Teraflu

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TeraFlu (THERAFLU®)

Composition:

Active substances: 1 sachet contains paracetamol 325 mg, pheniramine maleate 20 mg, phenylephrine hydrochloride 10 mg;

Excipients: sucrose, anhydrous citric acid, sodium citrate dihydrate, natural raspberry flavor, natural cranberry flavor, calcium phosphate, maltodextrin, potassium acesulfame, silicon dioxide, magnesium stearate, red dye AG (E 129), brilliant blue FCF dye (E 133).

Pharmaceutical form. Powder for oral solution with forest berries flavor.

Main physicochemical characteristics: free-flowing powder from white to yellowish-grey with purple granules. Soft lumps are permissible. Solution: opaque pink-purple solution with a berry odor.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol combinations without psychotropic agents.

ATC code N02B E51.

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).

Pheniramine maleate is an H1-receptor antagonist that exerts antihistaminic 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.

Phenylephrine hydrochloride is a sympathomimetic amine that primarily acts 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 that acts by vasoconstriction, reducing edema and hyperemia of the nasal mucosa.

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 protein 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. Approximately 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 in the intestinal wall and liver; thus, oral phenylephrine has reduced bioavailability. It is excreted in urine almost entirely 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, 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 treatment with tricyclic antidepressants, beta-blockers, and other sympathomimetics is contraindicated.

Drug interactions and other types of interactions.

Drug interactions of each individual component of the preparation are well known. There is no reason to assume that the use of these ingredients 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, 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 causes an increase in its peak plasma levels. Domperidone may similarly increase the rate of paracetamol absorption. Paracetamol may prolong the elimination half-life of chloramphenicol.

Paracetamol may reduce the bioavailability of lamotrigine, potentially reducing its effect, possibly due to 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 measured by the phosphotungstic acid method.

Paracetamol should be used with caution with flucloxacillin, as their concomitant use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors.

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 the drug is contraindicated in patients undergoing therapy with monoamine oxidase inhibitors (MAOIs) and in patients who have taken MAOIs within the previous 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 adverse effects.

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

Prolonged intake of large doses during disulfiram treatment inhibits the disulfiram–alcohol reaction.

Special precautions for use.

The medicinal product should be used with caution in patients with:

• renal and/or hepatic impairment;
• acute hepatitis;
• haemolytic anaemia;
• chronic malnutrition and dehydration;
• cardiovascular diseases;
• diabetes mellitus;
• benign prostatic hyperplasia, as patients may be prone to urinary retention;
• obstructive peptic ulcer.

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 product is not recommended for concomitant use 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 Raynaud's disease, cardiac disorders (including arrhythmia, bradycardia), thyroid disorders, glaucoma, chronic pulmonary diseases, and in patients taking medicinal products affecting the liver, as well as in elderly patients. Elderly patients with confusion should avoid taking this medicinal product. 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 do not improve within 5 days or are accompanied by high fever lasting more than 3 days, skin rash, or persistent headache;
• regarding the possibility of using the product in case of renal or hepatic impairment.

These conditions may indicate a more serious underlying disease.

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 those 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 5-oxoproline (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). These patients 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 close monitoring of the patient. 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 10 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 colourant AG red (E 129), 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 product authorization is important. It 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 established.

Pregnancy.

Analysis of a large amount of data from pregnant women has not revealed teratogenic or fetotoxic/neonatal toxic effects. However, epidemiological studies on the impact of paracetamol on fetal 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 on reproductive function or embryotoxic/fetotoxic effects from the use of pheniramine.

Only limited data are available on the use of phenylephrine hydrochloride in pregnant women. Vasoconstriction of the uterus and reduced 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 not considered clinically significant. Available published data do not justify recommending discontinuation of breastfeeding during treatment with this product.

There is insufficient information on the excretion of pheniramine into breast milk and the amount 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.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

For oral use. In adults and children aged 12 years and older, the recommended dose is 1 sachet every 4–6 hours (as needed to relieve symptoms), 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 one 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 possible duration should be used.

Patients with Hepatic Impairment

In 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 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; in severe cases, hepatic necrosis may develop. Paracetamol overdose, including high cumulative doses taken over a prolonged period, may cause analgesic-induced nephropathy with irreversible liver dysfunction.

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—such as chronic excessive ethanol consumption, glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, cachexia)—ingestion 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 fatal outcome.

With prolonged use of the drug in high doses, blood disorders such as aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop. Central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects may include nephrotoxicity (renal colic, interstitial nephritis, cortical necrosis).

Symptoms of paracetamol overdose appearing within the first 24 hours include pallor, nausea, vomiting, and anorexia. The first sign of liver damage may be abdominal pain, which does not always manifest within the first 24–48 hours and may appear later, within 4–6 days after ingestion. Liver injury typically occurs within 72–96 hours after drug intake. Abnormalities in glucose metabolism (hypoglycemia) and metabolic acidosis, as well as hemorrhages, 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:
In case of paracetamol overdose, immediate medical attention is required, even if no symptoms of overdose are apparent. Administration of intravenous or oral N-acetylcysteine 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 after 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, skin 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, impaired consciousness, arrhythmias, coma, and seizures may occur.

Cases of atropine-like "psychosis" following pheniramine overdose have been reported. 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 care should be provided, including administration of activated charcoal, saline laxative, and standard supportive measures for the cardiovascular and respiratory systems. Stimulants must not be used; vasoconstrictors may be used to treat arterial hypotension.

Alpha-receptor blockers (e.g., phentolamine) for intravenous administration may be used to counteract hypertensive effects.

Adverse Reactions

The adverse reactions listed below are categorized by frequency: very common (≥ 1/10), common (≥1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from 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 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 liver enzyme levels, usually without development of jaundice.

Renal and urinary disorders: rare – dysuria, nephrotoxicity, renal colic; very rare – urinary retention (more likely in patients with prostate 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 QT interval prolongation or cardiac arrhythmia.

Shelf life. 2 years.

Storage conditions.

Store in a place inaccessible to children, 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 (without prescription).

Manufacturer.

Haleon US Inc.

Manufacturer's address.

10401 HWY 6, Lincoln, Nebraska (NE) 68517, USA.