Theraflu for flu and cold with lemon flavor

INSTRUCTIONS for medical use of the medicinal product THERAFLU FOR COLD AND FLU with lemon flavour TherAFlu® flu and Cold with lemon flavour

Composition:

Active substances: paracetamol, pheniramine maleate, phenylephrine hydrochloride, ascorbic acid;

1 sachet contains paracetamol 325 mg, pheniramine maleate 20 mg, phenylephrine hydrochloride 10 mg, ascorbic acid 50 mg;

Excipients: sucrose, anhydrous citric acid, natural lemon flavour,
disodium hydrogen citrate dihydrate, calcium phosphate, malic acid, titanium dioxide (E 171), sunset yellow FCF (E 110), quinoline yellow (E 104).

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: free-flowing coarse granules of white colour with yellow specks and a citrus odour. Soft lumps may be present.

Pharmacotherapeutic group. Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02BE51.

Pharmacological properties.

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

Paracetamol exerts analgesic, antipyretic, and weakly expressed 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 suppression provides important properties of the drug, such as maintenance 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 on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, the drug does not exhibit 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 is an H1-receptor antagonist that exerts antiallergic effects, reduces the severity of local exudative manifestations, and alleviates lacrimation, rhinorrhea, and itching in the eyes and nose. Reduction of general allergic symptoms associated with respiratory tract diseases leads to a moderate sedative effect. It also exhibits antimuscarinic activity.

Ascorbic acid may be beneficial in compensating for the increased body requirement for vitamin C during fever and influenza.

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 distributes into most body tissues. It crosses the placental barrier and is excreted in 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 reached within 1–2.5 hours; the elimination half-life is 16–19 hours. 70–83% of the orally administered dose is excreted in urine either unchanged or as metabolites.

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

Ascorbic acid is rapidly and completely absorbed in the gastrointestinal tract and distributed to all body cells, with 25% bound to plasma proteins. Excess ascorbic acid not required for the body's needs is excreted in urine as metabolites.

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 hepatic and/or renal dysfunction, congenital hyperbilirubinemia, arterial hypertension, acute pancreatitis, hyperthyroidism, pheochromocytoma, blood disorders (including severe anemia, leukopenia), thrombosis, thrombophlebitis, closed-angle glaucoma, glucose-6-phosphate dehydrogenase deficiency, severe forms of diabetes mellitus, alcoholism, prostate hypertrophy with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, sleep disorders.

Should not be used during treatment with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of such therapy. Concomitant use with tricyclic antidepressants, beta-blockers, and other sympathomimetics is contraindicated.

Interaction with other medicinal products and other types of interactions.

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

Paracetamol.

With regular long-term use of paracetamol, the anticoagulant effect of warfarin or other coumarin derivatives may be enhanced, increasing the risk of bleeding. 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 agents rifampicin and isoniazid.

Metoclopramide increases the rate of paracetamol absorption and leads to higher plasma peak levels. Domperidone may similarly increase the rate of paracetamol absorption. Paracetamol may prolong the half-life of chloramphenicol. Paracetamol may reduce lamotrigine bioavailability, decreasing its effect, likely due to induction of its hepatic metabolism.

Paracetamol absorption may be reduced when used concomitantly with cholestyramine, but the reduction in absorption is negligible if cholestyramine is administered 1 hour apart.

Regular concomitant use of paracetamol with zidovudine may lead to neutropenia and increased risk of liver damage. Paracetamol reduces the effectiveness of diuretics. Probenecid affects paracetamol metabolism. Patients taking probenecid concurrently should receive a reduced dose of paracetamol. Paracetamol hepatotoxicity may be enhanced by prolonged or excessive alcohol consumption.

Paracetamol may interfere with test results for serum uric acid levels when measured 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 due to pyroglutamic acidosis, particularly 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, antiparkinsonian agents, barbiturates, anesthetics, tranquilizers, and narcotic analgesics). Pheniramine enhances the anticholinergic effects of atropine, spasmolytics, other antihistamines, antiparkinsonian agents, and phenothiazine neuroleptics. Pheniramine maleate may also inhibit the action of anticoagulants.

Phenylephrine hydrochloride.

The use of this product is contraindicated during therapy with monoamine oxidase inhibitors (MAOIs) and within 2 weeks after discontinuation of MAOI treatment. Phenylephrine may potentiate the effects 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 adverse effects.

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

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, methysergide) may increase the risk of ergotism.

