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MHRA-UKPAR – Night Nurse Hot Lemon Menthol powder for Oral Solution PL 00079/0671 - 1 -

NIGHT NURSE HOT LEMON MENTHOL POWDER FOR ORAL SOLUTION

PL 00079/0671

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

9

Steps taken after authorisation – summary

Page 20

Summary of Product Characteristics Page 21

Patient Information Leaflet

Page 28

Labelling Page 30



PL 00079/0671

LAY SUMMARY

The Medicines Healthcare products Regulatory Agency granted Beecham Group plc a Marketing Authorisation (licence) for the medicinal product Night Nurse Hot Lemon Menthol Powder for Oral Solution (PL 00079/0671) on 30 August 2011. This is a Pharmacy (P) medicine and available under the supervision of a pharmacist. Night Nurse Hot Lemon Menthol Powder for Oral Solution is used for the night-time relief of the major symptoms of colds, chills and flu. The medicine contains three active ingredients, paracetamol, promethazine hydrochloride and dextromethorphan hydrobromide. Paracetamol is used to relieve pain and reduce an increased body temperature; promethazine hydrochloride is an antihistamine which dries up a runny nose and aids restful sleep and dextromethorphan hydrobromide is a cough suppressant that helps relieve dry or tickly coughs. The medicine can also help to relieve a sore throat. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Night Nurse Hot Lemon Menthol Powder for Oral Solution outweigh the risks; hence a Marketing Authorisation has been granted.



PL 00079/0671

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 10

Clinical assessment

Page 11

Overall conclusions and risk benefit assessment Page 18


INTRODUCTION

The UK granted a Marketing Authorisation for the medicinal product Night Nurse Hot Lemon Menthol Powder for Oral Solution (PL 00079/0671) to Beecham Group plc on 30August 2011. This product is a pharmacy product and is available to the general public under the supervision of a pharmacist. This application was submitted as abridged, bibliographic application according to Article 10a (well-established use) of Directive 2001/83/EC, as amended. Night Nurse Hot Lemon Menthol Powder for Oral Solution is a different pharmaceutical form of the already approved medicinal product Night Nurse, PL 00079/0187 which was first registered on 23 January 1988. The finished product contains three active substances, paracetamol, which has analgesic and antipyretic properties; promethazine hydrochloride, an antihistamine with anticholinergic activity and dextromethorphan hydrobromide, an antitussive. No new non-clinical or clinical data have been submitted, which is acceptable given that the application was based on well-established medicinal use and the combination of actives substances has been in clinical use for over 10 years. The Marketing Authorisation Holder (MAH) has provided adequate justification for not submitting a Risk Management Plan (RMP). Paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride are well-known active drug substances and have been used to treat the symptoms of colds and flu for many years. This application refers to the Marketing Authorisation for Night Nurse (PL 00079/0187: Beechams Group plc) licensed for use the symptomatic relief of colds, chills and influenza at night. The safety profile of the product is therefore well-characterised and considered to be acceptable in the patient population in which it is indicated. The MAH has provided adequate justification for not submitting a detailed Environmental Risk Assessment (ERA). It is considered that the introduction of this product to the environment through use and proper disposal raises no significant environmental concerns. There are other product of the same drug combination already approved and marketed in the UK and the further authorisation and sale of this product is not expected to change the overall environmental exposure. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Night Nurse Hot Lemon Menthol Powder for Oral Solution outweigh the risks; hence a Marketing Authorisation was granted.


PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE (1)

Paracetamol INN: Paracetamol Chemical name: N-(4-hydroxyphenyl)ethanamide

Structure:

Molecular formula: C8H9NO2 Molecular weight: 151.2g/mol

General Properties Description: A white or almost white crystalline powder. Solubility: Sparingly soluble in water, freely soluble in alcohol, and very slightly soluble in methylene chloride. Paracetamol is the subject of a European Pharmacopoeia (Eur Ph.) monograph. Manufacture All aspects of the manufacture and control of the active substance paracetamol are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

DRUG SUBSTANCE (2)

Promethazine hydrochloride INN: Promethazine hydrochloride Chemical name: 10-(2-(dimethylamino)propyl)-, monohydrochloride

Structure:


Molecular formula: C17H21ClN2 S Molecular weight: 320.9 General Properties Description: It is a white or faintly yellow, odourless, crystalline powder. Solubility: Very soluble in water, freely soluble in ethanol/methanol and methylene chloride. Promethazine hydrochloride is the subject of a European Pharmacopoeia (Eur Ph.) monograph. Manufacture All aspects of the manufacture and control of the active substance promethazine hydrochloride are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

DRUG SUBSTANCE (3)

Dextromethorphan hydrobromide INN: Dextromethorphan hydrobromide Chemical name: ent-3-Methoxy-10-methylmorphinan hydrobromide monohydrate

Structure:

Molecular formula: C18H26BrNO.H2O Molecular weight: 370.3


General Properties Description: It is an almost white, crystalline powder Solubility: Sparingly soluble in water and freely soluble in ethanol/methanol Dextromethorphan hydrobromide is the subject of a European Pharmacopoeia (Eur Ph.) monograph. Manufacture All aspects of the manufacture and control of the active substance dextromethorphan hydrobromide are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.

