VICKS MEDINAIT 0.5 MG/ML + 0.25 MG/ML + 20 MG/ML Syrup with dispenser

VICKS MEDINAIT 0.5 MG/ML + 0.25 MG/ML + 20 MG/ML SYRUP

1 NAME OF THE MEDICINAL PRODUCT

Vicks MediNait 0.5 mg/ml + 0.25 mg/ml + 20 mg/ml syrup

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

100 ml of syrup contains:

Active ingredients

Dextromethorphan hydrobromide 0.05 g

Doxylamine succinate 0.025 g

Paracetamol 2 g

Excipients with known effects: sucrose, sodium, sodium benzoate, propylene glycol.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Syrup.

4 CLINICAL INFORMATION

4.1 Therapeutic indications

Treating cold and flu symptoms.

4.2 Dosage and method of administration

Dosage

Adults and adolescents over 12 years:

The recommended dose is 30 ml once daily.

30 ml contains 0.015 g of dextromethorphan hydrobromide, 0.0075 g of doxylamine succinate and 0.6 g of paracetamol

Do not exceed the recommended doses.

Duration of treatment

After 3 days of continuous use, in the absence of appreciable results, re-evaluate the clinical picture.

Method of administration

Vicks MediNait should be taken before going to bed for a good night's rest and on a full stomach.

Use the measuring cup included in the package.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in paragraph 6.1.
• Children and adolescents under 12 years of age.
• Asthma, diabetes, glaucoma, prostatic hypertrophy, gastrointestinal and urogenital tract stenosis, epilepsy, severe liver disease or severe renal impairment.
• Glucose-6-phosphate dehydrogenase deficiency and haemolytic anaemia (due to paracetamol content).
• History of gastrointestinal bleeding or perforation due to previous treatment with medicinal products with anti-inflammatory, antipyretic and analgesic activity or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
• Severe heart failure.

Do not administer concurrently or within two weeks of therapy with MAO inhibitor antidepressant drugs.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the shortest duration of treatment necessary to control symptoms.

Older people are more susceptible to the onset of adverse effects.

A chronic or persistent cough due to smoking, emphysema, asthma requires clinical evaluation.

In case of irritating cough with a significant production of mucus Vicks MediNait should be used with particular caution and after a careful risk-benefit assessment.

High or prolonged doses of paracetamol, present in the product, can cause high-risk liver disease and even serious kidney and blood alterations. Paracetamol should be used with caution in subjects with renal or hepatic insufficiency, including those with non-cirrhotic alcoholic liver disease. Damage from overdose is greater in subjects with alcoholic liver disease.

Vicks MediNait should not be used with other products containing paracetamol or medicines with anti-inflammatory, antipyretic and analgesic properties.

In rare cases of allergic reactions, administration should be suspended and appropriate treatment should be instituted.

The use of antihistamines with ototoxic antibiotics may mask the early signs of ototoxicity, which may be perceived late, when the damage is irreversible.

Vicks MediNait should be used with caution in patients with cardiovascular disease, hypertension and hyperthyroidism.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with Vicks MediNait only after careful consideration, given the risk of fluid retention and edema.

Alcohol intake should be avoided during treatment. Risks arising from concomitant use of sedative medicines such as benzodiazepines or related medicines

Concomitant use of Vicks MediNait and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines should be limited to patients for whom alternative treatment options are not possible. If a decision is made to prescribe Vicks MediNait with sedative medicines, the duration of treatment should be as short as possible.

Patients should be monitored closely for signs and symptoms of respiratory depression and sedation. It is strongly recommended that patients and their caregivers (where applicable) are informed of these symptoms (see section 4.5).

Dextromethorphan can be habit-forming. With prolonged use, patients may develop tolerance to the drug, as well as mental and physical dependence. Patients with a tendency to abuse or dependence should take Vicks MediNait for short periods and be carefully monitored.

Cases of abuse and dependence on dextromethorphan have been reported. Caution is recommended especially for adolescents and young adults, as well as in patients with a history of drug or psychoactive substance abuse.

Serotonin Syndrome

Serotonergic effects, including the development of a potentially life-threatening serotonin syndrome, have been reported for dextromethorphan with concomitant administration of serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors). [monoamine oxidase inhibitors, MAOI]) and CYP2D6 inhibitors.

Serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, treatment with Vicks Medinait should be discontinued.

