Fluber

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

Composition:

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

One sachet contains: paracetamol 500 mg, phenylephrine hydrochloride 10 mg, pheniramine maleate 20 mg, ascorbic acid 50 mg;

Excipients: citric acid monohydrate; glucose monohydrate; sodium citrate; colloidal anhydrous silicon dioxide; colouring agent "Quinoline yellow" (E104); flavouring agent "Lemon" or flavouring agent "Orange", or flavouring agent "Raspberry".

Pharmaceutical form. Powder for oral solution.

Main physicochemical characteristics: white or almost white powder with a fruity odour.

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

ATC code N02BE51.

Pharmacological Properties

Pharmacodynamics

Paracetamol has antipyretic, analgesic, and weak anti-inflammatory effects. It inhibits prostaglandin synthesis in the central nervous system (CNS) and blocks transmission of pain impulses.

Pheniramine maleate is an H1-histamine receptor blocker that reduces vascular permeability and relieves lacrimation, as well as itching of the eyes and nose.

Phenylephrine hydrochloride is an α-adrenomimetic agent with vasoconstrictive action, reducing swelling of the nasal mucosa and paranasal sinuses.

Ascorbic acid enhances non-specific resistance of the body.

Pharmacokinetics

Paracetamol is well absorbed, crosses the placental barrier, and passes slightly into breast milk. It is metabolized by the cytochrome P450 system, excreted by the kidneys, with a half-life of 1–4 hours. Duration of action is 3–4 hours.

Pheniramine maleate is well absorbed from the gastrointestinal tract. It is metabolized in the liver by the cytochrome P450 system, has a half-life of 16–18 hours, and 70–83% is excreted by the kidneys.

The effect of phenylephrine hydrochloride begins rapidly and lasts approximately 20 minutes. Phenylephrine hydrochloride is metabolized in the liver or gastrointestinal tract and excreted by the kidneys.

Ascorbic acid is rapidly absorbed from the gastrointestinal tract, metabolized in the liver, and excreted by the kidneys.

Clinical characteristics

Indications. For symptomatic treatment of acute respiratory infections and influenza:

• elevated body temperature;
• headache;
• nasal congestion;
• rhinitis;
• muscle pain and aching.

Contraindications. Hypersensitivity to the active substances or to other components of the medicinal product; severe impairment of liver and/or kidney function; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; phenylketonuria, alcoholism; blood disorders; leukopenia; anemia; severe forms of arrhythmia, arterial hypertension, atherosclerosis, ischemic heart disease; hyperthyroidism; acute pancreatitis; prostate hypertrophy with urinary retention; bladder neck obstruction; pyloroduodenal obstruction; bronchial asthma; closed-angle glaucoma; pheochromocytoma; thrombosis; thrombophlebitis; diabetes mellitus; epilepsy; states of increased excitation; sleep disorders, concurrent treatment with tricyclic antidepressants, β-blockers, other sympathomimetics, appetite-suppressing or appetite-enhancing agents, and amphetamine-like psychostimulants; concomitant use within 2 weeks after treatment with monoamine oxidase inhibitors (MAOIs).

Interaction with other medicinal products and other types of interactions

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone, and decreased when used with cholestyramine (this effect is negligible if cholestyramine is administered 1 hour apart). Long-term use of paracetamol may enhance the anticoagulant effect of warfarin and other coumarin derivatives, increasing the risk of bleeding. This effect is not pronounced with occasional use of paracetamol. Barbiturates reduce the antipyretic effect of paracetamol. Hepatotoxic drugs increase the likelihood of paracetamol accumulation and overdose. The risk of paracetamol hepatotoxicity increases with drugs that induce hepatic microsomal enzymes (barbiturates; anticonvulsants — phenytoin, phenobarbital, carbamazepine; antituberculosis agents — rifampicin, isoniazid). Paracetamol reduces the efficacy of diuretics, may prolong the half-life of chloramphenicol; may induce lamotrigine metabolism in the liver, thereby reducing its bioavailability and efficacy. Regular concomitant use of paracetamol and zidovudine may lead to neutropenia and increased risk of liver damage. When probenecid is taken, the dose of paracetamol should be reduced, as probenecid affects paracetamol metabolism. Paracetamol may interfere with the determination of uric acid levels by the phosphotungstic acid method. Hepatotoxicity of paracetamol may be enhanced by prolonged or excessive alcohol consumption. Do not use the medicinal product concomitantly with alcohol.

