Antiflu

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANTI-FLU®

Composition:

Active substances: paracetamol, phenylephrine hydrochloride, chlorpheniramine maleate;

One tablet contains 325 mg of paracetamol, 5 mg of phenylephrine hydrochloride, and 2 mg of chlorpheniramine maleate;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, stearic acid, magnesium silicate, magnesium stearate, hypromellose, polyethylene glycol, mineral oil, D&C Yellow No. 10 aluminum lake (E 104).

Medicinal form. Film-coated tablets.

Main physicochemical properties: capsule-shaped tablet, yellow in color, with a transparent film coating and engraved marking "AntiFlu" on one side.

Pharmacotherapeutic group. Analgesics and antipyretics.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

Acetaminophen (paracetamol) has analgesic, antipyretic, and weak anti-inflammatory effects. Its mechanism of action involves inhibition of prostaglandin synthesis and effects on the thermoregulatory center in the hypothalamus.

Phenylephrine hydrochloride is an α-adrenergic agonist that reduces edema and hyperemia of the mucous membranes of the upper respiratory tract and nasal sinuses through vasoconstrictive action.

Chlorpheniramine maleate is an antihistamine agent of the alkylamine class, an H1-histamine receptor blocker. It exerts antiallergic effects, relieving rhinorrhea, lacrimation, and itching in the eyes and nose. The therapeutic effect develops within 1 hour after oral administration and lasts for 24 hours.

The components of the drug are metabolized independently of each other.

Pharmacokinetics.

After oral administration, acetaminophen is rapidly absorbed, primarily in the upper gastrointestinal tract. It rapidly distributes into tissues. Protein binding in plasma is less than 10%. Acetaminophen is metabolized mainly in the liver: the majority conjugates with glucuronic acid, and a smaller portion with sulfuric acid. The elimination half-life of acetaminophen is 2–2.5 hours. It is prolonged in patients with hepatic disease.

Acetaminophen is excreted in urine (85% of a single dose is excreted within 24 hours). Excretion is significantly impaired in patients with renal dysfunction, which may lead to accumulation of acetaminophen and its metabolites in the body. The elimination half-life of chlorpheniramine maleate is 8 hours. Metabolites and unchanged portions of the drug are excreted in urine.

Phenylephrine hydrochloride is partially excreted unchanged in urine; the remainder is inactivated by monoamine oxidase in blood, liver, and other tissues. The inactive metabolites are partially excreted by the kidneys, and the rest via the liver as glucuronides.

Clinical characteristics.

Indications.

Symptomatic treatment of influenza, acute respiratory viral infections, and colds, aimed at reducing fever, and relieving headache, muscle and joint pain, as well as respiratory mucosa edema.

Contraindications.

Hypersensitivity to the active or excipient substances of the drug; severe hepatic (more than 9 points on the Child–Pugh scale) or renal impairment; congenital glucose-6-phosphate dehydrogenase deficiency (manifested by hemolytic anemia); Gilbert's syndrome (intermittent benign jaundice due to glucuronyltransferase deficiency); blood dyscrasias; blood disorders; severe leukopenia; anemia; severe cardiac conduction disorders; decompensated heart failure; severe coronary atherosclerosis; severe form of ischemic heart disease; severe arterial hypertension; bronchial asthma; congenital hyperbilirubinemia; Dubin–Johnson syndrome; diabetes mellitus; hyperthyroidism; closed-angle glaucoma; bladder neck obstruction; pyloroduodenal obstruction; active peptic ulcer disease; alcoholism; arrhythmias; benign prostatic hyperplasia with urinary retention; acute pancreatitis; increased excitability; sleep disorders; pheochromocytoma; epilepsy. Advanced age. Risk of respiratory depression.

Do not use concurrently with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs; with tricyclic antidepressants, β-blockers.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with acetaminophen, the following interactions may occur:

• The absorption rate of acetaminophen may increase when used concomitantly with antiemetics (metoclopramide and domperidone), and decrease with cholestyramine;
• Elimination of antibiotics from the body may be slowed;
• Barbiturates and alcohol may enhance the hepatotoxic and nephrotoxic effects of acetaminophen; barbiturates reduce the antipyretic effect;
• Anticonvulsants (phenytoin, barbiturates, carbamazepine), isoniazid, and rifampicin may enhance the hepatotoxic effect of acetaminophen;
• Concurrent use of high-dose paracetamol with isoniazid may increase the risk of hepatotoxicity;
• Tetracycline increases the risk of anemia and methemoglobinemia induced by acetaminophen;
• The effect of indirect anticoagulants may be enhanced, increasing the risk of bleeding during prolonged regular use of acetaminophen; prolonged concurrent use of coumarin derivatives may enhance their effect and increase bleeding risk—monitoring of blood coagulation is recommended;
• Tropisetron and granisetron, 5-hydroxytryptamine type 3 antagonists, may completely suppress the analgesic effect of paracetamol due to pharmacodynamic interaction;
• Concurrent use of paracetamol and AZT (zidovudine) increases the tendency to reduce white blood cell count (neutropenia); therefore, concomitant use of AZT and paracetamol should be avoided and is only permitted upon physician's recommendation;
• May reduce the effectiveness of diuretics;
• Antacids and food reduce acetaminophen absorption.

