For the use only of Registered Medical Practitioners or a Hospital or a Laboratory DILO DX TM SYRUP

Transcription

1 For the use only of Registered Medical Practitioners or a Hospital or a Laboratory DILO DX TM SYRUP Chlorpheniramine Maleate with Dextromethorphan Hydrobromide Syrup QUALITATIVE AND QUANTITATIVE COMPOSITION Each 5 ml (one teaspoonful) contains: Chlorpheniramine Maleate IP 4 mg Dextromethorphan Hydrobromide IP 10 mg In a flavoured syrup base containing Menthol IP Colour: Carmoisine PHARMACEUTICAL FORM Syrup. CLINICAL PARTICULARS Therapeutic Indications DILO DX is indicated for the temporary relief of cough due to throat irritation, sneezing and running nose. Posology and Method of Administration For oral administration only. Do not exceed the stated dose or frequency of dosing. Should not be used with other cough and cold medicines. Adults and Children aged 12 years and over 5 ml 4 hourly Children (6-12 years) 2.5 ml 4 hourly Children (2-6 years) 1.25 ml 4 hourly 1

2 DILO-DX should not be used in children aged less than 2 years. Special Populations Elderly 5 ml 4 to 6 hourly Maximum daily dose is 15 ml in any 24 hours. Renal Impairment Caution should be exercised while using in a patient with severe renal impairment (See Special Warnings and Special Precautions for Use). Hepatic Impairment Caution should be exercised while using in a patient with severe hepatic impairment (See Special Warnings and Special Precautions for Use). Contraindications DILO-DX is contraindicated in individuals: With a prior severe hypersensitivity reaction to dextromethorphan or history of hypersensitivity to chlorpheniramine maleate or antihistamines or any other ingredients of the preparations (see List of Excipients, Undesirable Effects). With, or at risk of developing, respiratory failure (e.g those with chronic obstructive airways disease or pneumonia, or during an asthma attack or an exacerbation of asthma). Who are being treated or have been treated with monoamine oxidase inhibitors (MAOIs) within the previous fourteen days. Anticholinergic properties of chlorpheniramine are intensified by MAOIs. Special Warnings and Special Precautions for Use Caution should be exercised before administering DILO-DX to the individuals with the following: Chronic or persistent cough, such as occurs with asthma and emphysema, or where cough is accompanied by excessive secretions. Severe hepatic impairment. Severe renal impairment. Concomitant use of a selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (see Interaction with Other Medicaments and Other Forms of Interaction). 2

3 Patient should be reassessed if the cough persists, or if it is accompanied by high fever, skin rash or persistent headache. DILO-DX should not be used with other cough and cold medicines and other anti-histamine containing products. Chlorpheniramine may increase the effects of alcohol. Concomitant use of alcohol with DILO-DX should be avoided. Concurrent use with drugs which cause sedation such as anxiolytics and hypnotics may cause an increase in sedative effects; therefore caution should be exercised before administering DILO-DX concurrently with these medicines. DILO-DX, due to its chlorpheniramine content which has anticholinergic effects, should be used with caution in epilepsy, severe hypertension and cardiovascular disease, raised intraocular pressure including glaucoma, prostatic hypertrophy, bronchitis, bronchiectasis and bronchial asthma. The anticholinergic properties of chlorpheniramine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery. Children and the elderly are more likely to experience neurological anticholinergic effects and paradoxical excitation of chlorpheniramine (e.g. increased energy, restlessness, nervousness). Maximum recommended dose or frequency of dosing should not be exceeded. DILO-DX contains sucrose. This should be taken into account in the case of diabetes or lowcalorie diets. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take DILO-DX. Long term treatment with DILO-DX syrup increases the risk of dental caries and it is essential that adequate dental hygiene is maintained. Keep out of sight and reach of children. Interaction with Other Medicaments and Other Forms of Interaction Chlorpheniramine Maleate Concurrent use of chlorpheniramine and hypnotics or anxiolytics may potentiate drowsiness. Concurrent use of alcohol may have a similar effect. (See Special Warnings and Special Precautions for Use). 3

4 Chlorpheniramine inhibits phenytoin metabolism and can lead to phenytoin toxicity. The anticholinergic effects of chlorpheniramine are intensified by MAOIs (see Contraindications). Dextromethorphan The use of DILO-DX with, or within two weeks of taking monoamine oxidase inhibitors (MAOIs) should be avoided as severe reactions including serotonin syndrome have been reported with dextromethorphan (see Contraindications). Caution should be exercised before taking DILO-DX in combination with the following drugs: Concomitant use of dextromethorphan with selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants may result in serotonin syndrome with changes in mental status, hypertension, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering and tremor (see Special Warnings and Special Precautions for Use). Serum levels of dextromethorphan may be increased by the concomitant use of inhibitors of cytochrome P450 2D6, such as the antiarrhythmics quinidine and amiodarone, antidepressants such as fluoxetine and paroxetine, or other drugs which inhibit cytochrome P450 2D6 such as haloperidol and thioridazine. Concomitant use of dextromethorphan and alcohol may increase the CNS depressant effects of both drugs. Pregnancy and Lactation Pregnancy There are no adequate data from the use of chlorpheniramine maleate in pregnant women. The potential risk for humans is unknown. Use during the third trimester may result in reactions in the newborn or premature neonates. No relevant data for dextromethorphan are available. Caution should be exercised when prescribing DILO-DX to pregnant women especially during the third trimester of pregnancy. Lactation Chlorpheniramine maleate and other antihistamines may inhibit lactation and may be secreted in breast milk. 4

