Dextromethorphan Hydrobromide 10mg / 5ml Syrup
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Dextromethorphan hydrobromide 10mg/5ml syrup
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
5 ml contains 10 mg of dextromethorphan hydrobromide monohydrate (equivalent to 7.35 mg of dextromethorphan).
Excipients with known effect:
Dextromethorphan 10mg/5ml syrup contains 4340 mg of maltitol liquid E965,310 mg of propylene glycol and 7,5 mg of methyl-parahydroxybenzoate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Syrup
Clear, colorless to slightly yellow liquid
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Dextromethorphan hydrobromide 10mg/5ml syrup is indicated in adults and children 12 years and older for symptomatic treatment of irritable cough (non-productive/dry cough)
4.2 Posology and method of administration
Posology
Adults and adolescents 12 years and over
15 ml of syrup up to 3 times daily, every 6 - 8 h, as required. A maximum dose of 45 ml per day should not be exceeded.
Method of administration
Use the measuring device included in the package.
Treatment should not be continued for more than 2 to 3 weeks.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Patients in, or at risk of developing respiratory failure (see section 4.4).
• Patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such treatment (see section 4.5)
• Dextromethorphan hydrobromide 10mg/5ml syrup is contraindicated in children aged below 12 years.
4.4 Special warnings and precautions for use
Dextromethorphan has minor addictive potential. Following prolonged use (i.e. exceeding the recommended treatment period) patients may develop tolerance as well as mental and physical dependence. Patients with a tendency towards abuse or dependence should only be given Dextromethorphan 10mg/5ml syrup for short periods and under strict medical supervision.
Cases of dextromethorphan abuse have been reported, predominately in adolescents.
Dextromethorphan hydrobromide 10mg/5ml syrup should be used with caution in patients receiving serotonergic drugs (other than MAO-inhibitors) such as selective serotonin reuptake inhibitors (SSRI) (e.g. fluoxetine, paroxetine) or tricyclic antidepressives (see section 4.5).
Should be used with caution in patients with respiratory conditions such as asthma, COPD, pneumonia.
Information on the use of dextromethorphan in patients with impaired liver or renal function is limited. Therefore, dextromethorphan hydrobromide 10mg/5ml syrup should be used with caution in those patients, particularly in patients with severe impairments.
Due to potential histamine release dextromethorphan hydrobromide 10mg/5ml syrup should be avoided in case of mastocytosis.
A chronic cough can be an early symptom of asthma and therefore Dextromethorphan hydrobromide 10mg/5ml syrup is not indicated for suppression of chronic cough, particularly in children.
In cases of productive cough with considerable mucus production (e.g. patients with conditions such as bronchiectasis and cystic fibrosis) or in patients with neurological illness associated with a markedly reduced cough reflex (such as stroke, Parkinson’s disease and dementia) antitussive treatment with Dextromethorphan hydrobromide 10mg/5ml syrup should be administered with particular caution and only after careful benefit-risk assessment.
Dextromethorphan hydrobromide 10mg/5ml syrup contains:
-39,06 g of maltitol liquid per maximum recommended daily dose equivalent to 89 kcal/g. Patients with rare hereditary problems of fructose intolerance should not take this medicine. It may have a mild laxative effect.
- 2,8 g of propylene glycol per maximum recommended daily dose.
- Methyl-parahydroxybenzoate, which may cause allergic reactions (possibly delayed).
4.5 Interaction with other medicinal products and other forms of interaction
Dextromethorphan possesses weak serotonergic properties. Thereby dextromethorphan may increase the risk of serotonin toxicity (serotonin syndrome) particularly if taken with other serotonergic agents, such as MAO-inhibitors or SSRIs. Especially pre-treatment or concomitant treatment with drugs that impair metabolism of serotonin, such as antidepressants of the MAO inhibitor type may result in the development of a serotonin syndrome with characteristic symptoms like neuromuscular hyperactivity (e.g. tremor, clonus, myoclonus, hyperreflexia, and pyramidal rigidity), autonomic hyperactivity (e.g. diaphoresis, fever, tachycardia, tachypnoea, mydriasis) and altered mental status (e.g. agitation, excitement, confusion) (see sections 4.3 (MAO inhibitors) and 4.4).