Concomitant use of medicinal products with anti-inflammatory, antipyretic and analgesic activity, including selective COX-2 inhibitors, should be avoided.

Dextromethorphan is metabolised by hepatic cytochrome P450 2D6 (see section 5.2). The activity of this enzyme is genetically determined. Approximately 10% of the population are slow CYP2D6 metabolisers. Exaggerated and/or prolonged effects of dextromethorphan may occur in poor metabolisers and patients with concomitant use of CYP2D6 inhibitors. Caution is advised in patients who are poor CYP2D6 metabolisers or who use CYP2D6 inhibitors (see section 4.5).

Elderly people:

Elderly patients have an increased frequency of adverse reactions to drugs with anti-inflammatory, antipyretic and analgesic activity, especially gastrointestinal bleeding and perforation, which may be fatal.

Gastrointestinal bleeding, ulceration and perforation: Gastrointestinal bleeding, ulceration and perforation, which can be fatal, have been reported with all anti-inflammatory, antipyretic and analgesic medicinal products at anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events.

In patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), the risk of gastrointestinal bleeding, ulceration or perforation is higher with increased doses of medicinal products with anti-inflammatory, antipyretic and analgesic activity. These patients should start treatment on the lowest dose available. Concomitant use of protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients who are taking low dose acetylsalicylic acid or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any gastrointestinal symptoms (especially gastrointestinal bleeding) early in treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).

If gastrointestinal bleeding or ulceration occurs in patients receiving Vicks MediNait the treatment should be withdrawn.

Medicines with anti-inflammatory, antipyretic and analgesic activity should be administered with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) since these conditions may be exacerbated (see section 4.8).

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of medicinal products with anti-inflammatory, antipyretic and analgesic activity (see section 4.8). Patients appear to be at higher risk early in the course of treatment.

Vicks MediNait should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Instruct the patient to contact the doctor before combining any other drugs.

Caution is advised if paracetamol is co-administered with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as in those using maximum daily doses of paracetamol. Careful monitoring, including measurement of urinary 5-oxoproline, is recommended.

Important information about some of the excipients

Vicks MediNait contains 8.25 g of sucrose per dose (equal to 30 ml). To be taken into consideration in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicine contains approximately 75 mg of sodium per dose (equal to 30 ml) equivalent to approximately 3.8% of the maximum daily intake recommended by the WHO which corresponds to 2 g of sodium for an adult.

Vicks MediNait contains 30 mg of sodium benzoate per dose (equal to 30 ml).

This medicine contains 3 g of propylene glycol per dose (equal to 30 ml). Clinical monitoring is required for patients with hepatic or renal insufficiency due to various adverse events attributed to propylene glycol such as renal dysfunction (acute tubular necrosis), acute kidney injury and hepatic dysfunction. Although propylene glycol has not shown reproductive and developmental toxicity in animals or humans, it can reach the fetus and has been found in breast milk. As a consequence, the administration of propylene glycol to pregnant or breastfeeding patients should be considered on a case-by-case basis.

Interference with serological tests

Paracetamol administration may interfere with the determination of uricemia (by the phosphotungstic acid method) and glycemia (by the glucose-oxidase-peroxidase method).

4.5 Interactions with other medicinal products and other forms of interaction

Concomitant administration with MAO inhibitor drugs is contraindicated (see section 4.3).

Use with extreme caution and under close monitoring during chronic treatment with drugs that can determine the induction of hepatic monooxygenases or in case of exposure to substances that can have this effect (for example rifampicin, cimetidine, antiepileptics such as glutethimide, phenobarbital, carbamazepine and alcohol) due to an increased risk of hepatotoxicity from paracetamol.

The rate of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption may be reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarin drugs may be enhanced by prolonged and regular use of paracetamol, increasing the risk of bleeding. Liver enzyme inducers (e.g. alcohol and antiepileptics) may increase the hepatotoxicity of paracetamol, particularly after an overdose.

CYP2D6 inhibitors

There is a potential for interaction between dextromethorphan and medicinal products that inhibit the CYP2D6 isoenzyme such as SSRIs (e.g., fluoxetine, paroxetine). Dextromethorphan is metabolized by CYP2D6 and has extensive first-pass metabolism. Concomitant use of potent inhibitors of the CYP2D6 enzyme may increase dextromethorphan concentrations in the body to levels several times higher than normal. This increases the patient's risk of toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and the development of serotonin syndrome. Potent inhibitors of CYP2D6 are fluoxetine, paroxetine, quinidine, and terbinafine. During concomitant use with quinidine, plasma concentrations of dextromethorphan are increased up to 20-fold, resulting in increased central nervous system adverse effects of the agent. Amiodarone, flecainide and propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be monitored and the dose of dextromethorphan may need to be reduced.