Concomitant use of paracetamol with hepatotoxic agents increases the toxic effects of the drugs on the liver.

The medicinal product is not recommended for concomitant use with sedatives, hypnotics, or medicinal products containing alcohol, due to increased risk of hepatotoxicity.

Concomitant use with vasoconstrictors is not recommended.

Concurrent use of Antiflu® with the following medicinal products may significantly enhance the depressant effect of chlorpheniramine maleate:

• Hypnotics;
• Barbiturates;
• Sedatives;
• Neuroleptics;
• Tranquilizers or alcohol;
• Anesthetics;
• Opioid analgesics.

Chlorpheniramine maleate may cause drowsiness. Concurrent use with sedatives, tranquilizers, or alcohol may increase this effect.

Chlorpheniramine enhances the anticholinergic effect of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents.

Chlorpheniramine maleate may inhibit the action of anticoagulants.

Chlorpheniramine may increase chloroquine levels when used concomitantly. The clinical significance of this interaction is unknown.

Phenylephrine hydrochloride may cause hypertensive crisis or arrhythmias when used concomitantly with other adrenomimetics or MAO inhibitors, and may cause severe arterial hypertension when combined with indomethacin or bromocriptine.

Concurrent use of phenylephrine with other sympathomimetic agents or tricyclic antidepressants (e.g., amitriptyline) may increase the risk of cardiovascular adverse effects. Rauwolfia alkaloids reduce the therapeutic effect of phenylephrine hydrochloride.

Phenylephrine may reduce the effectiveness of β-blockers and other antihypertensive agents (e.g., debrisoquin, guanethidine, reserpine, methyldopa). The risk of arterial hypertension and other cardiovascular adverse effects may increase.

Concurrent use of phenylephrine with digoxin and cardiac glycosides may increase the risk of cardiac arrhythmias or cardiac events.

Antidepressants, antiparkinsonian and antipsychotic agents, and phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation.

Concurrent use with ergot alkaloids (ergotamine, methysergide) increases the risk of ergotism.

Paracetamol should be used with caution concomitantly with flucloxacillin, as concurrent administration is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use.

Avoid concomitant use with other medicinal products intended for symptomatic treatment of cold and flu, medicinal products containing paracetamol, antihistamines, or oral decongestants.

This medicinal product is not recommended for concomitant use with sedatives, hypnotics, or medicinal products containing alcohol due to an increased risk of hepatotoxicity.

The product contains paracetamol, which due to its hepatotoxic potential must not be used for longer periods or in higher doses than recommended in the section "Dosage and administration". Prolonged use may lead to severe liver complications such as cirrhosis. Acute or chronic overdose may result in severe liver damage and, in rare cases, fatal outcomes.

Long-term use of paracetamol, especially in combination with other analgesics, may lead to irreversible kidney damage and risk of renal failure (analgesic nephropathy).

Long-term use of paracetamol at high doses may lead to liver and kidney damage. The concomitant use of multiple medications, alcoholism, alcoholic liver disease, sepsis, or diabetes mellitus may increase the risk of paracetamol-induced hepatotoxicity even at therapeutic doses. The risk of overdose is particularly relevant in patients with non-cirrhotic alcoholic liver disease.

Elevated serum ALT levels may occur during paracetamol use at therapeutic doses.

If the medicinal product is used long-term as directed by a physician, monitoring of liver function and peripheral blood picture is required.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, paracetamol use may increase the risk of metabolic acidosis (see "Overdose").

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe underlying conditions such as 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 of the patient. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

Consult a doctor before use:

• if the patient is taking warfarin or similar anticoagulant agents;
• if the patient has breathing difficulties, chronic lung diseases, emphysema, or chronic bronchitis;
• if the patient has liver disease or infectious liver conditions such as viral hepatitis;
• if the patient has kidney disease, as dose adjustment may be required. In cases of severe renal impairment (creatinine clearance < 10 mL/min), the physician should evaluate the risk-benefit ratio before initiating treatment. Dose adjustment is necessary, and close monitoring of the patient is required;
• in cases of arterial hypertension or cardiovascular diseases;
• in cases of daily analgesic use for mild forms of arthritis.

