Antiflu

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

Composition:

Active substances: 1 sachet contains paracetamol (acetaminophen) 650 mg, phenylephrine hydrochloride 10 mg, chlorpheniramine maleate 4 mg;

Excipients: confectionery sugar, sucrose, lemon flavoring, citric acid, colloidal anhydrous silicon dioxide, silicon dioxide, sodium citrate dihydrate, ascorbic acid, titanium dioxide (E 171), calcium phosphate, yellow FCF (E 110), quinoline yellow (E 104), corn starch.

Dosage form. Powder for oral solution.

Main physicochemical characteristics: white or almost white powder containing crystalline particles with a slight lemon odor.

Pharmacotherapeutic group.
Analgesics and antipyretics. ATC code N02B E51.

Pharmacological properties.

Pharmacodynamics.

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 swelling and hyperemia of the mucous membranes of the upper respiratory tract and nasal sinuses due to its vasoconstrictive action.

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

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

Pharmacokinetics.

After oral administration, paracetamol is rapidly absorbed, primarily in the upper gastrointestinal tract. It is rapidly distributed in tissues. Plasma protein binding is less than 10%. Paracetamol is mainly metabolized in the liver: the majority conjugates with glucuronic acid and a smaller portion with sulfuric acid. The elimination half-life of paracetamol is 2–2.5 hours. This half-life is prolonged in patients with hepatic impairment.

Paracetamol is excreted in the urine (85% of a single dose is excreted within 24 hours). Excretion is significantly impaired in renal dysfunction, which may lead to accumulation of paracetamol 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 the urine.

Phenylephrine hydrochloride is partially excreted unchanged in the urine; the remainder is inactivated by monoamine oxidase in the 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, relieving headache, muscle and joint pain, and decreasing edema of the respiratory tract mucosa.

Contraindications.

• Hypersensitivity to the active or excipient ingredients of the medicinal product;
• Severe hepatic (Child–Pugh score >9 points) or renal impairment;
• Congenital glucose-6-phosphate dehydrogenase deficiency (manifested by hemolytic anemia);
• Gilbert’s syndrome (intermittent benign jaundice due to glucuronyltransferase deficiency);
• Blood coagulation disorders;
• Hematological diseases;
• Severe leukopenia;
• Anemia;
• Severe cardiac conduction disturbances;
• Decompensated heart failure;
• Severe coronary atherosclerosis;
• Severe form of ischemic heart disease;
• Severe arterial hypertension;
• Bronchial asthma;
• Emphysema;
• Chronic obstructive pulmonary disease;
• Congenital hyperbilirubinemia;
• Dubin–Johnson syndrome;
• Diabetes mellitus;
• Hyperthyroidism;
• Closed-angle glaucoma;
• Bladder neck obstruction;
• Pyloroduodenal obstruction;
• Active peptic ulcer;
• Alcoholism;
• Arrhythmias;
• Benign prostatic hyperplasia with urinary retention;
• Acute pancreatitis;
• Increased excitability;
• Sleep disorders;
• Pheochromocytoma;
• Epilepsy;
• Advanced age;
• Risk of respiratory failure.

Do not use concurrently with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs; with tricyclic antidepressants or 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 with antiemetics (metoclopramide and domperidone), and decrease with cholestyramine;
• Elimination of antibiotics from the body may be delayed;
• Barbiturates and alcohol may enhance the hepatotoxic and nephrotoxic potential of acetaminophen; barbiturates may reduce the antipyretic effect;
• Anticonvulsants (phenytoin, barbiturates, carbamazepine), isoniazid, and rifampicin may enhance the hepatotoxic effects of acetaminophen;
• Concomitant 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;
• Concomitant use of paracetamol and zidovudine increases the tendency to reduce white blood cell count (neutropenia); therefore, zidovudine and paracetamol should not be used together unless specifically recommended by a physician;
• 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 concurrent use with sedatives, hypnotics, or medicinal products containing alcohol due to increased risk of hepatotoxicity.

Concomitant use with vasoconstrictors is not recommended.

Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration has been 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").

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

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

Chlorpheniramine maleate may cause drowsiness. Concurrent use of sedatives, tranquilizers, or alcohol may intensify this effect.

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

Chlorpheniramine maleate may suppress the effects 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 adrenergic agents or MAO inhibitors, and may lead to severe arterial hypertension when combined with indomethacin or bromocriptine.

Concomitant use of phenylephrine with other sympathomimetic agents or tricyclic antidepressants (e.g., amitriptyline) may increase the risk of cardiovascular adverse effects. Alkaloids of Rauwolfia 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 side effects may increase.

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

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

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

Special precautions for use.

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

This medicinal product should not be used concomitantly with sedatives, hypnotics, or medicinal products containing alcohol due to 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, may be fatal.

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

Prolonged use of paracetamol at high doses may cause liver and kidney damage. A large number of concomitantly administered drugs, alcoholism, alcoholic liver disease, sepsis, or diabetes mellitus may increase the risk of paracetamol hepatotoxicity even at therapeutic doses. Overdose risk is particularly elevated in patients with non-cirrhotic alcoholic liver disease.

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

If the product is used for prolonged periods as directed by a physician, monitoring of liver function and peripheral blood picture is necessary.

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").

Consult a physician 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 assess the risk-benefit ratio before initiating treatment. Dose adjustment is necessary, and continuous patient monitoring is required;
• in cases of arterial hypertension or cardiovascular diseases;
• with daily use of analgesics for mild forms of arthritis.

Use with caution in patients:

• with chronic malnutrition or dehydration;
• with mild to moderate hepatic insufficiency (Child–Pugh score < 9 points);
• with Raynaud's disease;
• with thyroid disorders, except hyperthyroidism specified in the section "Contraindications";
• with glaucoma, except closed-angle glaucoma specified in the section "Contraindications".

Seek medical advice:

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

Very rare cases of severe skin reactions have been reported. In case of skin redness, rash, blisters, or peeling, discontinue paracetamol use immediately and seek medical help without delay.

Elevated ALT levels may occur during therapeutic-dose paracetamol use.

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

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 therapeutic doses of paracetamol over prolonged periods or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful patient monitoring. 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.

Do not exceed the recommended dose or 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.

The excipient sunset yellow may cause allergic reactions.

Warning regarding sugar and sucrose content: if you have an intolerance to certain sugars, consult your physician before taking this medicinal product; the product may be harmful to teeth.

Use during pregnancy or breastfeeding.

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

Fertility.

Limited data are available regarding potential effects on female fertility. Medicinal products that inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible and resolves after discontinuation of treatment. Since paracetamol is believed 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 possible occurrence of drowsiness, avoid driving or operating machinery for 3–6 hours after taking the product.

Dosage and Administration.

Take orally. Dissolve the contents of the sachet in a glass of hot water before use.

The single dose for adults and children aged 12 years and older is 1 sachet. If necessary, repeat every 4 hours. Do not exceed the maximum daily dose of 4 sachets within 24 hours. The maximum duration of use without medical consultation is 3 days. Further use 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 per day or 4000 mg per day.

Overdose.

Symptoms of Antiflu® overdose consist of signs related to overdose of individual components of the medicinal product.

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

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

In isolated cases, acute renal failure with acute tubular necrosis has been reported following acetaminophen overdose, which may manifest as severe flank 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 lower in individuals with significantly reduced body weight.

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

In severe cases, especially in the presence of alcohol, liver damage (hepatocellular necrosis) and worsening liver function may progress to liver failure, potentially leading to hepatic encephalopathy, hepatic coma, cerebral edema, and fatal outcome. Clinical signs of liver damage may not appear within 12–48 hours after overdose. Acute and chronic poisoning may also 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 activity, increased bilirubin, prolonged prothrombin time, hemorrhage, reduced urine output, mild azotemia. Liver damage in adults may develop after ingestion of 10 g or more of paracetamol, and in children after doses exceeding 150 mg/kg body weight.

Common clinical manifestations appearing 3–5 days after overdose include jaundice, fever, hemorrhagic diathesis, hypoglycemia, hepatic breath odor, and liver failure.

Liver damage may occur in patients with risk factors after ingestion of 5 g or more of paracetamol (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione depletion due to malnutrition, cystic fibrosis, HIV infection, starvation, or cachexia).

Long-term use at high doses may lead to liver dysfunction, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia.

Emergency treatment. The patient should be immediately transferred to an intensive care unit, even in the absence of early symptoms of overdose, and vital functions, laboratory parameters, and cardiovascular status should be closely monitored. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be considered if the excessive dose of paracetamol was ingested within 1 hour. Hemodialysis and hemoperfusion enhance 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 paracetamol overdose. Cytotoxic effects may be reduced by administration of SH-group donors: methionine orally or intravenous cysteamine or N-acetylcysteine within 48 hours after overdose. The efficacy of antidotes decreases significantly after this period.

Overdose due to phenylephrine and chlorpheniramine maleate may cause increased sweating, psychomotor agitation or central nervous system depression, headache, dizziness, drowsiness, impaired consciousness, cardiac arrhythmias, tachycardia, extrasystoles, tremor, hyperreflexia, seizures, nausea, vomiting, irritability, restlessness, and elevated blood pressure.

Severe phenylephrine hydrochloride poisoning may lead to cyanosis, cardiac arrhythmias, myocardial ischemia or myocardial infarction, pulmonary edema, hypotension, seizures, stroke, and acidosis.

Emergency treatment for acute phenylephrine hydrochloride poisoning aims to prevent sympathomimetic effects related to stimulation of the CNS and cardiovascular system and consists of symptomatic and supportive therapy, including mechanical ventilation if necessary.

In chlorpheniramine maleate overdose, antimuscarinic (atropine-like) and gastrointestinal symptoms, as well as CNS effects, may occur. In mild to moderate intoxication, symptoms include nausea, vomiting, drowsiness, impaired 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. Central nervous system depression may be 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 failure).

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 collapse, and fatal outcome.

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

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), thrombocytosis, thrombocytopenia, thrombocytopenic purpura, leukopenia, agranulocytosis, hemolytic anaemia, bruising or bleeding;
• Gastrointestinal disorders: heartburn, nausea, vomiting, dry mouth, epigastric discomfort and pain, hypersalivation, decreased appetite, dyspepsia, constipation, diarrhoea, flatulence;
• Hepatobiliary disorders: liver function abnormalities, hepatitis, dose-dependent liver failure, increased liver enzyme activity, usually without development of jaundice; hepatonecrosis (including fatal cases); prolonged use without medical advice may lead to liver fibrosis and cirrhosis, which can be fatal;
• Endocrine disorders: hypoglycaemia up to hypoglycaemic 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, fear, sleep disturbances (drowsiness, insomnia), dyskinesia, behavioural changes, irritability or nervousness, tremor, confusion, depressive states, sensations of tingling and heaviness in limbs, tinnitus, 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 mucous membrane rashes (usually generalized rash, erythema, urticaria), allergic and angioneurotic edema, acute generalized exanthematous pustulosis, localized drug dermatitis, erythema multiforme (including Stevens–Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), which can be fatal;
• Cardiovascular disorders: tachycardia, reflex bradycardia, dyspnea, chest pain, elevated blood pressure, arrhythmia; prolonged use at high doses may lead to myocardial dystrophy; pain or discomfort in the precordial area;
• Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs;
• Metabolism and nutrition disorders: metabolic acidosis with high anion gap – frequency "unknown" (cannot be estimated from available data).

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

Reporting of adverse reactions after medicinal product registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, 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 the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

Powder, dosed at 17 g per sachet made of paper laminated with aluminium foil and polyethylene. 5 sachets in a cardboard box.

Availability category. Over-the-counter.

Manufacturer.

Contract Pharmacal Corporation.

Manufacturer's address.

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