5 No relevant data for dextromethorphan are available. DILO-DX should be administered only if considered to be essential during lactation. Effects on Ability to Drive and Use Machines The anticholinergic properties of chlorpheniramine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery (see Special Warnings and Special Precautions for Use). Patients should not drive or operate machinery if affected by drowsiness or dizziness. Undesirable Effects In absence of availability of adverse event data on the fixed dose combination of dextromethorphan and chlorpheniramine, adverse event data of the individual ingredient is presented below. Chlorpheniramine Maleate Adverse reactions which have been observed in clinical trials and which are considered to be common (occurring in 1% to <10% of subjects) or very common (occurring in 10% of subjects) are listed below by MedDRA System Organ Class. The frequency of other adverse reactions identified during post marketing use is unknown. Immune system disorders: Unknown: allergic reactions, angioedema, anaphylactic reactions Metabolism and nutritional disorders: Unknown: anorexia Psychiatric disorders: Unknown: confusion*, excitation*, irritability*, nightmares* Nervous system disorders*: Very common: sedation, somnolence Common: disturbance in attention, abnormal coordination, dizziness, headache Eye disorders Common: blurred vision Vascular disorders: Unknown: Hypotension 5

6 Respiratory, thoracic and mediastinal disorders: Unknown: thickening of bronchial secretions Gastrointestinal disorders: Common: nausea, dry mouth Unknown: vomiting, abdominal pain, diarrhoea, dyspepsia Skin and subcutaneous disorders: Unknown: exfoliative dermatitis, rash, urticaria, photosensitivity Musculoskeletal and connective tissue disorders: Unknown: muscle twitching, muscle weakness Renal and urinary disorders: Unknown: urinary retention General disorders and administration site conditions: Common: fatigue Unknown: chest tightness *Children and the elderly are more susceptible to neurological anticholinergic effects and paradoxical excitation (e.g. increased energy, restlessness, nervousness). Dextromethorphan The following adverse events have been observed in clinical trials with dextromethorphan and are likely to represent uncommon adverse reactions to dextromethorphan (i.e. occurring in 1/1,000 to <1/100 patients). Adverse reactions are listed below by MedDRA System Organ Class. Nervous system disorders: Drowsiness; dizziness Gastrointestinal disorders: Gastrointestinal disturbance; nausea; vomiting; abdominal discomfort Post Marketing Data (Dextromethorphan) Adverse reactions identified during post-marketing use are listed below. As these reactions are reported voluntarily from a population of uncertain size, the frequency of these reactions is unknown but likely to be very rare (occurring in < 1/10,000 patients). Nervous system disorders: Serotonin syndrome. 6

7 Serotonin syndrome (with changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor and hypertension) has been reported when dextromethorphan has been taken concurrently with MAOIs or serotonergic drugs such as SSRIs (see Contraindications and Interaction with Other Medicaments and Other Forms of Interaction). Skin and subcutaneous disorders: Allergic reactions (e.g. rash, urticaria, angioedema). Overdose Symptoms and Signs Chlorpheniramine overdose is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include paradoxical excitation, toxic psychosis, convulsions, apnoea, dystonic reactions and cardiovascular collapse including arrhythmias. Dextromethorphan overdose is likely to result in effects similar to those listed under Undesirable Effects. Following large overdoses, additional symptoms may include excitation, mental confusion, restlessness, nervousness and irritability, stupor, ataxia, dystonia, hallucinations, psychosis and respiratory depression. Treatment Supportive and symptomatic care should be provided as required and treatment should be directed towards specific symptom. If overdose is severe, naloxone may be helpful, particularly for patients with respiratory depression. Convulsions and marked CNS stimulation should be treated with parenteral diazepam. PHARMACOLOGICAL PROPERTIES Pharmacodynamic Properties Chlorpheniramine Maleate Pharmacotherapeutic group: Antihistamines for systemic use; ATC code: R06AB02. Mechanism of Action Chlorpheniramine maleate is a potent antihistamine (H1-antagonist). 7