Use with caution in patients:

• with chronic undernutrition or dehydration;
• with mild to moderate hepatic insufficiency (Child–Pugh score < 9 points);
• with Raynaud's disease;
• with thyroid disorders;
• with glaucoma.

Seek medical advice:

• if symptoms persist and/or are accompanied by high fever lasting more than 3 days;
• if headache becomes persistent.

Very rarely, severe skin reactions have been reported. In case of skin redness, rash, blisters, or peeling, discontinue paracetamol and seek immediate medical attention.

Elevated ALT levels may occur during therapeutic use of paracetamol.

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

Do not exceed the recommended dose and adhere to the recommended duration of treatment.

Antiflu® may cause nervousness, dizziness, or insomnia. In such cases, discontinuation of the medicinal product is recommended.

Use with caution when co-administered with sedatives or tranquilizers.

Use during pregnancy or breastfeeding.

The use of this medicinal product is not recommended during pregnancy and breastfeeding due to lack of data for this combination of active substances.

Fertility.

Limited data are available regarding potential effects on female fertility, as medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible and resolves after discontinuation of treatment. Since paracetamol is considered to inhibit prostaglandin synthesis, it may potentially impair fertility, although such cases have not been reported.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of drowsiness, avoid driving or operating machinery for 3–6 hours after taking the medicinal product.

Method of Administration and Dosage.

Adults and children aged 12 years and older: 2 tablets as a single dose every 4 hours. Swallow with water. The maximum daily dose of 12 tablets within 24 hours must not be exceeded.

Maximum duration of use without medical consultation – 3 days. Continued use beyond this period is possible only under medical supervision.

Children.

Do not use in children under 12 years of age. The maximum dose for children is up to 100 mg/kg/day or 4000 mg/day.

Overdose.

Symptoms of Antiflu® overdose consist of signs associated with overdose of individual components of the medicinal product.

In case of paracetamol overdose, seek immediate medical attention or contact a toxicology center. Timely medical intervention is critical for both adults and children, even if no symptoms are apparent.

Symptoms of overdose caused by acetaminophen within the first 24 hours include pallor, nausea, vomiting, anorexia, and abdominal pain. Following large doses, disorientation, psychomotor agitation or central nervous system depression, increased sweating, dizziness, and sleep disturbances may also occur. Cardiac arrhythmias and pancreatitis have also been reported.

In isolated cases following acetaminophen overdose, acute renal failure with acute tubular necrosis has been reported, which may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver damage; nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis) may also occur.

The threshold for overdose may be lowered in individuals with significantly reduced body weight.

The most significant effect in acute paracetamol poisoning is hepatotoxicity. Hepatocellular damage results from reactive metabolites of paracetamol binding to liver cell proteins. At therapeutic doses, these metabolites are bound by glutathione and form non-toxic conjugates. In massive overdose, the liver's supply of SH-groups necessary for glutathione formation becomes depleted, leading to accumulation of toxic metabolites and subsequent liver cell necrosis.

In severe cases, especially with concomitant alcohol consumption, liver damage (hepatocellular necrosis) and progressive impairment of liver function may lead to hepatic failure, which can progress to hepatic encephalopathy, hepatic coma, cerebral edema, and may be fatal. Clinical signs of liver damage may not appear within 12–48 hours after overdose. Acute and chronic poisoning may lead to disturbances in glucose metabolism, hypokalemia, and metabolic acidosis (including lactic acidosis). Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention is required if these symptoms occur. Other possible manifestations include elevated "liver" transaminase and bilirubin levels, prolonged prothrombin time, hemorrhages, reduced urine output, mild azotemia. Liver damage in adults may develop after ingestion of 10 g or more of paracetamol, and in children after administration of more than 150 mg/kg body weight. Common clinical manifestations appearing after 3–5 days include jaundice, fever, hemorrhagic diathesis, hypoglycemia, fetor hepaticus, and hepatic failure.

Administration of 5 g or more of paracetamol may lead to liver damage 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; regular excessive ethanol consumption; glutathione deficiency states (digestive disorders, cystic fibrosis, HIV infection, starvation, cachexia)).

With prolonged use at high doses, disturbances in liver function, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

Emergency Measures. The patient should be immediately transferred to an intensive care unit, even if early symptoms of overdose are absent, and vital functions, laboratory parameters, and cardiovascular status should be closely monitored. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Activated charcoal treatment should be considered if the excessive paracetamol dose was ingested within the past hour. Hemodialysis and hemoperfusion facilitate elimination of the active substance. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Gastric lavage should be performed within 6 hours after suspected acetaminophen overdose. Cytotoxic effects may be reduced by administration of SH-group donors—oral methionine or intravenous cysteamine or N-acetylcysteine—within 48 hours of overdose. The efficacy of the antidote decreases sharply after this period.

