Fervex for children

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FERVEX FOR CHILDREN

Composition:

Active substances: paracetamol, ascorbic acid (vitamin C), pheniramine maleate;

1 sachet contains 280 mg paracetamol, 100 mg ascorbic acid (vitamin C), 10 mg pheniramine maleate;

Excipients: mannitol (E 421), anhydrous citric acid, povidone, anhydrous trima­gnesium dicitrate, potassium acesulfame, raspberry flavoring containing the yellow-orange S dye (E 110).

Pharmaceutical form. Oral powder for solution.

Main physicochemical characteristics: Granular powder ranging from light pink to dark pink in color; small dark particles may be observed.

Pharmacotherapeutic group.

Other combination drugs used in colds.

ATC code N02B E51.

Pharmacological Properties.

Pharmacodynamics.

Pharmacological effects due to the components of the drug:

• pheniramine maleate – an H₁ histamine receptor blocker, provides a desensitizing effect manifested by a reduction in inflammatory reactions of the mucous membranes of the upper respiratory tract (improvement in nasal breathing, reduction in rhinorrhea, sneezing, and lacrimation);
• paracetamol exerts antipyretic and analgesic effects, alleviating pain and fever (headache, myalgia);
• ascorbic acid compensates for the body's need for vitamin C.

Pharmacokinetics.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Maximum plasma concentration of paracetamol is reached within 30–60 minutes after administration. Paracetamol is rapidly distributed in all tissues. Concentrations in blood, saliva, and plasma are similar. Plasma protein binding is weak.

Paracetamol is primarily metabolized in the liver, forming conjugates with glucuronic acid and sulfates. A minor metabolic pathway, catalyzed by cytochrome P450, leads to the formation of a reactive intermediate (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation with cysteine and mercapturic acid. However, in severe poisoning, the amount of this toxic metabolite increases.

It is excreted in urine, mainly as metabolites. Approximately 90% of the administered dose is eliminated by the kidneys within 24 hours, primarily as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%).

About 5% of the administered dose is excreted unchanged. The elimination half-life is approximately 2 hours.

Pheniramine maleate is well absorbed from the gastrointestinal tract. It is primarily excreted by the kidneys. The plasma half-life is 60–90 minutes.

Ascorbic acid is well absorbed from the gastrointestinal tract. It is primarily excreted in urine.

Clinical characteristics.

Indications.

Symptomatic treatment of colds, rhinopharyngitis in children (aged 6 years and older), and conditions manifested by rhinitis, lacrimation, sneezing, fever and/or headache.

Contraindications.

Hypersensitivity to the components of the drug or to other antihistamines; severe impairment of liver and/or kidney function; phenylketonuria; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders; marked anemia; leukopenia; severe arterial hypertension; unstable angina; severe cardiac conduction disorders; acute phase of myocardial infarction; severe atherosclerosis; decompensated heart failure; hyperthyroidism; acute urinary retention due to prostate hyperplasia; bladder neck obstruction; pyloroduodenal obstruction; gastric and duodenal ulcer in the stage of exacerbation; closed-angle glaucoma; thrombosis; thrombophlebitis; epilepsy; severe forms of diabetes mellitus. Do not use together with MAO inhibitors and within two weeks after discontinuation of MAO inhibitors. Contraindicated in patients taking tricyclic antidepressants or beta-blockers. Urolithiasis – under conditions where ascorbic acid enters the body in doses exceeding 1 g per day.

Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

Precautionary measures.

The use of sedatives (especially barbiturates) increases the sedative effect of pheniramine maleate; therefore, such combinations should be avoided during treatment.

Undesirable combinations.

Due to the presence of pheniramine, ethanol enhances the sedative effect of H1-blockers; therefore, during treatment, avoid using medicinal products containing ethyl alcohol.

Combinations to be taken into account.

Due to the presence of pheniramine, other sedatives may cause central nervous system depression; these include: morphine derivatives (analgesics, antitussives, replacement therapy), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (e.g., meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-blockers, centrally acting antihypertensives, baclofen, and thalidomide.

Due to the presence of pheniramine, medicinal products with anticholinergic (atropine-like) effects, such as: imipramine antidepressants, most antihistaminic H1-blockers with anticholinergic activity, anticholinergics, antiparkinsonian agents, atropine-like spasmolytics, disopyramide, phenothiazine neuroleptics, and clozapine, may add undesirable atropine-like effects, such as urinary retention, constipation, and dry mouth.

Concomitant use with oral anticoagulants may increase their effect and elevate the risk of bleeding when paracetamol is taken at maximum doses (4 g/day) for at least 4 days. Regular monitoring of INR (International Normalized Ratio) is recommended. If necessary, the dose of oral anticoagulant may be adjusted during and after paracetamol treatment.

Paracetamol intake may affect blood glucose determination by the glucose oxidase-peroxidase method, resulting in abnormally high concentrations.

Paracetamol intake may affect blood urea determination by the phosphotungstic acid method.

The absorption rate of paracetamol may be increased by concomitant use with metoclopramide and domperidone, and decreased by use with cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites. Concurrent use of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Do not use simultaneously with alcohol.

Ascorbic acid increases intestinal absorption of iron, increases levels of ethinylestradiol, penicillins, and tetracyclines; decreases blood levels of antipsychotic drugs and phenothiazine derivatives. Glucocorticosteroids reduce body stores of ascorbic acid. Concurrent administration of ascorbic acid and deferoxamine increases tissue toxicity of iron, especially in cardiac muscle, which may lead to circulatory decompensation. It should be administered only 2 hours after deferoxamine injection. High doses of ascorbic acid reduce the effectiveness of tricyclic antidepressants. Absorption of ascorbic acid is reduced when used concomitantly with oral contraceptives, fruit or vegetable juices, and alkaline drinks.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients at risk ("Special precautions for use").