Interaction of phenylephrine with MAO inhibitors causes a hypertensive effect; with tricyclic antidepressants (amitriptyline) — increases the risk of cardiovascular adverse effects; with digoxin and cardiac glycosides — may lead to arrhythmias and infarction; with other sympathomimetics — increases the risk of cardiovascular adverse reactions and hypertension; may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa, debrisoquin, guanethidine), increasing the risk of arterial hypertension and cardiovascular adverse reactions. Concomitant use of phenylephrine with ergot alkaloids (ergotamine and methysergide) increases the risk of ergotism.

Ascorbic acid, when taken orally, enhances iron absorption; increases blood levels of ethinylestradiol, penicillins, and tetracyclines; reduces blood levels of antipsychotic agents and phenothiazine derivatives; reduces the effectiveness of heparin and indirect anticoagulants; increases the risk of crystalluria during salicylate therapy and the risk of glaucoma during glucocorticoid therapy; large doses reduce the effectiveness of tricyclic antidepressants. Ascorbic acid should be taken only 2 hours after deferoxamine injection, as their concomitant use increases iron toxicity, especially in the myocardium, potentially leading to cardiac decompensation. Prolonged use of large doses during disulfiram therapy inhibits the disulfiram-alcohol reaction. Absorption of ascorbic acid is reduced when taking oral contraceptives, fruit or vegetable juices, or alkaline drinks.

Pheniramine enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents; it may inhibit the action of anticoagulants. Concomitant use of pheniramine with sedatives, barbiturates, tranquilizers, neuroleptics, anesthetics, narcotic analgesics, and alcohol may significantly increase its depressant effects.

Paracetamol should be used with caution concomitantly with flucloxacillin, as such combined use 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").

Special precautions for use

Do not exceed the recommended doses. If symptoms do not improve within 5 days or are accompanied by high fever lasting more than 3 days, rash, or persistent headache, consult a physician, as these may be signs of a more serious illness.

Due to the risk of severe liver damage in overdose, do not use simultaneously with other medications intended for symptomatic treatment of colds and nasal congestion (vasoconstrictors and drugs containing paracetamol). Use with caution in patients with Raynaud's disease, arterial hypertension, heart disease, arrhythmias, bradycardia, thyroid disorders, liver or kidney disease, acute hepatitis, glaucoma, chronic pulmonary diseases, prostate hypertrophy (due to risk of urinary retention), elderly patients, increased blood coagulability, hemolytic anemia, chronic malnutrition, dehydration, or stenosing peptic ulcer. The risk of hepatotoxicity is increased in patients with alcoholic liver disease or those who abuse alcohol.

The active ingredient phenylephrine may provoke angina attacks.

The medicinal product contains glucose, which is contraindicated in patients with intolerance or malabsorption of fructose, glucose-galactose, or sucrose-isomaltose. If a patient has been diagnosed with intolerance to certain sugars, consult a physician before taking this medicinal product. Use with caution in patients with diabetes mellitus. The medicinal product may be harmful to teeth.

Consult a physician before use in cases of: liver or kidney disease; concomitant use of warfarin or similar anticoagulants; daily use of analgesics for mild forms of arthritis; bronchopulmonary diseases (asthma, emphysema, chronic bronchitis).

The medicinal product may affect laboratory test results for blood glucose, uric acid, creatinine, and inorganic phosphates. Occult blood in stool may yield a false-negative result.

