Fervex for adults

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FERVEX FOR ADULTS

Composition:

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

1 sachet contains 500 mg of paracetamol, 200 mg of ascorbic acid (vitamin C), 25 mg of pheniramine maleate;

Excipients: sucrose; citric acid, anhydrous; sodium saccharin; Antillean flavoring, containing α-pinene, β-pinene, limonene, γ-terpinene, linalool, neral, α-terpineol, geranial, maltodextrin, acacia, dextrose, silicon dioxide (E551), butylated hydroxyanisole (E320), sugar syrup, ethanol, potassium, sodium, Peru balsam.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: granular light beige-colored powder.

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 reduction of inflammatory response in the mucous membranes of the upper respiratory tract (improvement of nasal breathing, reduction of rhinorrhea, sneezing, and lacrimation);
• Paracetamol exerts antipyretic and analgesic effects, relieving pain and fever (headache, myalgia);
• Ascorbic acid compensates for the body's requirement 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 mainly metabolized in the liver to form conjugates with glucuronic acid and sulfates. A minor metabolic pathway, catalyzed by cytochrome P450, leads to 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 cases of severe overdose, the amount of this toxic metabolite increases.

Paracetamol is excreted in urine primarily as metabolites. Approximately 90% of the administered dose is eliminated by the kidneys within 24 hours, mainly 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, rhinitis, rhinopharyngitis, and influenza-like conditions manifested by nasal discharge, lacrimation, sneezing, hoarseness, and/or headache.

Contraindications.

Hypersensitivity to the components of the drug or to other antihistamines; severe impairment of liver and/or kidney function; congenital hyperbilirubinemia; glucose-6-phosphate dehydrogenase deficiency; alcoholism; blood disorders; pronounced anemia; leukopenia; severe arterial hypertension; unstable angina pectoris; severe cardiac conduction disorders; acute phase of myocardial infarction; severe atherosclerosis; uncompensated heart failure; hyperthyroidism; acute urinary retention due to prostate hyperplasia; bladder neck obstruction; pyloroduodenal obstruction; active gastric or duodenal ulcer; closed-angle glaucoma; thrombosis; thrombophlebitis; severe forms of diabetes mellitus; epilepsy; elderly age; fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency due to sucrose content; phenylketonuria.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within two weeks after discontinuation of MAOIs. Fervex for adults is contraindicated in patients taking tricyclic antidepressants or β-blockers in urolithiasis when ascorbic acid intake exceeds 1 g per day.

Interaction with other medicinal products and other forms of interaction.

Undesirable combinations.

Due to the presence of pheniramine, ethanol enhances the sedative effect of H1-blockers; therefore, patients should refrain from driving or operating machinery. During treatment, avoid consumption of alcoholic beverages and use of medicinal products containing ethanol.

Combinations to be taken into account.

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

Due to the presence of pheniramine, medicinal products with anticholinergic (atropine-like) effects—such as imipramine-type antidepressants, most anticholinergic H1-blockers, anticholinergics, antiparkinsonian agents, atropine-like spasmolytics, disopyramide, phenothiazine neuroleptics, and clozapine—may enhance undesirable anticholinergic 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 four 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 interfere with blood glucose measurement by the glucose oxidase-peroxidase method, leading to abnormally high concentrations, and with blood urea measurement by the phosphotungstic acid method.

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

Anticonvulsants (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. Concomitant use of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the effectiveness of diuretics.

Ascorbic acid enhances intestinal absorption of iron, increases blood levels of ethinylestradiol, penicillins, and tetracyclines, and reduces blood levels of antipsychotics and phenothiazine derivatives. Glucocorticoids reduce ascorbic acid stores. Concurrent intake of ascorbic acid and deferoxamine increases tissue iron toxicity, particularly in cardiac muscle, potentially leading to circulatory decompensation. Ascorbic acid may be administered only two hours after deferoxamine injection. High doses of ascorbic acid reduce the effectiveness of tricyclic antidepressants. Absorption of ascorbic acid is reduced by concomitant use of oral contraceptives, fruit or vegetable juices, and alkaline drinks.

Paracetamol should be used with caution when administered concomitantly with flucloxacillin, as co-administration 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.

In case of high body temperature or prolonged fever persisting for 5 days despite using the medication, or if signs of superinfection appear, consult a physician to determine whether continued use of the medication is appropriate.

Use with caution in patients with diabetes mellitus.