Overdose due to phenylephrine and chlorpheniramine maleate may cause increased sweating, psychomotor agitation or central nervous system depression, irritability, restlessness, headache, dizziness, drowsiness, insomnia, nausea, vomiting, tremor, altered consciousness, cardiac arrhythmias, tachycardia, extrasystoles, hyperreflexia, elevated blood pressure, seizures, and coma. In severe phenylephrine hydrochloride poisoning, cyanosis, cardiac arrhythmias, myocardial ischemia or myocardial infarction, pulmonary edema, hypotension, seizures, stroke, and acidosis may occur.

Emergency management of acute phenylephrine hydrochloride poisoning involves preventing sympathomimetic effects related to stimulation of the CNS and cardiovascular system and consists of symptomatic and supportive therapy, including mechanical ventilation if necessary.

In case of chlorpheniramine maleate overdose, anticholinergic (antimuscarinic), gastrointestinal symptoms, and CNS changes may occur. In mild to moderate intoxication, symptoms include nausea, vomiting, drowsiness, depressed consciousness, hallucinations, facial flushing, mydriasis, photophobia, dry skin and mucous membranes, elevated body temperature, intestinal atony, tachycardia, and moderate increase in blood pressure. In severe intoxication, delirium, psychosis, dyskinesia, and seizures may occur. CNS depression is accompanied by respiratory depression and cardiovascular disturbances (decreased pulse rate, widened QRS complex, ventricular arrhythmias including torsade de pointes, decreased blood pressure up to circulatory collapse).

In children, initial CNS stimulation is followed by depression. Symptoms may include ataxia, agitation, tremor, psychosis, hallucinations, and seizures. Hyperpyrexia may also occur. Deterioration may lead to deep coma, cardiovascular dysfunction, and may be fatal.

In case of overdose, symptomatic and supportive therapy is required, including mechanical ventilation. In cases of severe arterial hypertension, α-adrenergic blockers should be administered.

Adverse Reactions

In most cases, the medicinal product is well tolerated.

Rarely, the following adverse effects may occur after prolonged use in amounts exceeding the recommended daily doses:

Blood and lymphatic system disorders – anaemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anaemia (in patients with glucose-6-phosphate dehydrogenase deficiency), thrombocytopenia, agranulocytosis, thrombocytopenic purpura, leukopenia, bruising or bleeding;

Gastrointestinal disorders – heartburn, nausea, vomiting, dry mouth, epigastric discomfort and pain, hypersalivation, decreased appetite, dyspepsia, constipation, diarrhea, flatulence;

Hepatobiliary disorders – liver function abnormalities, hepatitis, dose-dependent hepatic failure, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (including fatal cases); prolonged use without medical recommendation may lead to fibrosis and cirrhosis of the liver, which may be fatal;

Endocrine disorders – hypoglycemia up to hypoglycemic coma;

Immune system disorders – hypersensitivity reactions (including allergic reactions), anaphylactic reactions and anaphylactic shock;

Nervous system disorders – headache, weakness, dizziness, psychomotor agitation and disorientation, restlessness, anxiety, sleep disturbances (drowsiness, insomnia), dyskinesia, behavioral changes, irritability or nervousness, tremor, confusion, depression, tingling and heaviness in limbs, tinnitus, hallucinations, epileptic seizures, coma;

Renal and urinary disorders – renal colic and interstitial nephritis, urinary retention and difficulty in urination, aseptic pyuria, dysuria;

Eye disorders – visual disturbances and accommodation disorders, dry eyes, mydriasis, increased intraocular pressure;

Skin and subcutaneous tissue disorders – itching, skin and mucosal rashes (usually generalized rash, erythema, urticaria), allergic and angioneurotic edema, acute generalized exanthematous pustulosis, localized drug dermatitis, Stevens-Johnson syndrome (including other forms of erythema multiforme), toxic epidermal necrolysis (Lyell’s syndrome), which may be fatal;

Cardiovascular disorders – tachycardia, reflex bradycardia, dyspnea, chest pain, increased blood pressure, arrhythmia, myocardial dystrophy (a dose-dependent effect with prolonged use), pain or discomfort in the precordial area;

Respiratory system disorders – bronchospasm in patients with hypersensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs;

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

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 who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

12 tablets in a blister pack. 1 blister pack in a cardboard box.

Availability.

Over-the-counter.

Manufacturer.

Contract Pharmacal Corporation.

Manufacturer's address.

135 Adams Avenue, Hauppauge, New York, 11788, USA.