In patients with severe infections (sepsis), when glutathione levels are reduced, the use of paracetamol increases the risk of metabolic acidosis, the symptoms of which include: deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. In such cases, seek immediate medical attention.

It is not recommended to take this medicinal product in the evening, as high doses of ascorbic acid have a mild stimulating effect. Due to the stimulating effect of ascorbic acid on corticosteroid hormone production, kidney function and blood pressure should be monitored.

Use with particular caution in patients with iron metabolism disorders (hemochromatosis, hemosiderosis, thalassemia) and in those with a history of nephrolithiasis (risk of hyperoxaluria and oxalate precipitation in the urinary tract after high-dose ascorbic acid intake).

Prolonged use of high doses of ascorbic acid may accelerate its own metabolism, potentially leading to paradoxical hypovitaminosis after discontinuation. Do not use simultaneously with other products containing vitamin C. Absorption of ascorbic acid may be altered in cases of intestinal motility disorders, enteritis, or reduced gastric secretion.

Cases of high anion gap metabolic acidosis due to 5-oxoproline (pyroglutamic) acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with therapeutic doses of paracetamol for prolonged periods or with a combination of paracetamol and flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Warnings regarding excipients

The dye "Quinoline Yellow" (E104) contained in the medicinal product may cause allergic reactions.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy and breastfeeding. The effect of the drug on fertility has not been specifically studied. Preclinical studies have not shown any particular effect of paracetamol on fertility when used at therapeutic doses. Adequate studies on the reproductive toxicity of phenylephrine and pheniramine in animals have not been conducted.

Effect on ability to drive or operate machinery.
Since the medicinal product may cause drowsiness and other adverse reactions affecting the nervous system and vision, driving vehicles or operating complex machinery is not recommended during treatment.

Dosage and Administration

The medicinal product is intended for use in adults and children aged 14 years and older.

Dissolve the contents of the sachet in a glass of hot water (not boiling water) and drink. The dose may be repeated every 3–4 hours, but no more than 3 sachets should be used per day.

Maximum duration of use — 5 days.

Children. The medicinal product is contraindicated in children under 14 years of age.

Overdose

Paracetamol: Within the first 24 hours, symptoms may include pallor, nausea, vomiting, anorexia, and abdominal pain. After ingestion of large doses, disorientation, psychomotor agitation, dizziness, sleep disturbances, cardiac arrhythmias, pancreatitis, and hepatonecrosis may occur. Abdominal pain may be the first sign of liver damage, although it does not always appear within the first 12–48 hours and may manifest later, within 4–6 days after administration. Liver injury typically develops within 72–96 hours after intake. Glucose metabolism disturbances and metabolic acidosis, as well as hemorrhages, may occur. With prolonged use of high doses, aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia are possible.

In isolated cases, acute renal failure with tubular necrosis has been reported, which may occur even in the absence of severe liver damage and presents with severe lumbar pain, hematuria, and proteinuria. Nephrotoxicity may develop: renal colic, interstitial nephritis, capillary necrosis.

Ingestion of 10 g or more of paracetamol by adults, or more than 150 mg/kg body weight by children, especially when combined with alcohol, may lead to hepatocellular necrosis, resulting in encephalopathy, hemorrhages, hypoglycemia, hepatic coma, and fatal outcome. In patients with risk factors [long-term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; chronic alcohol abuse; glutathione depletion (digestive disorders, cystic fibrosis, HIV infection, fasting, cachexia)], ingestion of 5 g or more of paracetamol may cause liver damage.

In case of overdose, immediate medical assistance is required. The patient should be taken to hospital immediately, even in the absence of early symptoms. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Activated charcoal should be administered within the first hour after overdose. Paracetamol plasma concentration should be measured at least 4 hours after ingestion (earlier measurements are unreliable). Treatment with N-acetylcysteine can be initiated within 24 hours after paracetamol intake, but maximum efficacy is achieved when administered within the first 8 hours; after this, its effectiveness declines sharply. If intravenous N-acetylcysteine is required, it should be administered according to current dosing guidelines. Alternatively, in the absence of vomiting and in remote settings, oral methionine may be used.

