Fervex Cold tablets 16 tablets Rhinitis, flu, nasopharyngitis

Fervex Rhume is a medicine indicated to relieve  colds, rhinitis, nasopharyngitis and flu-like conditions in adults and children over 15 years of age.

It contains 500.00 mg of paracetamol and 4.00 mg of chlorphenamine maleate. The excipient with a known effect is carmoisine (E122).

The medicine Fervex Rhume is available in a box of 16 film-coated tablets. Each tablet contains 500 mg of paracetamol and 4 mg of chlorphenamine maleate.

Dosage of Fervex Cold tablet

The dose of Fervex Rhume for adults and children over 50 kg (15 years) is 1 tablet, to be repeated if necessary every 4 hours, without however exceeding 2000 mg of paracetamol and 16 mg of chlorphenamine per day, or 4 tablets.

The accidental taking of an additional dose or an overdose justifies contacting your doctor or pharmacist.

Note: in adults and children over 50 kg, the total paracetamol intake (taking into account all medicines containing paracetamol) must not exceed 4 g per day. The intake of chlorphenamine maleate, for its part, must not exceed 16 mg per day.

Contraindications of Fervex Cold tablets

Fervex Rhume is contraindicated for children under 15 years of age , in case of allergy to the active substances or to any of the other components contained in this medication, or in case of serious liver disease. In case of risk of glaucoma (increased pressure in the eye) or in the presence of difficulty urinating of prostatic origin, taking Fervex Rhume is contraindicated. Drug interactions

between  Fervex Rhume and oral anticoagulants (antivitamin K) should be the subject of precautions because this medication can increase the action of the anticoagulant. If in doubt, contact your doctor, who will adjust the dosage of the anticoagulant if necessary. Since the medication Fervex Rhume causes drowsiness , it is therefore not recommended to drink alcohol or any other products containing it, as well as sedative medications, during the treatment. Treatment is rather started in the evening. Be very careful if you drive or use machines because this medicine may cause drowsiness, especially at the start of treatment.  If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Pregnancy This medicine, under normal conditions of use, can be used during pregnancy, provided that it is for a short time (a few days) and at the recommended doses. However, at the end of pregnancy, excessive use of Fervex Rhume can cause neurological effects in the newborn. Therefore, you should always seek the advice of your doctor before using it and never exceed the recommended dose. Breast-feeding Fervex Rhume is very likely to pass into breast milk. Given its sedative properties which could affect your child (lethargy, loss of energy) or on the contrary exciting (insomnia), this medicine is not recommended if you are breast-feeding.

Please read the following full disclosure before taking or purchasing this product.

SUMMARY OF PRODUCT CHARACTERISTICS

ANSM - Updated on: 15/05/2023

1. NAME OF THE MEDICINE

FERVEXRHUME, film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Paracetamol.....................................................................................................................500.00 mg

Chlorphenamine maleate.................................................................................................... 4.00 mg

Per one film-coated tablet.

Notable excipients: Carmoisine (Azorubine) (E122), Sodium croscarmellose (see section 4.4).

For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oblong, violet, film-coated tablet.

4. CLINICAL DATA

4.1. Therapeutic indications

This medicine is indicated for the treatment of colds, rhinitis, rhinopharyngitis, and flu-like conditions in adults and children over 15 years of age, for:

• Clear nasal discharge and watery eyes,
• Sneezing,
• Headache and/or fever.

4.2. Dosage and administration

Dosage

For adults and children over 15 years old.

Do not exceed the maximum dosage of 4 tablets in 24 hours.

Patients with renal insufficiency

In case of renal insufficiency, and unless otherwise advised by a doctor, it is recommended to reduce the dose and increase the minimum interval between doses as per the following table:

In patients with renal insufficiency, the total dose of paracetamol (taking into account all medicines containing paracetamol) should not exceed 3 g/day.

Patients with hepatic insufficiency

In patients with chronic active or compensated liver disease, particularly those with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione reserves), or dehydration, the total dose of paracetamol (including other medications containing paracetamol) should not exceed 3 g/day.