DRUG PRODUCT Description and Composition The product is presented as a powder for oral solution. Each sachet contains 1000 mg of paracetamol, 20 mg of promethazine hydrochloride and 15 mg of dextromethorphan hydrobromide. Other ingredients consist of pharmaceutical excipients, maltodextrin, sucralose, citric acid, tartaric acid, sodium citrate, acesulfame potassium E 950, aspartame E 951, powdered menthol flavour, lemon flavour and quinoline yellow E 104. All ingredients within the powder for oral solution comply with their relevant Ph. Eur monographs with the exception of the lemon flavour, menthol flavour and quinoline yellow E 104 both of which comply with in-house specifications and sucralose which complies with its USP specification. Appropriate justification for the inclusion of each excipient has been provided. Satisfactory Certificates of Analysis have been provided for all the excipients. None of the excipients used contain material derived from animal or human origin. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients. Pharmaceutical Development The objective of the pharmaceutical development of this product was to develop a “hot drink” option for a “cold relief with sedative option”; currently marketed products are only available as liquid and capsule dosage formats. The active ingredients are quantitatively and qualitatively identical to the cross-reference product Night Nurse (PL 00079/0187). The applicant has provided suitable product development sections. Tests were carried out to demonstrate that dissolving the finished product in hot water had no significant effect on the chemical or physical properties of drug product. Dissolution and related substances are within the specified limits as described on the finished product specification. Manufacture A description and flow-chart of the manufacturing method has been provided.


In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted on three pilot-scale batches and are accepted. The applicant has committed to validate commercial batches. The validation data demonstrated consistency of the manufacturing process. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory; they provide an assurance of the quality and consistency of the finished product. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Container Closure System The finished product is licensed for marketing in sachets composed of aluminium, low density polyethylene and bleached paper; 5 sachets are packaged into a cardboard outer carton with the Patient Information Leaflet (PIL). Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs.

Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 15 months has been set, with no special storage conditions required for this medicinal product.

Expert Report A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the labelling and PIL have been provided. The labelling is satisfactory and fulfils the statutory requirements for Braille. A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Day and Night Nurse Capsules and Beechams Cold and Flu hot Lemon. The bridging report submitted by the applicant has been found acceptable. The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that is contains.


MAA Form The MAA form is pharmaceutically satisfactory. Conclusion There are no objections to the approval of Night Nurse Hot Lemon Menthol Powder for Oral Solution from a pharmaceutical point of view.


NON-CLINICAL ASSESSMENT

This is an abridged application, submitted under Article 10a of Directive 2001/83/EC, as amended, for Night Nurse Hot Lemon Menthol Powder for Oral Solution.

Pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride are well known. As these are widely used, well-known active substances, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. A non-clinical expert report has been written by a suitably qualified person and is satisfactory.

The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). This was a bibliographic application to add the product Night Nurse Hot Lemon Menthol Powder for Oral Solution as a line extension to Night Nurse (PL 00079/0187) in the UK. It is considered that the introduction of this product to the environment through use and proper disposal raises no significant environmental concerns. There are other products of the same drug combination already approved and marketed in the UK and the further authorisation and sale of this product is not expected to change the overall environmental exposure.


CLINICAL ASSESSMENT

PHARMACOKINETICS

Introduction and overview The pharmacokinetics of the separate medicines in the combination (paracetamol, dextromethorphan and promethazine) is well known. No clinical data has been generated for the combination or this formulation.

Absorption Paracetamol: It is readily absorbed from the upper small intestine to give peak plasma concentrations of 15-20 mcg/ml in 30-120 minutes in adults when given a 1g oral dose. The speed of gastric emptying and therefore food modifies the rate of absorption. Dextromethorphan: Following oral administration it is well absorbed from the gastrointestinal tract. It undergoes extensive first pass metabolism in the liver. Peak plasma concentrations of 0.1 µg/l are seen after 2.5 hours. Promethazine: It is well absorbed but undergoes extensive first pass metabolism, with only 25% reaching the systemic circulation unchanged. Peak plasma concentration is reached after 2-3 hours.