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

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

Risk of primarily psychological dependence may occur with doses exceeding the recommended levels or with prolonged treatment.

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

For adults with body weight over 50 kg, the total daily dose of paracetamol should not exceed 4 g.

Metabolic acidosis with a high anion gap (high anion gap metabolic acidosis (HAGMA)) due to pyroglutamic acidosis has been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses over a prolonged period 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.

Precautionary measures.

Consumption of alcoholic beverages or use of sedatives (especially barbiturates) increases the sedative effect of pheniramine maleate; therefore, avoid using these substances during treatment.

Each sachet contains 7.6 g of sucrose, which should be taken into account by patients with diabetes mellitus and those on a low-sugar diet.

This medicinal product contains 5 mg of fructose in one sachet. The additional effect from concomitant intake of products containing fructose (or sorbitol) and dietary consumption of fructose (or sorbitol) should be considered.

This medicinal product contains 195 mg of glucose in one sachet. This medicinal product should not be used by patients with glucose-galactose malabsorption (a rare inherited disorder).

This medicinal product should not be used by patients with fructose intolerance, glucose-galactose malabsorption, or sucrase/isomaltase deficiency (rare inherited disorders).

This medicinal product contains less than 1 mmol of sodium (23 mg) per sachet, i.e., it is practically sodium-free.

This medicinal product contains 7 mg of ethanol (alcohol) per sachet, equivalent to less than 1 ml of beer or 1 ml of wine, which is unlikely to have a noticeable effect.

Use during pregnancy or breastfeeding.

Since the effect of the medication on pregnancy or breastfeeding has not been sufficiently studied, it should not be administered during these periods.

Ability to affect reaction speed when driving or operating machinery.

The medication may cause drowsiness; therefore, patients should refrain from driving vehicles or operating machinery while taking this medication.

Dosage and Administration

For oral use. Adults and children aged 15 years and older should take 1 sachet 2–3 times daily. The contents of the sachet should be dissolved in a sufficient amount of cold or warm water. The solution should be taken immediately after preparation. For patients with symptoms of a cold, it is preferable to take the warm solution in the evening. The interval between doses should be at least 4 hours.

Maximum duration of treatment is 5 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

Do not use in children under 15 years of age.

Overdose

Related to pheniramine

Overdose of pheniramine may cause seizures (especially in children), impaired consciousness, and coma.

Related to paracetamol

There is a risk of toxicity in elderly individuals and particularly in young children (therapeutic overdose and accidental poisoning occur quite frequently).

Paracetamol overdose can be fatal.

Symptoms

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

An intake exceeding 10 g of paracetamol in a single dose in adults or 150 mg/kg body weight in a single dose in children may lead to hepatic cytolysis, which can result in complete and irreversible necrosis and hepatocellular insufficiency, metabolic acidosis, encephalopathy, potentially progressing to coma and death.

Elevated levels of liver transaminases, lactate dehydrogenase, and bilirubin, along with increased prothrombin time, may be observed 12–48 hours after ingestion.

Emergency measures:

• Immediate hospitalization;
• Determination of initial plasma paracetamol concentration;
• Immediate removal of the ingested 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

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia, and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia; thrombosis, hyperprothrombinemia, erythrocytopenia, thrombocytopenia, agranulocytosis, neutrophilic leukocytosis, purpura, leukopenia, neutropenia.

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

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

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

Endocrine system disorders: hypoglycemia up to hypoglycemic coma.

Nervous system disorders: rarely – headache, dizziness, sleep disturbances, insomnia, somnolence, confusion, hallucinations, nervousness, tremor; in individual cases – coma, seizures, dyskinesia, behavioral changes, increased excitability; disturbances of balance and memory, inattention, especially in elderly patients.

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

Metabolic and nutritional disorders: disturbances in zinc and copper metabolism, metabolic acidosis with high anion gap.

Renal and urinary system disorders: urinary retention and difficulty in urination, aseptic pyuria, renal colic.

Skin disorders: eczema.

Eye disorders: 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 (hyperglycemia, glucosuria), and impaired glycogen synthesis up to the development of diabetes mellitus.

Description of specific adverse reactions

Metabolic acidosis with high anion gap

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

Shelf life. 3 years.

Storage conditions.

Store at a temperature 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 place of business.

304, avenue du Docteur Jean Bru, 47000 Agen, France;
979, avenue des Pyrenees, 47520 Le Passage, France.