Diuretics, ACE inhibitors and Angiotensin II antagonists:

Medicines with anti-inflammatory, antipyretic and analgesic activity may reduce the effect of diuretics and other antihypertensive drugs. In subjects with impaired renal function (for example dehydrated or elderly patients) co-administration with an ACE inhibitor or an angiotensin II antagonist may lead to a further deterioration of renal function.

Hydration prior to initiating concomitant therapy and close monitoring of renal function after initiation of treatment are recommended.

Corticosteroids: Concomitant administration may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anticoagulants: Medicines with anti-inflammatory, antipyretic and analgesic activity may increase the effects of anticoagulants, such as warfarin (see section 4.4).

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): co-administration may lead to an increased risk of gastrointestinal bleeding (see section 4.4).

Sedative medicines such as benzodiazepines or related medicines

Concomitant use of opioids and sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Caution should be exercised when paracetamol is used concomitantly with flucloxacillin as the concomitant intake has been associated with high anion gap metabolic acidosis, especially in patients with risk factors (see section 4.4).

4.6 Fertility, pregnancy and breastfeeding

Data on the safety of using Vicks MediNait during pregnancy and breastfeeding are limited.

Vicks MediNait during pregnancy and breastfeeding is not recommended. Use should be considered only if the expected benefit to the mother outweighs the risk to the fetus or child.

Pregnancy

The extensive data on the use of paracetamol during pregnancy do not indicate malformative or fetal/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically necessary, paracetamol can be used during pregnancy, however it should be used for the shortest possible time and as little as possible.

Literature data do not show a proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus induced by dextromethorphan. Use during the advanced stage of pregnancy may expose the newborn to respiratory depression.

Epidemiological studies do not indicate malformative toxicity induced by doxylamine. Given the anticholinergic and sedative activity of doxylamine, monitoring of the newborn is strongly recommended in case of use of Vicks MediNait close to delivery.

Breastfeeding

Although excreted in breast milk, the use of paracetamol is compatible with breastfeeding. The excretion of dextromethorphan and doxylamine in breast milk is not known.

4.7 Effects on ability to drive and use machines

Vicks MediNait may affect your ability to drive or use machines.

The product may cause drowsiness (especially in conjunction with the intake of alcohol or other medicines that can reduce reaction times), this must be taken into account by those who may drive vehicles or carry out operations requiring a high level of alertness, who must refrain from such tasks after taking the product.

4.8 Undesirable effects

Undesirable effects are classified according to their frequency and listed in decreasing order of seriousness.

The frequency of adverse reactions is defined using the following convention: 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), not known (cannot be estimated from the available data).

*Paradoxical stimulation of the central nervous system, especially in children

**sometimes fatal, particularly in elderly patients

Class side effects:

Antihistamines

asthenia, photosensitivity, convulsions (at high doses), breathing difficulties due to increased bronchial secretions, and, especially in the elderly, hypotension and rhythm disturbances (extrasystoles and tachycardia).

Medicines with anti-inflammatory, antipyretic and analgesic activity

edema, hypertension and heart failure.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions that occur after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed on the website https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

4.9 Overdose

In case of overdose, paracetamol can cause hepatic cytolysis, which can evolve into massive and irreversible necrosis.

Symptoms and signs

Paracetamol:

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may occur 12 to 48 hours after ingestion. Abnormalities in glucose metabolism and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias have been reported.

Other symptoms may include CNS depression, cardiovascular effects, and renal damage.

Dextromethorphan or Doxylamine:

Symptoms such as excitation, mental confusion, convulsions and respiratory depression may occur following overdose with doxylamine.

Dextromethorphan overdose may be associated with nausea, vomiting, dystonia, agitation, confusion, somnolence, stupor, nystagmus, cardiotoxicity (tachycardia, abnormal ECG including QTc prolongation), ataxia, toxic psychosis with visual hallucinations, hyperexcitability.

In case of massive overdose, the following symptoms may be observed: coma, respiratory depression, convulsions.

