For the use only of Registered Medical Practitioners or a Hospital or a Laboratory ACTIFED DM COUGH SYRUP Triprolidine Hydrochloride and Dextromethorphan Hydrobromide Syrup QUALITATIVE AND QUANTITATIVE COMPOSITION Each 5 ml contains: Triprolidine Hydrochloride IP 1.25 mg Dextromethorphan Hydrobromide IP 10.0 mg in a flavoured syrup base containing Menthol IP Colour: Ponceau 4R PHARMACEUTICAL FORM Syrup for oral administration. CLINICAL PARTICULARS Therapeutic Indications ACTIFED DM COUGH SYRUP is indicated for symptomatic relief of persistent, dry and irritating cough associated with respiratory tract disorders. Posology and Method of Administration Consider re-evaluation of patient if symptoms persist more than 7 days. Adults and children aged 12 years and over Oral 10 ml every 5 hours. Maximum daily dose 40 ml (Dextromethorphan 80 mg and Triprolidine 10 mg). Children aged 6-11 years Oral 5 ml every 5 hours. Maximum daily dose 20 ml (Dextromethorphan 40 mg and Triprolidine 5 mg). Children aged 2-6 years Oral 2.5 ml every 5 hours. Maximum daily dose 10 ml (Dextromethorphan 20 mg and Triprolidine 2.5 mg). Children under 2 years of age Not recommended in children under 2 years of age. 1
Elderly The elderly are more likely to experience the neurological anticholinergic effects of triprolidine, including confusion, and to develop paradoxical excitation (see Special Warnings and Special Precautions for Use). Hepatic impairment Triprolidine is eliminated primarily by hepatic metabolism therefore consideration should be given to reducing the dose in those with severe hepatic impairment. Renal impairment Caution should be exercised when administering ACTIFED DM COUGH SYRUP to patients with severe renal impairment. Do not exceed the stated dose. Keep out of the reach and sight of children. Contraindications ACTIFED DM COUGH SYRUP is contraindicated in patients: Who are hypersensitive to any of the ingredients. 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 taking or have taken monoamine oxidase inhibitors (MAOIs) in the last two weeks. Special Warnings and Special Precautions for Use Caution should be exercised while prescribing ACTIFED DM COUGH SYRUP in patients with: Chronic or persistent cough, such as occurs with asthma and emphysema, chronic bronchitis, 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). Cases of dextromethorphan abuse have been reported. Caution is particularly recommended for adolescents and young adults as well as in patients with a history of drug abuse or psychoactive substances. Dextromethorphan is metabolised by hepatic cytochrome P450 2D6. The activity of this enzyme is genetically determined. About 10% of the general population are poor metabolisers of CYP2D6. Poor metabolisers and patients with concomitant use of CYP2D6 inhibitors may 2
experience exaggerated and/or prolonged effects of dextromethorphan. Caution should therefore be exercised in patients who are slow metabolizers of CYP2D6 or use CYP2D6 inhibitors ACTIFED DM Cough Syrup should be used cautiously in patients with asthma, bronchitis, chronic obstructive pulmonary disease (COPD), or emphysema. Thickened bronchial secretions that aggravate these conditions may result from the anticholinergic activity of H1- antagonists. ACTIFED DM Cough Syrup use may be possible in patients with these illnesses, particularly if thick bronchial secretions are not a primary component of the illness. The anticholingeric effects of triprolidine may worsen symptoms in patients with symptomatic prostatic hypertrophy or bladder obstruction. Use ACTIFED DM Cough Syrup conservatively in patients with cardiac disease or hypertension. Quinidine-like local anesthetic and anticholingeric properties of H1-antagonists may produce adverse cardiovascular effects such as tachycardia, ECG changes, or arrhythmias. Closed-angle glaucoma may be exacerbated by ACTIFED DM Cough Syrup use. The anticholinergic effects of H1-antagonists may increase intraocular pressure, which can precipitate an acute attack of glaucoma. Triprolidine may also cause dry eyes or blurred vision, which can impact the ability of patients to wear contact lenses. ACTIFED DM Cough Syrup should be used with caution in geriatric patients, as they may be more susceptible to adverse anticholinergic effects. Other anticholinergic medications, may intensify these effects, particularly in the elderly. Existing medical conditions and pharmacotherapy should be considered before using sedating antihistamines in the older adult. If administered, antihistamines should be used in the smallest possible dose in individuals who are susceptible to anticholinergic side effects or who are receiving other medications with anticholinergic properties. Anticholinergics may cause excessive sedation, confusion, cognitive impairment, distress, dry mouth, constipation, and urinary retention. Many of these effects may lead to other adverse consequences, such as falls. Use H1-antagonists such as triprolidine with caution in patients with pyloroduodenal GI obstruction or stenosing peptic ulcer disease. Anticholinergic activity may contribute to delayed gastric emptying, which may produce greater GI occlusion. Triprolidine is extensively metabolized by the liver. The metabolism of triprolidine may be reduced in patients with hepatic impairment. Patients with pre-existing hepatic disease may require dosage adjustments. Liver function tests and adverse effects should be monitored. Antihistamines such as triprolidine may exacerbate hyperthyroidism and cause tachycardia. Use ACTIFED DM Cough Syrup with caution in this patient population. Patients should be monitored for adverse effects. ACTIFED DM Cough Syrup may cause excitability and CNS stimulation in children, infants, and neonates. Cyanosis and apnea may also occur in infants and neonates who receive H1- antagonists. Patient should be reassessed if the cough persists despite treatment with ACTIFED DM COUGH SYRUP or if it is accompanied by high fever, skin rash or persistent headache. 3