Special clinical situations

The lowest effective daily dose of paracetamol should be considered, not exceeding 60 mg/kg/day (without exceeding 3 g/day), in the following situations:

• Adults weighing less than 50 kg,
• Mild to moderate hepatocellular insufficiency,
• Chronic alcoholism,
• Chronic malnutrition (low hepatic glutathione reserves),
• Dehydration.

Maximum recommended doses:

• In adults and children over 50 kg, the TOTAL DOSE OF PARACETAMOL (INCLUDING ALL OTHER MEDICINES CONTAINING PARACETAMOL) SHOULD NOT EXCEED 4 GRAMS PER DAY (see section 4.9).
• In adults and children over 50 kg, the TOTAL DOSE OF CHLORPHENAMINE MALEATE SHOULD NOT EXCEED 16 MILLIGRAMS PER DAY (see section 4.9).

Method of administration

Oral route.

The tablets should be swallowed whole with a drink (e.g., water, milk, fruit juice).

It is preferable to take the tablets in the evening due to the sedative effect of chlorphenamine maleate.

Frequency of administration

1 tablet to be repeated as needed after a minimum of 4 hours, not exceeding 4 tablets per day.

Duration of treatment

If fever or pain persists beyond 3 days or if symptoms do not improve after 5 days of treatment, the treatment plan should be re-evaluated.

4.3. Contraindications

• Hypersensitivity to the active substances or any of the excipients listed in section 6.1.
• In children under 15 years old.

Due to the presence of paracetamol:

• Severe hepatocellular insufficiency or decompensated active liver disease.

Due to the presence of chlorphenamine maleate:

• Risk of angle-closure glaucoma.
• Risk of urinary retention associated with urethroprostatic disorders.

• 4.4. Special warnings and precautions for use

  In cases of high or persistent fever, or signs of superinfection, or if symptoms persist beyond 5 days, treatment should be re-evaluated.

  To avoid the risk of overdose:

  • Ensure that no other medications being taken contain paracetamol or chlorphenamine maleate (including both prescription and non-prescription medications),
  • Respect the maximum recommended doses (see section 4.2).

  Related to the presence of paracetamol:

  Paracetamol should be used with caution in the following situations:

  • In individuals weighing less than 50 kg,
  • In cases of mild to moderate hepatocellular insufficiency,
  • In cases of renal insufficiency (see the table in section 4.2),
  • In individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (which can lead to hemolytic anemia),
  • In cases of chronic alcoholism,
  • In cases of anorexia, bulimia, or cachexia,
  • In cases of chronic malnutrition (low hepatic glutathione reserves),
  • In cases of dehydration or hypovolemia (see section 4.2).

  Alcohol consumption during treatment is not recommended.

  Very rare cases of severe skin adverse reactions have been reported. Patients should be informed about the early signs of these severe skin reactions, and the appearance of a rash or any other sign of hypersensitivity should result in discontinuation of the treatment.

  Related to the presence of chlorphenamine maleate:

  This medication should be used with caution, especially in elderly individuals who may have:

  • Greater sensitivity to orthostatic hypotension, dizziness, and sedation,
  • Chronic constipation (due to the risk of paralytic ileus),
  • Potential prostatic hypertrophy,
  • Severe hepatic and/or renal insufficiency, due to the risk of drug accumulation.

  Because chlorphenamine is present, it is not recommended to consume alcoholic beverages or medications containing alcohol or sodium oxybate during treatment, as they potentiate the sedative effect of antihistamines (see section 4.5).

  Rare cases of serotonin syndrome have been reported when chlorphenamine is combined with other serotonergic medications, primarily selective serotonin reuptake inhibitors (SSRIs) and dextromethorphan.

  Serotonin syndrome may present with symptoms such as diarrhea, tachycardia, sweating, tremors, muscle rigidity, confusion, or even coma. If serotonin syndrome is suspected, treatment with FERVEXRHUME should be discontinued.

  This medication contains azorubine (a coating agent) (E122) and may cause allergic reactions.

  This medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning it is essentially "sodium-free."