Concomitant administration of other substances including alcohol with a suppressant effect on the CNS may lead to mutual potentiation.
Concomitant administration of medication that inhibits the cytochrome P450-2D6 enzyme system in the liver and thus the metabolism of dextromethorphan - such as amiodarone, quinidine, fluoxetine, haloperidol, paroxetine, propafenon, thioridazine, cimetidine, ritonavir, berberine, bupropion, cinacalcet, flecainide and terbinafine - can increase the concentration of dextromethorphan. These effects may occur if any of the medicines concerned have been administered recently, even if they are no longer being taken.
If dextromethorphan is used in combination with secretolytics in patients with pre-existing chest disease such as cystic fibrosis and bronchiectasis who are affected by mucus hypersecretion a reduced cough reflex can lead to serious accumulation of mucus.
4.6 Fertility, pregnancy and lactation
Pregnancy
The results of epidemiological studies of limited populations have not indicated an increase in the frequency of malformations in children who were exposed to dextromethorphan during the prenatal period. However, these studies do not adequately document the time and duration of treatment with dextromethorphan.
Animal studies on reproduction toxicity do not indicate that dextromethorphan poses a potential risk to man (see section 5.3).
Therefore, dextromethorphan should be used during pregnancy only after a careful assessment of the benefits and risks and only in exceptional cases.
Breastfeeding
No information is available on the secretion of dextromethorphan into breast milk. It is recommended that the product should not be used by breast feeding mothers since a respiratory depressive effect on infants cannot be ruled out
Fertility
There are no reported effects of the use of dextromethorphan on fertility. Pre-clinical experience is limited (see section 5.3.)
4.7 Effects on ability to drive and use machines
Even when used as prescribed, this medication may cause mild drowsiness and alter reaction times to the extent that the ability to drive or to operate machinery is impaired. This risk is increased when it is taken in combination with alcohol or with other medications that can themselves impair reaction times.
4.8 Undesirable effects
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data)
|
System Organ Class |
Frequency |
Adverse Drug Reaction |
|
Immune system disorder |
Not known |
Hypersensitivity reactions including anaphylactic |
|
reaction, angioedema, urticaria, pruritus, rash and erythema | ||
|
Psychiatric disorders |
Very rare |
Hallucinations, drug dependence has been reported in individuals abusing dextromethorphan |
|
Nervous system Disorders |
Common |
dizziness |
|
Very rare |
somnolence | |
|
Gastrointestinal disorders |
Common |
vomiting, gastrointestinal disorder and nausea |
|
Skin and subcutaneous tissue disorders |
Not known |
fixed drug eruption (FDE) |
|
General disorders and administration site conditions |
Common |
fatigue |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
In case of overdose known side effects may occur with higher frequency or severity: nausea, vomiting and gastrointestinal disorders, dizziness, fatigue and somnolence and hallucinations. Likewise, restlessness and excitability may develop into agitation with increasing overdose.
In addition, symptoms such as impaired concentration and consciousness up to coma as a sign of severe intoxication, changes in mood such as dysphoria and euphoria, psychotic disorders like disorientation and delusions up to confusional or paranoid states, increased muscle tone, ataxia, dysarthria, nystagmus and vision disturbance as well as respiratory depression, changes in blood pressure and tachycardia may occur.
Dextromethorphan may increase the risk of serotonin syndrome, and this risk is increased by overdose, particularly if taken with other serotonergic agents.