Concomitant use of other cough and cold medicines should be avoided. Concomitant use of alcohol should be avoided. Do not exceed the maximum recommended dose or frequency of dosing. Precautions for specific ingredients ACTIFED DM COUGH SYRUP contains Sorbitol - Patients with rare hereditary problems of fructose intolerance should not take this medicine. ACTIFED DM COUGH SYRUP contains methylparaben and propylparaben which may cause allergic reactions (possibly delayed). Interaction with Other Medicaments and Other Forms of Interaction The use of dextromethorphan with, or within two weeks of taking monoamine oxidase inhibitors (MAOIs) should be avoided as severe reactions including serotonin syndrome have been reported (see Contraindications). 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). Dextromethorphan is metabolized by CYP2D6 and has an extensive first pass metabolism. Concomitant use of potent CYP2D6 enzyme inhibitors can increase the dextromethorphan concentrations in the body to levels multifold higher than normal. This increases the patient's risk for toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhoea and respiratory depression) and development of serotonin syndrome. Potent CYP2D6 enzyme inhibitors include fluoxetine, paroxetine, quinidine and terbinafine. In concomitant use with quinidine, plasma concentrations of dextromethorphan have increased up to 20fold, which has increased the CNS 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 dextromethorphan dose may need to be reduced. Concomitant use of dextromethorphan and alcohol may increase the CNS depressant effects of both drugs. Concurrent use of triprolidine and hypnotics, sedatives or anxiolytics may potentiate drowsiness [See Special Warnings and Special Precautions for Use]. Concurrent use of alcohol may have a similar effect [See Special Warnings and Special Precautions for Use]. The anticholinergic effects of triprolidine are intensified by MAOIs [see Contraindications]. Concurrent use of bupropion and agents lowering seizure threshold may result in lower seizure threshold. 4
Pregnancy and Lactation Fertility There is no experience of the effect of ACTIFED DM COUGH SYRUP on human fertility. There is insufficient information available to determine whether dextromethorphan has teratogenic potential. In rats and rabbits, systemic administration of triprolidine up to 75 times the human daily dosage did not produce teratogenic effects. No studies have been conducted in animals to determine whether triprolidine has potential to impair fertility. Pregnancy Although dextromethorphan and triprolidine have been in widespread use for many years without apparent ill consequence, there are no specific data on their use during pregnancy. Caution should therefore be exercised by balancing the potential benefit of treatment to the mother against any possible hazards to the developing foetus. Lactation Triprolidine is excreted in breast milk in small amounts but the effect of this on breast-fed infants is not known. It is not known whether dextromethorphan or its metabolites are excreted in breast milk. Caution should be exercised while prescribing ACTIFED DM COUGH SYRUP to lactating women. Effects on Ability to Drive and Use Machines Dextromethorphan may cause drowsiness and dizziness. The anticholinergic properties of triprolidine may cause drowsiness, dizziness, blurred vision and psychomotor impairment in some patients which may seriously affect ability to drive and use machinery. Those affected should not drive or operate machinery. Undesirable Effects The following adverse events have been reported for the ingredients of ACTIFED DM COUGH SYRUP. Dextromethorphan Clinical Data 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. 5
Post Marketing Data 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 rare or very rare (occurring in < 1/1000 patients). Nervous system disorders Serotonin syndrome. 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) Triprolidine Clinical Trial Data Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Post Marketing Data The following adverse reactions have been reported with triprolidine hydrochloride: Psychiatric disorders Unknown: paradoxical excitation*, confusion**, nightmares***, hallucinations*** * Children and the elderly are more susceptible to paradoxical excitation (e.g. increased energy, restlessness, nervousness). ** The elderly are more prone to confusion. ***Hallucinations and nightmares have been reported mainly in children Nervous System Disorders Very common ( 1/10): sedation, drowsiness Common ( 1/100 to <1/10): disturbance in attention, abnormal coordination, dizziness Eye disorders Unknown: blurred vision Respiratory, thoracic and mediastinal disorders Unknown: thickening of bronchial secretions Gastrointestinal disorders 6
