Fluber forte

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

Composition:

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

One sachet contains: paracetamol 650 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; lemon flavoring; colorant "Quinoline yellow" (E104).

Pharmaceutical form. Powder for oral solution.

Main physicochemical characteristics: white or almost white powder with a lemon odor.

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 a histamine H1-receptor antagonist that reduces vascular permeability and relieves tearing, as well as itching of eyes and nose.

Phenylephrine hydrochloride is an α-adrenomimetic agent with vasoconstrictive properties, 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, penetrates slightly into breast milk, 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 about 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 associated with:

• elevated body temperature,
• headache,
• nasal congestion,
• runny nose,
• muscle pain and aching.

Contraindications. Hypersensitivity to the components of the drug; 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; concomitant therapy with tricyclic antidepressants, β-blockers, other sympathomimetics, drugs that suppress or enhance appetite, and amphetamine-like psychostimulants; simultaneous use or within 2 weeks after treatment with monoamine oxidase inhibitors (MAOIs).

Interaction with Other Medicinal Products and Other Forms of Interactions

The absorption rate of paracetamol may be increased when used concomitantly 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 significant 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 paracetam0l 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. The drug should not be used concomitantly with alcohol.

Phenylephrine interaction 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 adverse cardiovascular reactions and hypertension; may reduce the effectiveness of β-blockers and other antihypertensive agents (reserpine, methyldopa, debrezine, guanethidine), increasing the risk of arterial hypertension and cardiovascular adverse reactions. Concomitant use of phenylephrine with ergot alkaloids (ergotamine, 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 antipsychotics 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; high 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 high 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 beverages.

Pheniramine enhances the anticholinergic effects of atropine, spasmolytics, tricyclic antidepressants, and antiparkinsonian agents, and inhibits 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 when administered concomitantly with flucloxacillin, as such concomitant 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 Warnings and Precautions for Use").

Special precautions for use

Do not exceed the recommended doses. If the condition does not improve within 5 days or is accompanied by high fever, persistent chills lasting more than 3 days, rash, or prolonged headache, consult a physician, as these symptoms may indicate a more serious illness.

Due to the risk of severe liver damage in case of overdose, do not use simultaneously with other medications for symptomatic treatment of colds and nasal congestion (vasoconstrictors, paracetamol-containing products). 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 lung diseases, prostate hyperplasia (due to the 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. If the 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.

This medicinal product contains sodium. It should be used with caution in patients on a sodium-controlled diet.

Consult a physician before use if the patient has liver or kidney disease; is taking warfarin or similar anticoagulants; takes analgesics daily for mild forms of arthritis; or has 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), in which glutathione levels are reduced, 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. In such cases, seek immediate medical attention.

It is not recommended to take this medicinal product late in the day, 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 arterial blood pressure should be monitored.

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

Long-term 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-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe conditions such as severe renal insufficiency or sepsis, or in patients with inadequate nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. If high anion gap metabolic acidosis due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, and the patient's condition should be closely monitored. Measurement of urinary 5-oxoproline levels may be helpful in identifying pyroglutamic acidosis as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy or breastfeeding. The effect of the medicinal product on fertility has not been specifically studied. Preclinical studies have not revealed 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.

Ability to affect reaction speed when driving or operating machinery
Since this medicinal product may cause drowsiness and other adverse reactions affecting the nervous system and visual organs, driving a vehicle or operating complex machinery is not recommended during treatment.

Method of Administration and Dosage

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

Maximum duration of use — 5 days.

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

Overdose.

Paracetamol: within the first 24 hours, symptoms include pallor, nausea, vomiting, anorexia, and abdominal pain. After ingestion of large doses, disturbances in orientation, psychomotor agitation, dizziness, sleep disturbances, cardiac arrhythmias, pancreatitis, and hepatonecrosis may occur. The first sign of liver damage may be abdominal pain, which does not always manifest within the first 12–48 hours and may appear later, within 4–6 days after administration. Liver injury typically develops within 72–96 hours after drug 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, presenting as severe lumbar pain, hematuria, and proteinuria. Nephrotoxicity is possible: renal colic, interstitial nephritis, capillary necrosis.

Ingestion of 10 g or more of paracetamol (especially with alcohol) in adults or more than 150 mg/kg body weight in children may lead to hepatocellular necrosis, resulting in encephalopathy, hemorrhages, hypoglycemia, hepatic coma, and potentially 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; alcohol abuse; glutathione deficiency (digestive disorders, cystic fibrosis, HIV infection, starvation, cachexia)], ingestion of 5 g or more of paracetamol may lead to liver damage.

In case of overdose, immediate medical assistance is required. The patient should be taken to hospital immediately, even if no early symptoms of overdose are present. 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 blood concentration should be measured 4 hours or later after ingestion (earlier concentrations 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 time, the effectiveness of N-acetylcysteine decreases sharply. If intravenous administration of N-acetylcysteine is required, it should be given in doses according to current guidelines. Alternatively, in the absence of vomiting and outside hospital 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, arterial hypertension; in severe cases — coma. To counteract hypertensive effects, intravenous alpha-receptor blockers may be used; for seizures — diazepam.

Pheniramine: anticholinergic-like symptoms occur: mydriasis, photophobia, dryness of skin and mucous membranes, hyperthermia, intestinal atony. CNS depression leads to respiratory and cardiovascular system dysfunction (bradycardia, arterial hypotension, collapse). Symptoms caused by mutual potentiation of the anticholinergic effect of pheniramine and the sympathomimetic effect of phenylephrine: drowsiness, which may progress to agitation (especially in children) or CNS depression, visual disturbances, rash, persistent headache, nervousness, insomnia, hyperreflexia, irritability, circulatory disturbances, bradycardia. 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 cardiopulmonary system. Stimulants must not be used; vasoconstrictors may be used to treat arterial hypotension.

Ascorbic acid: symptoms include nausea, vomiting, or diarrhea (which resolve after discontinuation); bloating and abdominal pain, itching, skin rashes, increased excitability. Doses exceeding 3000 mg may cause temporary osmotic diarrhea and gastrointestinal disturbances, disturbances in zinc and copper metabolism, myocardial dystrophy; prolonged use in high doses may lead to suppression of the pancreatic islet apparatus function and glucosuria. Overdose may lead to changes in renal excretion of ascorbic and uric acids during urine acidification, resulting in precipitation of oxalate stones.

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

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, fear, insomnia, drowsiness, confusion, hallucinations, psychomotor agitation, disorientation, depression, paraesthesia, tinnitus; in isolated cases — coma, seizures, 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 (when high doses are used).

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 system disorders: nephrotoxicity, interstitial nephritis, capillary necrosis, dysuria, urinary retention and difficulty in micturition, 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, pheniramine use is not associated with QT interval prolongation or cardiac arrhythmia.

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

Shelf life. 2 years.

Storage conditions

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

Keep out of reach of children.

Packaging

20 g in sachets, 10 sachets per box.

Availability category. Over-the-counter.

Manufacturer: ASTRAFARM LLC.

Manufacturer’s address and location of operations: 6 Vulytsia Kyivska, Vyshneve, Buchanskyi District, Kyiv Oblast, 08132, Ukraine.

Marketing Authorization Holder: BERKANA+ LLC.

Address of Marketing Authorization Holder: 20/1 Pushkina Street, m. Bohodukhiv, Bohodukhiv District, Kharkiv Oblast, 62103, Ukraine.