Ascorbic acid enhances the absorption of penicillin and iron when administered orally, reduces the effectiveness of heparin and indirect anticoagulants, increases the risk of crystalluria during salicylate therapy, and increases the risk of glaucoma during glucocorticoid therapy. High doses reduce the effectiveness of tricyclic antidepressants. Antidepressants, antiparkinsonian and antipsychotic agents, phenothiazine derivatives increase the risk of urinary retention, dry mouth, and constipation. Ascorbic acid should be taken only 2 hours after deferoxamine injection, as their simultaneous use increases iron toxicity, especially in the myocardium. Prolonged use of high doses during disulfiram treatment inhibits the disulfiram-alcohol reaction.

Special precautions for use.

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

• Impaired kidney and/or liver function;
• Acute hepatitis;
• Hemolytic anemia;
• Chronic malnutrition and dehydration;
• Cardiovascular diseases;
• Diabetes mellitus;
• Prostatic hypertrophy, as patients may be prone 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 require liver transplantation or lead to fatal outcomes. The medicinal product is not recommended to be used simultaneously with vasoconstrictors. Do not exceed the recommended doses.

Alcoholic beverages 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 alcohol dependence, Raynaud's disease, heart diseases (including arrhythmia, bradycardia), thyroid disorders, glaucoma, chronic lung diseases, as well as in patients taking medicinal products affecting the liver and in elderly patients. The medicinal product should be avoided in elderly patients with confusion. There is a known risk of premature closure of the fetal ductus arteriosus 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 persist for more than 5 days or are accompanied by high fever, chills lasting more than 3 days, rash, or prolonged headache;
• Regarding the possibility of using the product in case of impaired kidney or liver 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, such as in patients suffering severely from malnutrition, anorexia, low body mass index, or chronic alcohol dependence.

The product should be used with caution in patients with recurrent uric acid kidney stones. In patients with severe infections such as sepsis, 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 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.

In case of suspected HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient's condition. 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 20 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 colorant Sunset Yellow (E 110), which may cause allergic reactions. One sachet of the product contains 28.3 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 on 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 data from reproductive function studies or data on embryotoxicity/fetotoxicity with the use of pheniramine.

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

Breastfeeding.

Paracetamol is excreted in breast milk, but in amounts that are not clinically significant. Available published data do not support recommendations to discontinue breastfeeding during paracetamol therapy.

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 whether phenylephrine passes into breast milk. The use of phenylephrine should be avoided in women who are breastfeeding.

Ascorbic acid is excreted in breast milk but reaches saturation levels. The use of ascorbic acid is compatible with breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

For oral use. Adults and children aged 12 years and older should take 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. It is not recommended to use the drug 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 required to achieve symptom relief for the shortest possible duration should be used.

Patients with hepatic impairment.

Patients with impaired liver function require a reduced dose or increased dosing interval.

Elderly patients. Dose adjustment in elderly patients is not required.

Children.

The drug is contraindicated in 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 cumulative doses taken over a prolonged period, may cause analgesic-induced nephropathy with irreversible liver function impairment.

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. In patients with risk factors—chronic excessive ethanol consumption, glutathione depletion (digestive 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, and in patients receiving hepatic enzyme inducers (long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort). In severe poisoning, hepatic failure may progress to encephalopathy, coma, and may be fatal.

With prolonged use of the drug in high doses, hematological disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. Central nervous system effects from high doses include dizziness, psychomotor agitation, and disorientation. Urinary system effects include nephrotoxicity (renal colic, interstitial nephritis, cortical 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 occur later, within 4–6 days after drug intake. Liver injury typically occurs within 72–96 hours after 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 back 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 N-acetylcysteine intravenously or orally as an antidote to paracetamol at an early stage, gastric lavage, and/or oral administration of methionine may be beneficial for at least 48 hours following overdose.

Administration of activated charcoal and monitoring of respiration and circulation may be helpful. In case of seizures, diazepam may be administered.

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, dry skin and mucous membranes, hyperthermia, and intestinal atony.

Symptoms of ascorbic acid overdose are attributable to severe hepatic failure caused by paracetamol overdose.

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

To counteract hypertensive effects, an alpha-receptor blocker (phentolamine) may be administered intravenously, and 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 the available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia, agranulocytosis, leukopenia, anemia including hemolytic anemia, pancytopenia, 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, anxiety, 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.

Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

1 sachet with powder;

10 sachets with powder in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

Delpharm Orleans / Delpharm Orleans.

Manufacturer's address and place of business.

5 avenue de Concyr, ORLEANS CEDEX 2, 45071, France /
5 avenue de Concyr, ORLEANS CEDEX 2, 45071, France.