Management
If necessary close intensive care monitoring with symptom-related treatment should be initiated. Naloxone can be used as an antagonist.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cough and cold preparations. ATC code: R05DA09
Dextromethorphan hydrobromide is a 3-methoxy derivative of levorphanol. It has an antitussive effect, but does not possess analgesic, respiratory-suppressant or psychotomimetic properties in therapeutic doses.
Dextromethorphan has minor addictive potential. Dextromethorphan possesses weak serotonergic properties.
Onset of effect occurs 15 - 30 minutes after oral ingestion, and the duration of the effect is approximately 3 - 6 hours.
5.2 Pharmacokinetic properties
Absorption
Dextromethorphan is rapidly absorbed after oral administration, and peak plasma levels ranging from 5.2 to 5.8 ng/mL after a single dose administration of 60 mg dextromethorphan are reached within 2 hours.
Distribution
The volume of distribution at the steady state following the administration of 50 mg dextromethorphan doses has been calculated as 7.3 L ± 4.8 L (mean ± SD).
Biotransformation
Dextromethorphan undergoes a first pass effect in the liver. The principal stages of metabolism are oxidative O- and N-demethylation mediated by CYP3A and CYP2D6 with subsequent conjugation.
The primary active metabolite is dextrorphan; (+)-3-methoxymorphinan and (+)-3-hydroxymorphinan are also formed. As CYP2D6 is a polymorphic enzyme, metabolism of dextromethorphan depends on the genotype of the individual. The frequency of poor metaboliser phenotype (with impaired CYP 2D6 activity) in the Caucasian population is between 5% and 10% (see subsection Special populations).
Elimination
The renally excreted proportion (up to 48 hours after oral administration) can range from 20% to 86 % of the administered dose. Free or conjugated metabolites are recovered in the urine and only a small proportion of the active ingredient is eliminated in an unchanged form.
Less than 0.1 % is found in the faeces. Following either single or multiple dose administration, the mean elimination half-life varies from 3.2 to 4 hours.
Special populations
Poor CYP 2D6 metabolizers (PMs) vs. extensive metabolizers (EM)
The Cmax-, AUC- and tJ/2-values for dextromethorphan are higher amongst PMs than those amongst EMs, i.e. 16-fold higher for Cmax, 150-fold for AUC and 8-fold for tJ/2 (19.1 vs. 2.4 hours).
The tJ/2-values can be extended to as much as 45 hours in some cases of PMs.
5.3 Preclinical safety data Chronic and subchronic toxicity
Subchronic and chronic toxicity studies carried out in the dog and rat revealed no evidence of any toxic effects specific to dextromethorphan.
Mutagenic and tumorigenic potential
A bacterial test for point mutations was negative. A chromosome aberration assay was negative. For structurally related chemicals including morphine, codeine, nalbuphine, buprenorphine, naloxone, hydromorphone, levorphanol, and oxycodone mostly negative genotoxicity and carcinogenicity data are available. The overall weight of evidence for dextromethorphan and its structural analogues, supports the conclusion that this class of phenanthrene-based chemicals, and dextromethorphan in particular, are not genotoxic in vitro and in vivo, and do not represent a carcinogenic risk to the patient. No long-term animal studies have been conducted to determine the tumorigenic potential.
Reproductive toxicity
Studies on embryotoxicity, perinatal/postnatal toxicity and fertility in the rat have shown negative results up to a dose of 50 mg/kg/day.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Saccharin sodium dihydrate, Maltitol liquid (E965)
Propylene glycol Apricot flavour Vanilla flavour
Methylparahydroxybenzoat (E218) Purifed water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
After first opening: 12 months
6.4 Special precautions for storage
Store in the original packaging in order to protect from light.
6.5 Nature and contents of container
Type III amber glass bottle and 1 measuring device.
Pack-sizes:
1 x 190ml bottle and 1 measuring device.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim International GmbH
Binger Str. 173
55216 Ingelheim am Rhein
Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 14598/0098
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/05/2013
10 DATE OF REVISION OF THE TEXT
14/10/2015