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  4.5. Interactions with other medicines and other forms of interactions

  Related to the presence of paracetamol:

  Associations requiring precautions for use

  • Antivitamin K
    There is an increased risk of enhanced antivitamin K effect and hemorrhagic risk when paracetamol is taken at maximum doses (4 g/day) for at least 4 days.
    More frequent monitoring of INR is required, and the antivitamin K dosage may need adjustment during and after paracetamol treatment.

  • Flucloxacillin
    Caution is advised when paracetamol is co-administered with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA), especially in patients with a glutathione deficiency risk factor such as severe renal impairment, sepsis, malnutrition, or chronic alcoholism. Close monitoring is recommended to detect the onset of HAGMA by measuring urinary 5-oxoproline.

  Interactions with laboratory tests

  • Paracetamol may interfere with blood glucose measurements using the glucose oxidase-peroxidase method in cases of abnormally high concentrations.
  • Paracetamol may interfere with blood uric acid measurements using the phosphotungstic acid method.

  Related to the presence of chlorphenamine maleate:

  Discouraged combinations

  • Alcohol (beverage or excipient)
    Alcohol increases the sedative effect of H1 antihistamines. Impaired alertness may make driving and the use of machines dangerous.
    Avoid consuming alcoholic beverages and medications containing alcohol.

  • Sodium oxybate
    Increased central depression. Impaired alertness may make driving and the use of machines dangerous.

  Combinations to consider

  • Other serotonergic medications
    Rare cases of serotonin syndrome (including altered mental status, autonomic nervous system instability, and neuromuscular disorders) have been reported when chlorphenamine is combined with other serotonergic medications, mainly SSRIs and dextromethorphan (see section 4.4).

  • Other anticholinergic medications: Imipramine antidepressants, most anticholinergic H1 antihistamines, anticholinergic antiparkinsonians, antispasmodic anticholinergics, disopyramide, phenothiazine neuroleptics, and clozapine.
    There is an additive risk of anticholinergic side effects such as urinary retention, constipation, and dry mouth.

  • Other sedative medications: Morphine derivatives (analgesics, antitussives, and substitution treatments), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (e.g., meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1 antihistamines, central antihypertensives, others: baclofen, thalidomide.
    Increased central depression. Impaired alertness may make driving and the use of machines dangerous.

  • Anticholinesterases
    There is a risk of reduced efficacy of anticholinesterases due to antagonism of acetylcholine receptors by chlorphenamine.

  • Morphine derivatives
    There is a significant risk of colonic akinesia, leading to severe constipation.

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  4.6. Fertility, pregnancy, and breastfeeding

  Pregnancy

  If clinically necessary, FERVEXRHUME tablets can be used during pregnancy; however, they should be taken at the lowest effective dose, for the shortest possible duration, and with the lowest possible frequency.

  Related to paracetamol:

  A large body of data on pregnant women shows no evidence of malformations or fetal/neonatal toxicity associated with paracetamol. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero have produced inconclusive results.

  Related to chlorphenamine maleate:

  Epidemiological studies appear to exclude a specific malformative or fetotoxic risk associated with chlorphenamine. However, if administered late in pregnancy, possible effects on the newborn due to the anticholinergic and sedative properties of chlorphenamine should be considered.

  Breastfeeding

  The transfer of chlorphenamine into breast milk is unknown. Given the potential for sedation or paradoxical excitation in the newborn, this medicine is not recommended during breastfeeding.

  Fertility

  Due to its potential effect on cyclooxygenases and prostaglandin synthesis, paracetamol may impair female fertility by affecting ovulation, which is reversible upon discontinuation of the treatment.

  Effects on male fertility have been observed in animal studies. The relevance of these effects in humans is unknown.

• 4.7. Effects on the ability to drive and use machines

  FERVEXRHUME, film-coated tablet, has a significant impact on the ability to drive and use machines.

  Particular attention should be paid to drivers and machine operators, as this medication can cause drowsiness, especially at the beginning of treatment.

  This effect is intensified by the consumption of alcoholic beverages, medications containing alcohol, or sedative medications. It is preferable to start this treatment in the evening.