Management:

Immediate treatment is essential in the management of paracetamol overdose. Despite the lack of significant early symptoms, patients should urgently seek immediate medical attention in hospital and any patient who has ingested approximately 7.5 g or more of paracetamol in the preceding 4 hours should undergo gastric lavage.

Oral methionine or intravenous N-acetylcysteine may be necessary and may have a beneficial effect for at least 48 hours after overdose. General supportive measures should be available.

Activated charcoal may be administered to asymptomatic patients who have ingested overdoses of dextromethorphan within the previous hour.

For patients who have ingested dextromethorphan and are sedated or comatose, naloxone may be considered in the usual doses for the treatment of opioid overdose. Benzodiazepines may be used for seizures and benzodiazepines and external cooling measures for serotonin syndrome hyperthermia.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: cough suppressants, excluding combinations with expectorants, ATC code: R05DA20.

Vicks MediNait administered orally at doses of 2 - 4 - 8 ml/kg did not cause any significant modification in blood pressure, cardiac dynamics, bile flow, or duodenal motility in normotensive dogs. Vicks MediNait has been shown to have a marked antitussive action in guinea pigs, through ammonia aerosol tests, acrolein inhalation, and electrical stimulation of the superior laryngeal nerve. Finally, Vicks MediNait has shown a very significant action in inhibiting histamine-induced bronchospasm in guinea pigs.

5.2 Pharmacokinetic properties

The maximum blood levels of the active ingredients are reached between 30 and 40 minutes after oral administration of Vicks MediNait. The active ingredients are widely distributed in the tissues and organic fluids and their half-life is between 7 and a half and 10 hours. When Vicks MediNait is administered, the bioavailability of the active ingredients occurs according to curves that are completely superimposable to those obtained by administering the active ingredients separately and individually in aqueous solutions. They are eliminated almost entirely by the kidneys, to a small extent unchanged, but mainly in the form of metabolites.

Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation (CYP2D6) is the major determinant of dextromethorphan pharmacokinetics in human volunteers.

Distinct phenotypes appear to exist for this oxidation process, resulting in highly variable pharmacokinetics among subjects. Unmetabolized dextromethorphan and the three demethylated morphinan metabolites, dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3-hydroxymorphinan, and 3-methoxymorphinan, have been identified as conjugated products in urine. Dextrorphan, which also has antitussive action, is the major metabolite. In some subjects, metabolism proceeds more slowly, and unchanged dextromethorphan predominates in blood and urine.

5.3 Preclinical safety data

There are no conventional toxicity studies of paracetamol using the current accepted gold standards for reproductive and developmental toxicity.

Preclinical data collected for Vicks Medinait show that LD₅₀ by oral route in mice is 33.7 ml/kg, in rats 32.0 ml/kg and in dogs it is greater than 15 ml/kg. Chronic oral toxicity studies in two animal species, dogs and rats, have not shown any damage to the tested animals or their organs. Vicks MediNait has been shown, in rats and rabbits, to be free of teratogenic effects, nor did it influence the fertility of the tested animals.

6 PHARMACEUTICAL INFORMATION

6.1 List of excipients

Propylene glycol, sodium citrate, citric acid monohydrate, potassium sorbate, sodium benzoate, macrogol, sucrose, glycerol, anethole, quinoline yellow (E 104), brilliant blue FCF (E 133) and purified water.

6.2 Incompatibility

No incompatibilities with other drugs have ever been reported.

6.3 Validity period

3 years.

6.4 Special precautions for storage

Keep the bottle in the outer carton in order to protect from light.

Any variation in the colour of the syrup does not alter the quality of the product.

6.5 Nature and contents of the container

90 or 180 ml glass bottle.

6.6 Special precautions for disposal and handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

PROCTER & GAMBLE Srl - Viale Giorgio Ribotta, 11 - 00144 Rome.

8 MARKETING AUTHORISATION NUMBER(S)

024449050 - “0.5 mg/ml + 0.25 mg/ml + 20 mg/ml syrup“, 90 ml glass bottle with measuring cup

024449062 - “0.5 mg/ml + 0.25 mg/ml + 20 mg/ml syrup“, 180 ml glass bottle with measuring cup

9 DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION

Date of first authorization: June 1981

Most recent renewal date: January 2016

10 DATE OF REVISION OF THE TEXT

July 2022

11 DOSIMETRY

12 INSTRUCTIONS FOR PREPARING RADIOPHARMACEUTICALS