Phenylephrine: Symptoms include hyperhidrosis, psychomotor agitation or CNS depression, headache, dizziness, drowsiness, impaired consciousness, arrhythmias, tremor, hyperreflexia, seizures, nausea, vomiting, irritability, restlessness, and arterial hypertension; in severe cases — coma. To counteract hypertensive effects, intravenous alpha-receptor blockers may be used; for seizure control — diazepam.

Pheniramine: Anticholinergic-like symptoms occur: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, intestinal atony. CNS depression may lead to respiratory and cardiovascular system dysfunction (bradycardia, arterial hypotension, collapse). Symptoms resulting from the mutual potentiation of the anticholinergic effect of pheniramine and the sympathomimetic effect of phenylephrine include drowsiness, which may progress to agitation (especially in children) or CNS depression, visual disturbances, skin rash, persistent headache, nervousness, insomnia, hyperreflexia, irritability, circulatory disturbances, and bradycardia. 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 cardiorespiratory function. CNS stimulants are contraindicated; vasoconstrictors may be used to treat arterial hypotension.

Ascorbic acid: Symptoms include nausea, vomiting, or diarrhea (which resolve after discontinuation); bloating and abdominal pain, pruritus, skin rashes, and increased excitability. Doses exceeding 3000 mg may cause transient osmotic diarrhea and gastrointestinal disturbances, disturbances in zinc and copper metabolism, and myocardial dystrophy. With prolonged high-dose use, suppression of pancreatic islet function and glucosuria are possible. Overdose may alter renal excretion of ascorbic and uric acids during acetylation of urine, leading to precipitation of oxalate stones.

Treatment is symptomatic: gastric lavage should be performed within the first 6 hours; within the first 8 hours, oral methionine or intravenous cysteamine or N-acetylcysteine should be administered.

Adverse Reactions

Skin and subcutaneous tissue disorders: rash, pruritus, dermatitis, urticaria, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome.

Immune system disorders: hypersensitivity reactions, including anaphylactic shock and angioedema.

Nervous system disorders: headache, dizziness, tremor, restlessness, nervousness, irritability, anxiety, insomnia, somnolence, confusion, hallucinations, psychomotor agitation, disorientation, depression, paraesthesia, tinnitus; in isolated cases — coma, convulsions, dyskinesia, behavioral changes.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and nonsteroidal anti-inflammatory drugs.

Eye disorders: visual disturbances and accommodation disorders, mydriasis, increased intraocular pressure, dry eyes.

Gastrointestinal disorders: nausea, vomiting, heartburn, dry mouth, abdominal discomfort and pain, constipation, diarrhea, flatulence, anorexia, aphthae, hypersalivation, hemorrhages, mucosal irritation.

Hepatobiliary disorders: liver function abnormalities, hypertransaminasemia (usually without jaundice), hepatonecrosis (with high-dose use).

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

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

Renal and urinary disorders: nephrotoxicity, interstitial nephritis, capillary necrosis, dysuria, urinary retention and difficulty in urination, renal colic, renal failure.

Cardiovascular system disorders: arterial hypertension, tachycardia, bradycardia, palpitations, arrhythmia, dyspnea, chest pain, angina attacks.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap (frequency unknown).

Other: general weakness, malaise.

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

Description of selected adverse reactions

Metabolic acidosis with high anion gap. Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been observed in patients with risk factors who were taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 20 g per sachet. 10 sachets per cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer: LLC "ASTRAFARM".

Manufacturer's address and location of business activity: 6, Kyivska Street, Vyshneve, Bucha district, Kyiv region, 08132, Ukraine.

Marketing Authorization Holder: LLC "BERKANA+".

Address of the Marketing Authorization Holder: 20/1 Pushkina Street, m. Bohodukhiv, Bohodukhiv district, Kharkiv region, 62103, Ukraine.