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  4.8. Undesirable effects

  Related to paracetamol

  Adverse effects are classified by system organ class (SOC), and their frequency is defined as follows:

  • Very common (≥1/10)
  • Common (≥1/100 to <1/10)
  • Uncommon (≥1/1,000 to <1/100)
  • Rare (≥1/10,000 to <1/1,000)
  • Very rare (<1/10,000)
  • Unknown frequency (cannot be estimated from available data)

  System organ class	Frequency	Adverse effect
  Blood and lymphatic system disorders	Very rare	Thrombocytopenia, neutropenia, leukopenia
  Immune system disorders	Rare	Anaphylactic reaction (including hypotension)¹, anaphylactic shock¹, hypersensitivity¹, angioedema (Quincke’s edema)¹
  Gastrointestinal disorders	Unknown frequency	Diarrhea, abdominal pain
  Hepatobiliary disorders	Unknown frequency	Elevated liver enzymes
  Skin and subcutaneous tissue disorders	Rare	Urticaria¹, erythema¹, rash¹, purpura²
  	Very rare	Severe skin reactions¹

  ¹ The occurrence of these effects requires the permanent discontinuation of this medication and similar medications.
  ² The occurrence of this effect requires the immediate discontinuation of this medication. The product can only be reintroduced upon medical advice.

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  Related to chlorphenamine maleate

  The pharmacological characteristics of chlorphenamine are the cause of adverse effects of varying intensity, related or unrelated to dosage (see section 5.2):

  System organ class	Adverse effect
  Blood and lymphatic system disorders	Leukopenia, neutropenia, thrombocytopenia, hemolytic anemia
  Immune system disorders	Edema, more rarely angioedema (Quincke’s edema), anaphylactic shock
  Nervous system disorders	Sedation or drowsiness, especially at the start of treatment; anticholinergic effects such as dry mucous membranes, constipation, accommodation disorders, mydriasis, palpitations, urinary retention risk; orthostatic hypotension; balance disorders, dizziness, memory or concentration impairment (more frequent in elderly patients); motor incoordination, tremors; mental confusion, hallucinations; less frequently, effects such as excitement: agitation, nervousness, insomnia
  Skin and subcutaneous tissue disorders	Erythema, pruritus, eczema, urticaria. Their occurrence requires the permanent discontinuation of this medication and similar medications. Purpura. The occurrence of this effect requires the immediate discontinuation of this medication. The product can only be reintroduced upon medical advice

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  Reporting of suspected adverse reactions

  Reporting suspected adverse reactions after the authorization of the medicine is important. It allows for continuous monitoring of the benefit-risk ratio of the medication. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centers – Website: https://signalement.social-sante.gouv.fr.

• 4.9. Overdose

  The risk of severe poisoning (therapeutic overdose or accidental intoxication) is particularly high in the elderly, young children, patients with liver impairment, chronic alcoholism, those suffering from chronic malnutrition, and patients receiving enzyme inducers. In such cases, intoxication can be fatal.

  Paracetamol Overdose:

  Symptoms:

  Nausea, vomiting, loss of appetite, pallor, malaise, sweating, and abdominal pain typically appear within the first 24 hours.

  An overdose, starting from 10 g of paracetamol in a single dose for adults and 150 mg/kg body weight in a single dose for children, causes hepatic cytolysis, which may lead to complete and irreversible necrosis resulting in hepatocellular failure, metabolic acidosis, encephalopathy, and potentially coma and death.

  Simultaneously, elevated liver transaminases, lactate dehydrogenase, and bilirubin levels, along with a decreased prothrombin level, can be observed 12 to 48 hours after ingestion. Clinical signs of liver damage usually appear after 1 to 2 days, reaching a maximum after 3 to 4 days.

  Rare cases of acute pancreatitis have been reported.

  Emergency management:

  • Immediate transfer to a hospital.
  • Blood sampling to measure the initial plasma paracetamol level as soon as possible, starting from the 4th hour after ingestion.
  • Rapid evacuation of the ingested product via gastric lavage.
  • Overdose treatment generally includes administering the antidote N-acetylcysteine as early as possible, either intravenously or orally, preferably before the 10th hour.
  • Symptomatic treatment.
  • Liver function tests should be performed at the start of treatment and repeated every 24 hours. In most cases, liver transaminases return to normal within 1 to 2 weeks, with full recovery of liver function. However, in very severe cases, liver transplantation may be necessary.