Distribution Paracetamol: The distribution volume of is between 0.7 and 1.01 l/kg. Plasma protein binding is minimal and there is distribution into all tissues. Dextromethorphan: There is no discussion of the distribution of dextromethorphan. Promethazine: It has a large volume of distribution (13.4 +/- 3.6 kg/l), which is consistent with wide body tissue distribution. It is also known to be extensively protein bound.

Metabolism Paracetamol: There is limited first pass metabolism, with around 80% of a 1g dose being bioavailable. It is mainly metabolised by the liver, by two principle pathways, glucuronidation and sulphuric acid conjugation. 50-60% of a therapeutic dose is converted into the glucoronide conjugate, 25-25% to the sulphate conjugate, 5% unchanged and 2-5% as others. In overdose these can become saturated and the highly reactive metabolite, NAPQI, is then found in high concentrations and causes hepatic injury. Dextromethorphan: The main metabolite is dextrophan, which is created in the liver by the cytochrome p450 enzyme CYP2D6. The metabolite is active and has an anti-tussive action. There are also conversions to other, inactive, metabolites, mainly by demethylation and sulphate and gluconic acid conjugation. Promethazine: It undergoes extensive first pass metabolism, with only 25% reaching the systemic circulation. The two primary pathways for metabolism are sulfoxidation and N-


dealkylation. The major metabolite, promethazine sulfoxide, is inactive with regards H1 receptors.

Excretion Paracetamol: It is renally excreted, with a plasma half life of 2.3 hours. Dextromethorphan: It is renally excreted. 8% is excreted unchanged in six hours, with 50% over the first 24 hours. Another 25% is excreted as the major metabolites over 24 hours. Promethazine: Most is excreted in the faeces via biliary excretion. Small amounts of unchanged drug and sulfoxide metabolite are excreted in the urine. Promethazine Is known to cross the placenta and other medicines in its class are secreted into breast milk.

Drug-drug interactions Paracetamol: The action of warfarin and other coumarins may be enhanced by regular daily usage of paracetamol. Chronic alcohol use has been reported to increase the risk of hepatotoxicity following paracetamol overdose. Dextromethorphan: As it is mainly metabolised by CYP2D6, use of inhibitors such as quinidine, amiodarone, fluoxetine, paroxetine and haloperidol may increase its serum concentrations. Concomitant use of dextromethorphan and SSRI’s, tricyclics or monoamine oxidase inhibitors can lead to serotonin syndrome. Promethazine: Concomitant use of promethazine with other CNS sedatives such as opiates, barbiturates, tranquilizers or antihistamines may lead to an additive or potentiating effect. Alcohol can also enhance the CNS sedative effects of promethazine. As promethazine has anticholinergic effects, the effects of drugs such as atropine, and tricyclic antidepressants may be potentiated. Concurrent administration of such drugs could lead to anticholinergic toxicity; this can be a particular problem in the elderly taking multiple medications. Overall Conclusions On Pharmacokinetics

The pharmacokinetics of the individual component medicines in the combination are well recognised, and have been satisfactorily discussed.

BIOEQUIVALENCE As a ‘well established use’ application, no bioequivalence data has been submitted.

PHARMACODYNAMICS Paracetamol: Paracetamol is an effective analgesic and antipyretic with little anti-inflammatory action. The antipyretic activity of paracetamol is thought to be mediated by its ability to selectively inhibit prostaglandin synthesis in the central nervous system. The precise mechanism for the analgesic properties of paracetamol remains to be established. Data suggest that central prostaglandin synthetase inhibition is likely to be of primary importance. Paracetamol is a weak inhibitor of COX-1 and COX-2 leading to the suggestion that there may be another form of COX that is more sensitive to inhibition by paracetamol. A third distinct COX isoenzyme has been described, COX-3, which is


inhibited by paracetamol and expressed in specific tissues with highest levels in human cerebral cortex and heart. Whether this is the target for paracetamol is uncertain. Paracetamol, unlike non-steroidal anti-inflammatory drugs (NSAIDs), does not appear to inhibit the peripheral generation of prostaglandins. For example, it does not alter the gastric mucosal generation of prostaglandins and these data are supported by clinical evidence demonstrating the extreme rarity of serious renal and gastro-intestinal adverse events associated with paracetamol. Paracetamol is, therefore, particularly suitable for patients with a history of disease or on concomitant medication where peripheral prostaglandin inhibition would be undesirable (e.g. with gastro-intestinal bleeding, cardiovascular disease or in the elderly). Dextromethorphan: The precise mechanism of action of dextromethorphan is not known. An active metabolite of dextromethorphan is dextrophan, the 3-hydroxy derivative of dextromethorphan and the effects of dextromethorphan are believed to be caused by both dextromethorphan and dextrophan. