Theraflu extra with lemon flavor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THERAFLEU EXTRA with lemon flavour (TherAFlu® EXTRA with lemon flavour)

Composition:

Active ingredients: 1 sachet contains paracetamol 650 mg, pheniramine maleate 20 mg, phenylephrine hydrochloride 10 mg;

Excipients: sucrose, anhydrous citric acid, lemon flavouring, sodium citrate, calcium phosphate, maltodextrin, potassium acesulfame, colloidal anhydrous silicon dioxide, D&C Yellow No. 10 (E 104) colouring, FD&C Yellow No. 6 (E 110) colouring.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: white free-flowing powder with yellow specks, without hard particles; soft lumps may be present; solution: cloudy yellow solution.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psycholeptics.

ATC code N02BE51.

Pharmacological properties.

Pharmacodynamics.

A combination medication for the treatment of flu and cold symptoms.

Paracetamol exerts analgesic, antipyretic, and weak anti-inflammatory effects, primarily mediated through inhibition of prostaglandin synthesis in the central nervous system. It does not affect platelet function or hemostasis. The absence of peripheral prostaglandin inhibition confers important properties to the drug, such as preservation of protective prostaglandins in the gastrointestinal tract. Therefore, paracetamol can be administered to patients for whom peripheral prostaglandin inhibition is undesirable (e.g., patients with a history of gastrointestinal bleeding or elderly patients).

Phenylephrine hydrochloride is a sympathomimetic amine that acts predominantly directly on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, the drug does not exert a significant stimulatory effect on cardiac beta-adrenergic receptors or a significant effect on the central nervous system. It is a well-established nasal decongestant and acts by vasoconstriction, reducing swelling and hyperemia of the nasal mucosa.

Pheniramine maleate, an H1-receptor blocker, exerts antiallergic effects, reduces the intensity of local exudative manifestations, and alleviates lacrimation, rhinorrhea, and itching in the eyes and nose. Reduction of general allergic symptoms associated with respiratory tract disorders is accompanied by a moderate sedative effect. It also possesses antimuscarinic activity.

Pharmacokinetics.

After oral administration, paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 10–60 minutes.

Paracetamol is distributed into most body tissues. It crosses the placental barrier and is excreted into breast milk. At usual therapeutic doses, paracetamol is only slightly bound to plasma proteins; however, the extent of binding increases with rising concentrations.

Paracetamol is primarily metabolized in the liver via two pathways: glucuronidation and sulfation. It is excreted in urine, mainly as glucuronide and sulfate conjugates. Less than 5% of the dose is excreted unchanged. The elimination half-life ranges from 1 to 3 hours.

Maximum plasma concentration of pheniramine maleate is achieved within 1–2.5 hours; the elimination half-life is 16–19 hours. 70–83% of the orally administered dose is excreted in urine unchanged or as metabolites.

Phenylephrine hydrochloride is unevenly absorbed in the gastrointestinal tract and undergoes presystemic metabolism by monoamine oxidase (MAO) in the intestinal wall and liver; thus, oral phenylephrine has reduced bioavailability. It is excreted almost completely in urine, primarily as a sulfate conjugate. Maximum plasma concentrations are observed within 45 minutes to 2 hours, and the plasma elimination half-life is 2–3 hours.

Clinical characteristics.

Indications.

Treatment of symptoms of influenza and cold, including fever and chills, headache, runny nose, nasal and sinus congestion, sneezing, and body aches.

Contraindications.

Hypersensitivity to any component of the drug. Severe cardiovascular disorders, severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, hyperthyroidism, pheochromocytoma, glucose-6-phosphate dehydrogenase deficiency, severe forms of diabetes mellitus, alcoholism, acute pancreatitis, prostatic hypertrophy with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, blood disorders (including severe anemia, leukopenia), thrombosis, thrombophlebitis, closed-angle glaucoma, arterial hypertension, sleep disorders. Do not use during treatment with MAO inhibitors and within 2 weeks after discontinuation of such treatment.

Concomitant use with tricyclic antidepressants, beta-blockers, and other sympathomimetics is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Drug interactions of each individual component of the preparation are well known. There is no reason to assume that the use of these components in combination may affect the drug interaction profile.

Paracetamol.

With regular long-term use of paracetamol, the anticoagulant effect of warfarin or other coumarin derivatives may be enhanced, and the risk of bleeding may increase. This effect is not pronounced with occasional use of paracetamol.

Hepatotoxic drugs may increase the likelihood of paracetamol accumulation and overdose. The risk of hepatotoxic effects of paracetamol may increase in patients receiving drugs that induce hepatic microsomal enzymes, such as barbiturates and antiepileptic agents (phenytoin, phenobarbital, carbamazepine), and antituberculosis drugs rifampicin and isoniazid.

Metoclopramide increases the rate of paracetamol absorption and leads to an increase in its maximum plasma levels. Domperidone may similarly increase the rate of paracetamol absorption.

Paracetamol may prolong the half-life of chloramphenicol.

Paracetamol may reduce the bioavailability of lamotrigine, decreasing its effect due to possible induction of its hepatic metabolism.

Absorption of paracetamol may be reduced when used concomitantly with cholestyramine, but the reduction in absorption is insignificant if cholestyramine is administered 1 hour apart.

Regular concomitant use of paracetamol with zidovudine may lead to the development of neutropenia and increased risk of liver damage. Paracetamol reduces the effectiveness of diuretics.

Probenecid affects paracetamol metabolism. For patients taking probenecid concomitantly, the dose of paracetamol should be reduced. Paracetamol hepatotoxicity may be enhanced by prolonged or excessive alcohol consumption.

Paracetamol may affect test results for serum uric acid levels when determined by the phosphotungstic acid method.

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

Pheniramine maleate.

First-generation antihistamines, such as pheniramine maleate, may enhance the central nervous system depressant effects of other drugs (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, hypnotics and sedatives, neuroleptics, alcohol, anti-Parkinson agents, barbiturates, anesthetics, tranquilizers, and narcotic analgesics).

Pheniramine enhances the anticholinergic effect of atropine, spasmolytics, other antihistamines, anti-Parkinson drugs, and phenothiazine neuroleptics. Pheniramine maleate may also inhibit the action of anticoagulants.

Phenylephrine hydrochloride.

The use of the drug is contraindicated in patients undergoing therapy with monoamine oxidase inhibitors (MAOIs) and in patients who have taken MAOIs within the last 2 weeks. Phenylephrine may potentiate the action of MAO inhibitors and provoke a hypertensive crisis.

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

Phenylephrine may reduce the effectiveness of beta-blockers and other antihypertensive drugs (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.

Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methysergide) may increase the risk of ergotism.

Special precautions for use.

The medicinal product should be used with caution in the following cases:

• Impaired renal and/or hepatic function;
• Acute hepatitis;
• Hemolytic anemia;
• Chronic malnutrition and dehydration;
• Cardiovascular diseases;
• Diabetes mellitus;
• Prostatic hypertrophy, as patients may be predisposed to urinary retention;
• Obstructive peptic ulcer.

Since this medicinal product contains paracetamol, concomitant use of other medicinal products containing paracetamol should be avoided due to the risk of severe liver damage in case of overdose. Paracetamol overdose may cause hepatic failure, which may necessitate liver transplantation or result in death. The medicinal product is not recommended to be used concomitantly with vasoconstrictors. Do not exceed the recommended doses.

Alcohol consumption should be avoided during treatment, as ethanol taken concomitantly with paracetamol may cause liver function impairment. Paracetamol should be used with caution in patients with Raynaud's disease, cardiac disorders (including arrhythmias, bradycardia), thyroid disorders, glaucoma, chronic lung diseases, as well as in patients taking medicinal products affecting the liver and in elderly patients. Elderly patients with mental confusion should avoid taking this medicinal product. There is a known risk of premature closure of the fetal arterial duct associated with paracetamol use during pregnancy.

Patients should consult a physician:

• If they have breathing problems such as asthma, emphysema, or chronic bronchitis;
• If symptoms do not improve within 5 days or if symptoms are accompanied by high fever, chills lasting more than 3 days, rash, or persistent headache;
• Regarding the possibility of using the product in case of impaired renal or hepatic function.

These conditions may be symptoms of a more serious illness.