Common ( 1/100 to <1/10): dry mouth, nose and throat Unknown: gastrointestinal disturbance including nausea, vomiting Skin and subcutaneous tissue disorders Unknown: rash, urticaria Renal and urinary disorders Unknown: urinary retention Overdose Symptoms and Signs Dextromethorphan 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. Triprolidine Triprolidine overdose is likely to result in effects similar to those listed under Undesirable Effects. Additional symptoms may include ataxia, weakness, respiratory depression, dryness of the skin and mucous membranes, hyperpyrexia, tremor, psychosis, convulsions, tachycardia and arrhythmias. Treatment For dextromethorphan overdose: Supportive and symptomatic care should be provided as required. If overdose is severe, naloxone may be helpful, particularly for patients with respiratory depression. For triprolidine overdose: Treatment should be supportive and directed towards specific symptoms. PHARMACOLOGICAL PROPERTIES Pharmacodynamic Properties Dextromethorphan Dextromethorphan has an antitussive action. It controls cough spasms by depressing the medullary cough centre. Dextromethorphan is a cough suppressant which has a central action on the cough centre of the medulla. Triprolidine hydrochloride 7
Triprolidine hydrochloride is an antihistamine which acts as a histamine H1- receptor antagonist. Triprolidine belongs to the group of alkylamines (propylamine) and has minimal anticholinergic effect. Pharmacokinetic Properties Dextromethorphan Absorption Dextromethorphan hydrobromide is well absorbed from the gastrointestinal tract. Distribution Due to extensive pre-systemic metabolism by the liver, detailed analysis of the distribution of orally administered dextromethorphan is not possible. Metabolism Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation (CYD2D6) is the main determinant of dextromethorphan pharmacokinetics in human volunteers. It appears that there are distinct phenotypes for this oxidation process resulting in highly variable pharmacokinetics between subjects. Unmetabolised dextromethorphan, together with the three demethylated morphinan metabolites dextrorphan (also known as 3-hydroxy-Nmethylmorphinan), 3- hydroxymorphinan and 3-methoxymorphinan have been identified as conjugated products in the urine. Dextrorphan, which also has antitussive action, is the main metabolite. In some individuals metabolism proceeds more slowly and unchanged dextromethorphan predominates in the blood and urine. Elimination Dextromethorphan and its metabolites are excreted in urine for up to 50% of the ingested dose at 24 hours. Only a very small quantity of unchanged dextromethorphan is found in the urine. The elimination half-lives of dextromethorphan vary greatly depending on the dose administered and on the patient s CYP2D6 phenotype. In one study, the half-life of the elimination phase of dextromethorphan was on average approximately 7 times higher in some subjects. The half-life of main metabolite dextrorphan is 2.5-3.5 hours. Triprolidine hydrochloride Absorption The maximum effect of oral administration is observed 60 minutes after taking and persists for approximately five hours. Peak plasma concentration (Cmax) is observed two hours (Tmax) after administration and the plasma half-life is approximately 3.2 hours. Triprolidine is metabolised 8
by the hepatic microsomes. Approximately 1% of the dose administered appears in the urine in unaltered form. Distribution No relevant data available. Metabolism Metabolised by the hepatic microsomes. Approximately 1% of the dose administered appears in the urine in unaltered form. Elimination No relevant information. Preclinical Safety Data No relevant data available. PHARMACEUTICAL PARTICULARS List of Excipients Sorbitol 70% solution, Glycerin, Propylene Glycol, Methylparaben, Propylparaben, Sodium Chloride, Sodium Citrate, Menthol, Sodium saccharin, Ponceau 4R ISI (*), Flavour Mixed Fruit RSV IFF, Purified water Incompatibilities No incompatibilities have been identified. Shelf Life The expiry date is indicated on the label and packaging. Special Precautions for Storage Store in a well closed container at temperatures not exceeding 30ºC. Protect from direct sunlight. Keep out of reach of children. Nature and Specification of Container Amber PET bottle with a measure cup. Instructions for Use / Handling. There are no special requirements for use or handling of the product. For further information please contact: 9
GlaxoSmithKline Pharmaceuticals Limited. Registered Office Dr. Annie Besant Road, Worli Mumbai 400 030, India. Trade marks are owned by or licensed to the GSK group of companies Version: ACTDM/PI/IN/2018/01 dated 06 May 2018 Adapted from: Dextromethorphan GDS (Cx) version 04 dated 20-July-2017 Phenylephrine Hydrochloride & Triprolidine Hydrochloride GDS (Cx) version 01 dated 22 Dec 2011. Multi-Action Actifed Dry Coughs SPC last updated on 20-Dec-2016, date of revision of text 07-Dec-2016 Triprolidine Available from https://www.clinicalkey.com/pharmacology/monograph/1606?n=triprolidine Accessed on 27-Feb-2018. 10