Fluban

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUBAN (FLUBAN)

Composition:

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

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

Excipients: sugar coating, maltodextrin, pregelatinized starch, colloidal silicon dioxide, lemon flavor, sodium citrate dihydrate, citric acid, sucrose, colorant yellow D&C No. 10 (E104), colorant FD&C red No. 40 (E129).

Pharmaceutical form. Oral powder for solution.

Main physicochemical properties: free-flowing granular white powder with specks of various shades of yellow and/or orange.

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 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 paracetamol, such as maintaining 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 primarily acts directly on alpha-adrenergic receptors. When used in therapeutic doses to relieve nasal congestion, it does not produce 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 blocker that exerts antiallergic effects, reduces the intensity of local exudative manifestations, and alleviates lacrimation, rhinorrhea, and itching in the eyes and nose. The reduction of systemic allergic symptoms associated with respiratory tract diseases produces a moderate sedative effect. Pheniramine maleate also exhibits antimuscarinic activity.

Ascorbic acid may help compensate for the increased demand 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 is distributed into most body tissues. It crosses the placental barrier and is excreted in breast milk. At usual therapeutic doses, paracetamol is only minimally 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 (MAO) in the intestine and liver; thus, oral phenylephrine has reduced bioavailability. It is excreted in urine almost entirely as sulfate conjugate. Peak plasma concentrations occur 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 throughout all body cells. Approximately 25% is protein-bound in plasma. Excess ascorbic acid is excreted in urine as metabolites.

Clinical Characteristics

Indications. For the treatment of symptoms of influenza and colds, particularly fever and chills, headache, nasal discharge, 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, prostatic hypertrophy with urinary retention, bladder neck obstruction, pyloroduodenal obstruction, bronchial asthma, epilepsy, sleep disorders.

Do not use 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

Interactions of each individual component of the drug are well known. There is no reason to assume that the use of these substances 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 increase the likelihood of paracetamol accumulation and overdose. The risk of hepatotoxic effects of paracetamol increases in patients receiving drugs that induce hepatic microsomal enzymes, such as barbiturates and antiepileptic agents (phenytoin, phenobarbital, carbamazepine), and antituberculosis drugs rifampicin and isoniazid.

Paracetamol should be used cautiously with flucloxacillin, as concomitant administration is associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions").

Metoclopramide increases the absorption rate of paracetamol and leads to higher plasma peak levels. Domperidone may similarly increase the rate of paracetamol absorption.

Paracetamol may prolong the elimination half-life of chloramphenicol.

Paracetamol may reduce lamotrigine bioavailability, decreasing its effect, likely 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 use of paracetamol with zidovudine may lead to neutropenia and increase the risk of liver damage.

Paracetamol reduces the effectiveness of diuretics.

Probenecid affects paracetamol metabolism. The dose of paracetamol should be reduced in patients taking probenecid concomitantly.

Hepatotoxicity of paracetamol 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.

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. Use of the drug is contraindicated during therapy with monoamine oxidase inhibitors (MAOIs) and for 2 weeks after discontinuation of MAOI treatment. Phenylephrine may potentiate the action of MAOIs and provoke a hypertensive crisis.

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

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

Concomitant use of phenylephrine with digoxin and cardiac glycosides may lead to cardiac arrhythmias or cardiac events.

Concomitant use of phenylephrine with ergot alkaloids (ergotamine, methysergide) increases 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, and 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 concomitant use increases iron toxicity, especially in the myocardium. Prolonged use of high doses during disulfiram therapy inhibits the disulfiram–alcohol reaction.

Special precautions for use.

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

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

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 lead to liver failure, which may require liver transplantation or result in fatal outcome.

The medicinal 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 alcohol dependence, Raynaud's disease, cardiac disorders (particularly arrhythmia, bradycardia), thyroid disorders, glaucoma, chronic pulmonary 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 known risk of premature closure of the fetal ductus arteriosus associated with paracetamol use during pregnancy.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria (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. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and careful monitoring are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

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 renal or hepatic dysfunction.

These symptoms may indicate a more serious underlying condition.

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.

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 risk of metabolic acidosis increases during paracetamol treatment. 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.