The product may affect laboratory test results for blood glucose levels.

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

Cases of hepatic dysfunction/failure have been reported in patients with reduced glutathione levels, for example, in patients suffering from severe malnutrition, anorexia, low body mass index, or chronic alcohol dependence.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the use of paracetamol increases 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 pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with inadequate nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses over a prolonged period or in combination with flucloxacillin.

In case of suspected HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of 5-oxoproline levels in urine may be helpful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

One sachet of the medicinal product contains 12.6 g of sucrose, which should be taken into account by patients with diabetes mellitus. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this product.

The medicinal product contains the dye FD&C Yellow No. 6 (E 110), which may cause allergic reactions. One sachet of the product contains 42.2 mg of sodium. Patients on a sodium-restricted diet should take into account the sodium content.

Reporting suspected adverse reactions after the medicinal product has been authorized is important. This allows continued monitoring of the benefit-risk balance of the medicinal product.

Use during pregnancy or breastfeeding.

The use of the medicinal product is not recommended during pregnancy or breastfeeding, as its safety in these conditions has not been studied.

Pregnancy.

Analysis of a large amount of data from pregnant women has not revealed congenital or fetal/neonatal toxicity. However, epidemiological studies on the impact of paracetamol on intrauterine nervous system development are not sufficiently conclusive. If clinically necessary, paracetamol may be used during pregnancy at the lowest effective dose, for the shortest duration, and with the lowest frequency possible.

Currently, there are no adequate reproductive toxicity studies or data on embryotoxicity/fetotoxicity with pheniramine use.

There are only limited data on the use of phenylephrine hydrochloride in pregnant women. Vasoconstriction of the uterine vessels and impaired uterine blood flow associated with phenylephrine use may lead to fetal hypoxia. The use of phenylephrine hydrochloride should be avoided during pregnancy.

Breastfeeding.

Paracetamol is excreted in breast milk, but in amounts that are not clinically significant. Available published data do not justify recommending discontinuation of breastfeeding during treatment with this product.

There is insufficient information regarding the excretion of pheniramine into breast milk and the amount of the drug that may reach the infant.

There are no data on the excretion of phenylephrine into breast milk. The use of phenylephrine should be avoided in women who are breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery.

The medicinal product may cause drowsiness in some patients (especially due to pheniramine), which may significantly impair the ability to drive vehicles or operate machinery. Caution should be exercised when driving vehicles or operating machinery requiring concentration.

Dosage and Administration

For oral use. In adults and children aged 12 years and older, administer 1 sachet every 4–6 hours (as needed for symptom relief), but not more than 4 sachets per day. The single dose must not exceed 1 sachet. The drug should not be used for longer than 7 days without consulting a physician. The minimum interval between doses is 4 hours. The contents of 1 sachet should be dissolved in a glass of boiled hot water (but not boiling water) and taken while hot. The lowest effective dose for the shortest duration required to achieve efficacy should be used.

Patients with hepatic impairment

For patients with impaired liver function, the dose should be reduced or the interval between administrations increased.

Elderly patients
Dose adjustment in elderly patients is not required.

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

Overdose

In case of overdose, symptoms caused by paracetamol will be the most prominent.

Symptoms caused by paracetamol: hepatotoxic effect, which in severe cases may lead to liver necrosis. Paracetamol overdose, including high total doses taken over a prolonged period, may cause analgesic-induced nephropathy with irreversible liver function impairment. 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—such as chronic excessive ethanol consumption, glutathione depletion (e.g., gastrointestinal disorders, cystic fibrosis, HIV infection, cachexia)—the use of 5 g or more of paracetamol may lead to liver injury.

There is a risk of poisoning, particularly in elderly patients, young children, patients with liver disease, chronic malnutrition, or those receiving hepatic enzyme inducers (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort). In severe poisoning, liver failure may progress to encephalopathy, coma, and fatal outcome.

With prolonged use of the drug in high doses, hematological disorders may develop, including aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Central nervous system effects from high-dose intake may include dizziness, psychomotor excitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis).