  Chlorphenamine Maleate Overdose:

  • Chlorphenamine overdose may cause convulsions (especially in children), loss of consciousness, or coma.

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  5. PHARMACOLOGICAL PROPERTIES

  5.1. Pharmacodynamic properties

  Pharmacotherapeutic class: ANALGESIC, ANTIPYRETIC, ANTIHISTAMINE, H1 RECEPTOR INHIBITOR, ATC code: R05X
  (R: Respiratory system)

  Mechanism of action

  This medicine combines an analgesic and antipyretic (paracetamol) with an antihistamine (chlorphenamine).

  Chlorphenamine maleate: H1 antihistamine of the propylamine class, with anticholinergic activity responsible for adverse effects.

  H1 antihistamines work by competitively antagonizing histamine, particularly affecting the skin, bronchi, intestines, and blood vessels.

  Crossing the blood-brain barrier leads to sedative effects of a histaminergic and adrenolytic nature, with the latter potentially impacting hemodynamics (risk of orthostatic hypotension).

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  5.2. Pharmacokinetic properties

  Paracetamol:

  • Absorption: Paracetamol is rapidly and completely absorbed via the oral route. Maximum plasma concentrations are reached 30 to 60 minutes after ingestion.
  • Distribution: Paracetamol is quickly distributed throughout all tissues. Concentrations in the blood, saliva, and plasma are comparable. Plasma protein binding is low.
  • Biotransformation: Paracetamol is mainly metabolized in the liver. The two primary metabolic pathways are glucuronidation and sulfation. The sulfation pathway becomes saturated at doses higher than therapeutic levels. A minor pathway, catalyzed by cytochrome P450, forms a reactive intermediate (N-acetyl benzoquinone imine), which, under normal conditions, is rapidly detoxified by reduced glutathione and excreted in the urine as cysteine and mercapturic acid conjugates. However, in cases of massive intoxication, the quantity of this toxic metabolite increases.
  • Elimination: Elimination occurs primarily via the kidneys, with 90% of the ingested dose excreted in 24 hours, mainly as glucuronide (60-80%) and sulfate conjugates (20-30%). Less than 5% is excreted unchanged. The elimination half-life is approximately 2 hours.

  Physiopathological variations:

  • Renal insufficiency: In cases of severe renal insufficiency (see section 4.2), paracetamol and its metabolites are excreted more slowly.
  • Elderly patients: Conjugation capacity is not altered (see section 4.2).

  Chlorphenamine Maleate:

  • Bioavailability: The bioavailability of chlorphenamine maleate is between 25% and 50%, with significant first-pass hepatic metabolism.
  • Distribution: The time to reach maximum plasma concentration is 2 to 6 hours, with maximum effect occurring 6 hours after ingestion. The duration of effect ranges from 4 to 8 hours. Plasma protein binding is 72%.
  • Biotransformation: Hepatic metabolism leads to an inactive metabolite via demethylation.
  • Elimination: Elimination is renal, with a comparable proportion of unchanged and metabolized product excreted. The elimination half-life ranges from 14 to 25 hours.

  Physiopathological variations:

  • Hepatic or renal insufficiency increases the elimination half-life of chlorphenamine maleate.
  • Chlorphenamine maleate crosses the placenta. It is not known whether it passes into breast milk.

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  5.3. Preclinical safety data

  Related to paracetamol:

  No conventional studies adhering to current standards are available to evaluate reproductive and developmental toxicity.

• 6. PHARMACEUTICAL DATA

  6.1. List of excipients

  Sodium croscarmellose, hypromellose, microcrystalline cellulose, povidone K90, glyceryl behenate, magnesium stearate, film coating*, glossing agent**

  *Film coating:
  Hypromellose (E464), propylene glycol (E1520), titanium dioxide (E171), carmoisine (azorubine) (E122), indigo carmine (E132)

  Glossing agent:
  Purified water, white beeswax (E901), carnauba wax (E903), polysorbate 20 (E432), sorbic acid (E200)

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  6.2. Incompatibilities

  Not applicable.

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  6.3. Shelf life

  36 months.