Excipients

One sachet contains 20 g of sucrose, which should be taken into account in patients with diabetes mellitus. This product should not be used by patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

The medicinal product contains the colouring agents D&C Yellow No. 10 (E 104) and FD&C Red No. 40 (E129), which may cause allergic reactions.

The product contains sodium. This should be considered by patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

The use of this medicinal product is not recommended during pregnancy or breastfeeding, as its safety under these conditions has not been established.

Pregnancy. Extensive data from pregnant women have not shown congenital or foetal/neonatal toxicity associated with paracetamol. 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 studies or data on embryotoxicity/foetotoxicity with the use of pheniramine.

There are only limited data available on the use of phenylephrine hydrochloride during pregnancy. Vasoconstriction of the uterine vessels and reduced uterine blood flow associated with phenylephrine use may lead to fetal hypoxia.

Breastfeeding. Paracetamol is excreted in breast milk, but in amounts that are not clinically significant. Available published data do not justify discontinuation of breastfeeding during paracetamol therapy.

There is insufficient information regarding the excretion of pheniramine into breast milk and the amount that may be transferred to the infant.

There are no data on whether phenylephrine passes into breast milk.

Ascorbic acid is excreted in breast milk but reaches saturation levels. The use of ascorbic acid is considered compatible with 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 working with machines requiring concentration.

Method of Administration and Dosage

For oral use.

For adults and children aged 12 years and older, administer 1 sachet every 4–6 hours (to relieve symptoms), but not more than 4 sachets per day. The single dose must not exceed 1 sachet. The minimum interval between doses is 4 hours. It is not recommended to use the medicinal product for longer than 7 days without consulting a physician. The lowest effective dose for the shortest duration should be used.

The contents of 1 sachet should be dissolved in a glass of boiled hot water (but not boiling water) and taken warm.

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. Do not use 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, liver necrosis may develop. Paracetamol overdose, particularly due to high total doses administered over a prolonged period, may lead to nephropathy with irreversible liver function impairment.

Liver damage is possible in adults who have taken 10 g or more of paracetamol, and in children who have taken 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, especially 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, liver failure may progress to encephalopathy, coma, and may be fatal.

With prolonged use of the drug in high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia may develop from the hematopoietic system. When large doses are taken, dizziness, psychomotor agitation, and disorientation may occur from the central nervous system; from the urinary system—nephrotoxicity (renal colic, interstitial nephritis, capillary necrosis) may occur.

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 administration. Liver damage usually occurs within 72–96 hours after drug intake. Deviations from normal 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 damage, 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 assistance is required, even if symptoms of overdose are not apparent. N-acetylcysteine may be administered intravenously or orally as an antidote to paracetamol in the early phase. Gastric lavage and/or oral administration of methionine may be beneficial within 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 used.

Symptoms caused by pheniramine maleate and phenylephrine hydrochloride are due to the mutual potentiation of the anticholinergic effect of the antihistamine and the sympathomimetic effect of phenylephrine hydrochloride. These include, in particular, 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, impaired 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.

Symptoms of ascorbic acid overdose will be attributed to severe hepatic failure caused by paracetamol overdose.

Treatment. There is no specific antidote for the treatment of antihistamine overdose. Standard emergency care should be provided to the patient, including administration of activated charcoal, a saline laxative, and standard supportive measures for the cardiopulmonary system. 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 in case of seizures—diazepam.

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 (≥1/10000, < 1/1000), very rare (< 1/10000), 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: rare – mydriasis, acute angle-closure glaucoma (more frequently in patients with glaucoma); frequency not known – accommodation disorders.

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

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

Metabolism and nutrition disorders: frequency not known – metabolic acidosis with high anion gap.

Gastrointestinal disorders: common – nausea, vomiting; rare – dry mouth, constipation, abdominal pain and discomfort, diarrhea, heartburn, decreased appetite, hypersalivation.

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 prostatic hyperplasia).

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

General disorders: rare – general weakness, malaise.

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

Description of selected adverse reactions

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions"). Pyroglutamic acidosis may develop due to low glutathione levels in these patients.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Packaging. 10 sachets per cardboard box.

Prescription status. Over-the-counter.

Manufacturer. Vivimed Labs Ltd

Manufacturer's address and location of its operations. D-125 and 128, Phase-III, IDA, Jeedimetla, Medchal-Malkajgiri District - 500055, Telangana State, India