8 Antihistamines diminish or abolish the actions of histamine in the body by competitive reversible blockade of histamine H 1 -receptor sites on tissues. Chlorpheniramine also has anticholinergic activity. Pharmacodynamic Effects Antihistamines act to prevent the release of histamine, prostaglandins and leukotrienes, and have been shown to prevent the migration of inflammatory mediators. The actions of chlorpheniramine include inhibition of histamine on smooth muscle, capillary permeability and hence reduction of oedema and wheal in hypersensitivity reactions such as allergy and anaphylaxis. Dextromethorphan Pharmacotherapeutic group: Cough suppressants (opium alkaloids and derivatives); ATC Code: R05DA09. Mechanism of Action Dextromethorphan has an antitussive action. It controls cough spasms by depressing the medullary cough centre. It is also an antagonist of N-methyl-d-aspartate (NMDA) receptors and a σ-receptor agonist. Pharmacodynamic Effects Dextromethorphan is a cough suppressant which has a central action on the cough centre of the medulla. Pharmacokinetic Properties Chlorpheniramine Maleate Chlorpheniramine is well absorbed from the gastro-intestinal tract, following oral administration. The effects develop within 30 minutes, are maximal within 1 to 2 hours and last 4 to 6 hours. The plasma half-life has been estimated to be 12 to 15 hours. Chlorpheniramine is metabolised to the monodesmethyl and didesmethyl derivatives. About 22% of an oral dose is excreted unchanged in the urine. Only trace amounts have been found in the faeces. Dextromethorphan Absorption Dextromethorphan hydrobromide is well absorbed from the gastrointestinal tract. 8

9 Distribution Due to extensive pre-systemic metabolism by the liver, detailed analysis of the distribution of orally administered dextromethorphan is not possible. Metabolism Dextromethorphan is metabolised in the liver and excreted in the urine as demethylated metabolites including dextromethorphan, and as a minor proportion of unchanged dextromethorphan. In a small proportion of individuals, metabolism proceeds more slowly and dextromethorphan predominates in blood and urine. Special patient populations Renal Impairment No specific studies have been conducted on the effect of renal impairment on the pharmacokinetics of dextromethorphan. Caution should be exercised while using in patients with severe renal impairment (See Special warnings and Special Precautions for Use) Hepatic Impairment Severe liver disease can impair the metabolism of dextromethorphan. Caution should be exercised while using in patients with severe hepatic impairment (See Special warnings and Special Precautions for Use) Preclinical Safety Data Preclinical safety data on chlorpheniramine maleate and dextromethorphan obtained from the literature or in house have not revealed findings which are of relevance to the recommended dosage and use of the product. Dextromethorphan Carcinogenesis and Mutagenesis While no carcinogenicity studies have been conducted with dextromethorphan, it did not exhibit evidence of mutagenicity in the in vitro Ames assay in both the presence and absence of metabolic activation. 9

10 Reproductive Toxicology While there are no clinical data available, the results of preclinical studies have demonstrated a lack of adverse effects on fertility, fetal development and postnatal viability following oral administration of 50 mg/kg/day or less of dextromethorphan to rats and rabbits during pregnancy. PHARMACEUTICAL PARTICULARS List of Excipients Sucrose, Sodium Benzoate, Sodium Chloride, Citric Acid Monohydrate, Sodium Citrate, Saccharin Sodium, Glycerin, Sorbitol Solution, Propylene Glycol, Colour Carmoisine, Flavour Strawberry, Flavour Raspberry, Flavour peppermint, Menthol, Purified Water. Incompatibilities No incompatibilities have been identified. Shelf Life 18 months. The expiry date is indicated on the label and packaging. Special Precautions for Storage Store at a temperature not exceeding 30 o C. Protect from direct sunlight. Keep out of reach of children. Nature and Specification of Container Bottle with a measure cup in a carton. Instructions for Use / Handling For oral use only. It is dangerous to take this preparation except under medical supervision. There are no other special requirements for use and handling of this product 10

11 For further information please contact: GlaxoSmithKline Pharmaceuticals Limited. Registered Office Dr. Annie Besant Road, Worli Mumbai , India. DILO-DX is a trademark of GSK group of companies Version No: DDX/PI/IN/2016/01 dated 24-Nov-2016 Adapted from: 1. Chlorpheniramine Maleate GDS Version Number 1.0 Approval Date: 13th February Dextromethorphan GDS Version Number 3.0 Approval Date: 17 January Chlorpheniramine Maleate Micromedex. Available from: videncexpert/cs/48b0cb/nd_appproduct/evidencexpert/duplicationshieldsync/a19 2D8/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencex pert.displaydrugpointdocument?docid=120650&contentsetid=100&title=chlorpheniramin e+maleate&servicestitle=chlorpheniramine+maleate&topicid=adverseeffectssection&sub topicid=commonsection. Accessed on 20 th June Dextromethorphan Martindale. Available from: t.htm?q=dextromethorphan&t=advanced&ss=mn&p=1#_hit. Accessed on: 20th June Dextromethorphan. DrugDex Evaluations. Available from: videncexpert/cs/d9fa18/nd_appproduct/evidencexpert/duplicationshieldsync/8a2 B74/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencex pert.displaydrugpointdocument?docid=174080&contentsetid=100&title=dextromethorph an+hydrobromide&servicestitle=dextromethorphan+hydrobromide&topicid=dosingandi ndicationssection&subtopicid=fdasection. Accessed on 26 June