Symptoms of paracetamol overdose appearing within the first 24 hours include pallor, nausea, vomiting, and loss of appetite. The first sign of liver damage may be abdominal pain, which does not always manifest within the first 24–48 hours but may appear later, within 4–6 days after drug intake. Liver injury typically occurs within 72–96 hours after drug administration. Abnormalities in glucose metabolism (hypoglycemia) and metabolic acidosis, as well as bleeding, may occur. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver injury, presenting as severe flank pain, hematuria, and proteinuria. Cases of cardiac arrhythmias and acute pancreatitis have been reported.

Treatment: Immediate medical attention is required in case of paracetamol overdose, even if no symptoms are apparent. Administration of intravenous or oral N-acetylcysteine as an antidote to paracetamol at an early stage is essential. Gastric lavage and/or oral methionine may be beneficial within at least 48 hours after overdose. Activated charcoal administration and monitoring of respiration and circulation may be helpful. Diazepam may be administered in case of seizures.

Symptoms caused by pheniramine maleate and phenylephrine hydrochloride

Symptoms resulting from the mutual potentiation of the anticholinergic effect of the antihistamine and the sympathomimetic effect of phenylephrine hydrochloride include drowsiness, which may be followed by excitation (especially in children) or central nervous system depression, visual disturbances, rash, nausea, vomiting, persistent headache, hyperhidrosis, nervousness, dizziness, tremor, insomnia, hyperreflexia, irritability, restlessness, circulatory disturbances, arterial hypertension, and bradycardia. In severe cases of phenylephrine overdose, disturbances of consciousness, arrhythmias, coma, and seizures may occur. Cases of atropine-like psychosis have been reported following pheniramine overdose. Atropine-like symptoms may include: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, and intestinal atony.

Treatment. There is no specific antidote for antihistamine overdose. Standard emergency measures should be provided, including administration of activated charcoal, a saline laxative, and standard supportive measures for cardiovascular and respiratory systems. Stimulants must not be used; vasoconstrictors may be used to treat arterial hypotension.

To counteract hypertensive effects, an α-receptor blocker (phentolamine) may be administered intravenously. Diazepam may be used in case of seizures.

Adverse Reactions

The adverse reactions listed below are categorized by frequency: very common (≥ 1/10), common (≥1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

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

Immune system disorders: rare – hypersensitivity, Quincke's edema; frequency not known – anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Psychiatric disorders: rare – nervousness, insomnia, confusion, psychomotor agitation and disorientation, restlessness, fear, irritability, sleep disturbances, hallucinations, depressive states.

Nervous system disorders: common – drowsiness; rare – dizziness, headache, paresthesia, tinnitus, tremor.

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

Cardiac and vascular disorders: rare – tachycardia, palpitations, arterial hypertension.

Endocrine disorders: rare – hypoglycemia, up to hypoglycemic coma.

Gastrointestinal disorders: common – nausea, vomiting; rare – dry mouth, constipation, abdominal pain and discomfort, diarrhea, heartburn, decreased appetite, hypersalivation; frequency not known – metabolic acidosis with high anion gap.

Respiratory system disorders: very rare – bronchospasm in patients sensitive to aspirin and other NSAIDs.

Hepatobiliary disorders: rare – liver function abnormalities, increased levels of liver enzymes, usually without development of jaundice.

Renal and urinary disorders: rare – dysuria, nephrotoxicity, renal colic; very rare – urinary retention (more likely in patients with benign prostatic hyperplasia).

Skin and subcutaneous tissue disorders: rare – rash, pruritus, erythema multiforme, urticaria, eczema, purpura, allergic dermatitis.

General disorders: rare – general weakness, malaise.

In contrast to second-generation antihistamines, pheniramine use is not associated with QTc interval prolongation or cardiac arrhythmias.

Shelf life. 2 years.

Storage conditions.

Keep out of reach of children and store at a temperature not exceeding 25 °C.

Packaging.

1 sachet without secondary packaging or 10 sachets in a cardboard box.

Supply category. Over-the-counter.

Manufacturer.

Haleon Alcala S.A. / Haleon Alcala S.A.

Manufacturer's address and location of its operations.

Calle Ajalvir, km. 2.500, Alcalá de Henares, Madrid, 28806, Spain /
carretera Ajalvir, km. 2.500, Alcalá de Henares, Madrid, 28806, Spain.