severe cardiovascular insufficiency, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, alcoholism, blood disorders (including severe anemia, leukopenia), thrombosis, thrombophlebitis, states of increased excitement, acute pancreatitis, prostate hyperplasia, diabetes mellitus, epilepsy, hyperthyroidism, pheochromocytoma, closed-angle glaucoma, arterial hypertension, severe forms of atherosclerosis, ischemic heart disease; sleep disorders.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOIs, with tricyclic antidepressants, beta-blockers or other antihypertensive drugs, and sympathomimetics.

Interaction with other medicinal products and other types of interactions.

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, with long-term regular daily use of paracetamol. These interactions are not clinically significant when paracetamol is used short-term according to the recommended regimen. Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsant drugs (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 developing hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics. Do not use concomitantly with alcohol.

Paracetamol should be used with caution concomitantly with flucloxacillin, as co-administration has been associated with high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Interaction of phenylephrine with monoamine oxidase inhibitors 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 cardiac 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) may increase the risk of ergotism.

Ascorbic acid, when administered orally, 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 drugs, phenothiazine derivatives increase the risk of urinary retention, dry mouth, constipation. Glucocorticosteroids increase the risk of developing glaucoma.

Absorption of vitamin C is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, and alkaline drinks. Ascorbic acid should be taken only 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, especially in the myocardium. Prolonged use of high doses in individuals treated with disulfiram inhibits the disulfiram-alcohol reaction.

Special precautions for use.

Before using the medicine, consult a doctor.

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

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, chronic alcohol dependence, or sepsis.

Patients taking warfarin; 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 or kidney function should consult a doctor before using the medicine.

The medicine contains phenylephrine, which may provoke angina attacks.

This medicinal product should not be used by patients taking other sympathomimetics (e.g. decongestants, appetite suppressants, and amphetamine-type psychostimulants). Use with caution in patients taking digoxin, cardiac glycosides, or ergot alkaloids (e.g. ergotamine, methysergide).

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

In patients with severe infections such as sepsis, associated with reduced glutathione levels, paracetamol use may increase 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 (HAGMA) due to 5-oxoproline (pyroglutamic acid) accumulation have been reported in patients with severe underlying conditions such as severe renal failure and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g. chronic alcoholism), who received 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 close monitoring of the patient. Measurement of urinary 5-oxoproline levels may be helpful in confirming pyroglutamic acidosis as the primary cause of HAGMA in patients with multiple risk factors.

This medicinal product contains 69 mg of sodium per sachet in the form of sodium citrate. Caution is advised when administering to patients on a sodium-restricted diet. Aspartame is a phenylalanine derivative and may be harmful to patients with phenylketonuria.

The medicine may have a mild laxative effect due to the presence of mannitol in its composition. If a patient has known intolerance to certain sugars, consult a doctor before taking this medicine.

Use during pregnancy or breastfeeding.

Do not use the medicine during pregnancy.

Paracetamol and phenylephrine may pass into breast milk; therefore, if use of the medicine is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

In case of development of certain adverse effects such as dizziness, the medicine may affect the ability to drive or operate complex machinery.

Method of administration and dosing.

Dissolve the contents of 1 sachet in a glass of hot water, stir until completely dissolved, and drink.

For adults and children aged 12 years and older: 1 sachet.

The medication should be taken every 4–6 hours, as needed.

Minimum interval between doses – 4 hours.

Maximum daily dose – 5 sachets.

Do not use the medication 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 possible duration.

Children.

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

Overdose.

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

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 consumption; 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 at 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; in some cases, liver transplantation may be required or death may occur. 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.

Acute kidney injury with acute tubular necrosis may manifest 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 at high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

Treatment: in case of paracetamol overdose, prompt medical attention is required, even if no 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. Gastric lavage should be performed, activated charcoal administered (within 1 hour of overdose), and symptomatic therapy initiated. Administration of paracetamol antidotes – intravenous N-acetylcysteine and oral methionine – may be effective within 24 hours after overdose.

Overdose caused by phenylephrine may lead to effects similar to those described in the section "Adverse reactions." Other symptoms may include irritability, restlessness, hypertension, and possibly 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 needed to cause paracetamol-induced hepatotoxicity.

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 required.

High doses of ascorbic acid (over 3000 mg) may cause temporary osmotic diarrhea and gastrointestinal disturbances such as nausea and abdominal discomfort. Consequences of ascorbic acid overdose may be attributed to those caused by severe liver damage resulting from paracetamol overdose.

Adverse Reactions

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, allergic dermatitis, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis.

Immune system disorders: allergic reactions (including angioedema), anaphylactic shock, hypersensitivity reactions.

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

Psychiatric disorders: psychomotor agitation and disorientation, anxiety, restlessness, fear, irritability, sleep disturbances, insomnia, confusion, depression, hallucinations.

Nervous system disorders: headache, dizziness, paresthesia.

Ear and labyrinth disorders: tinnitus.

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

Gastrointestinal disorders: nausea, vomiting, dry mouth, abdominal discomfort and pain, hypersalivation, decreased appetite, heartburn, diarrhea.

Hepatobiliary disorders: liver function abnormalities, increased liver enzyme activity, hepatonecrosis (dose-dependent effect), hepatic failure.

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

Renal and urinary disorders: urinary disturbances, urinary retention (more likely in patients with benign prostatic hyperplasia), renal colic, nephrotoxic effect.

Cardiac and vascular disorders: arterial hypertension, tachycardia or reflex bradycardia, palpitations, dyspnea, chest pain.

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

Other: general weakness, fever, hypoglycemia, 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 due to pyroglutamic acidosis have been observed in patients with risk factors who were treated with paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in such patients.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

5 g of powder in sachets; 5 or 10 sachets per cardboard box.

Pharmaceutical schedule.

Over-the-counter (without prescription).

Manufacturer.

Nabros Pharma Pvt. Ltd., India.

Manufacturer's address.

Survey No. 110/A/2, Amit Farm, Jain Upasrya, Near Coca Cola Factory, N.H. No. 8, Kajipura – 387411, Kheda, India.

Marketing Authorization Holder.

Nabros Pharma Pvt. Ltd., India.

Address of the Marketing Authorization Holder.

Nabros House, 3rd floor, Behind British Library, Opp. Art Gallery, Law Garden, Ellisbridge, Ahmedabad – 380006, Gujarat, India.