Special precautions for use

In case of high body temperature or prolonged fever persisting for 3 days despite using the medication, or if signs of superinfection appear, consult a physician to determine whether continued use of the medication is appropriate.

Alcohol enhances the sedative effect of pheniramine maleate and the hepatotoxicity of paracetamol.

Ascorbic acid may alter the results of laboratory tests (blood glucose, bilirubin, transaminase activity).

The risk of developing psychological dependence may occur when recommended doses are exceeded or with prolonged treatment.

To prevent overdose, check and exclude all medications containing paracetamol.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over a prolonged period or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring. 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.

This medicinal product contains an azo dye (E110) which may cause allergic reactions.

Maximum recommended doses

• Children with body weight less than 37 kg: total daily dose of paracetamol should not exceed 80 mg/kg body weight per day;
• Children with body weight from 38 kg to 50 kg: total daily dose of paracetamol should not exceed 3 g/day;
• Children with body weight over 50 kg: total daily dose of paracetamol should not exceed 4 g/day.

Use during pregnancy or breastfeeding

This medicinal product in this pharmaceutical form should be used only in children.

Effect on ability to drive vehicles or operate machinery

This medicinal product in this pharmaceutical form should be used only in children.

Dosage and Administration.

For oral use. Dissolve the contents of the sachet in a sufficient amount of cold or warm water.

This dosage form is intended for use in children only (aged 6 years and older):

• 6–10 years: 1 sachet twice daily.
• 10–12 years: 1 sachet three times daily.
• 12–15 years: 1 sachet four times daily.

The interval between doses should be at least 4 hours. The maximum duration of treatment is 3 days.

For patients with impaired renal function (creatinine clearance less than 10 mL/min), the interval between doses should be at least 8 hours.

If symptoms do not resolve or worsen, medical advice should be sought.

Children.

The medicinal product is indicated for children aged 6 to 15 years.

Overdose.

Related to pheniramine.

Pheniramine overdose may cause seizures, disturbances of consciousness, and coma.

Related to paracetamol.

There is a risk of intoxication, particularly in young children (therapeutic overdose and accidental poisoning occur relatively frequently).

Paracetamol overdose can be fatal.

Symptoms:

Nausea, vomiting, anorexia, pallor, excessive sweating, abdominal pain, usually appearing within the first 24 hours.

Paracetamol overdose exceeding 150 mg/kg body weight in a single dose in children causes hepatic cytolysis, which may lead to complete and irreversible necrosis and hepatocellular failure, metabolic acidosis, encephalopathy, potentially resulting in coma and fatal outcome.

Concurrently, elevated levels of liver transaminases, lactate dehydrogenase, and bilirubin are observed, along with increased prothrombin levels, which may manifest 12–48 hours after administration.

Emergency measures:

• Immediate hospitalization;
• Determination of initial plasma paracetamol concentration;
• Immediate removal of the administered drug by gastric lavage;
• Standard treatment for overdose includes administration of the antidote N-acetylcysteine, either intravenously or orally. The antidote should be administered as early as possible, preferably within 10 hours after overdose;
• Methionine as symptomatic therapy.

Adverse Reactions

Haematopoietic and lymphatic system: anaemia, sulfhaemoglobinaemia, and methaemoglobinaemia (cyanosis, dyspnoea, chest pain), haemolytic anaemia; thrombosis, hyperprothrombinaemia, erythrocytopaenia, thrombocytopenia, agranulocytosis, neutrophilic leucocytosis, purpura, leucopenia, neutropenia.

Immune system: anaphylaxis, anaphylactic shock, hypersensitivity skin reactions including pruritus, skin and mucous membrane rashes (usually erythematous, urticaria), angioneurotic oedema, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Respiratory system: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Gastrointestinal system: dry mouth, nausea, heartburn, vomiting, constipation, epigastric pain, diarrhoea, liver function disturbances, increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect).

Endocrine system: hypoglycaemia up to hypoglycaemic coma.

Nervous system: rarely – headache, dizziness, sleep disturbances, insomnia, drowsiness, confusion, hallucinations, nervousness, tremor; in individual cases – coma, seizures, dyskinesia, behavioural changes, increased excitability; disturbances of balance and memory, inattention.

Cardiovascular system: in isolated cases – tachycardia, myocardial dystrophy (dose-dependent effect with prolonged use), orthostatic hypotension.

Metabolism: disturbances in zinc and copper metabolism.

Urinary system: urinary retention and difficulty in micturition, aseptic pyuria, renal colic.

Skin: eczema.

Eye organs: dry eyes, mydriasis, accommodation disorders.

With prolonged use in high doses: glomerular apparatus damage in kidneys, crystalluria, formation of urate, cystine and/or oxalate calculi in kidneys and urinary tract; damage to the islet apparatus of the pancreas (hyperglycaemia, glucosuria) and impaired glycogen synthesis up to the development of diabetes mellitus.

Metabolism and nutrition disorders: Metabolic acidosis with high anion gap with frequency "unknown" (cannot be estimated from available data).

Description of individual adverse reactions.

Metabolic acidosis with high anion gap.

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 occur as a consequence of low glutathione levels in these patients.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

8 sachets in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

UPSA SAS, France / UPSA SAS, France.

Manufacturer's address and location of its business activity.

304, avenue du Docteur Jean Bru, 47000 Agen, France / 304, avenue du Docteur Jean Bru, 47000 Agen, France;

979, avenue des Pyrenees, 47520 Le Passage, France / 979, avenue des Pyrenees, 47520 Le Passage, France.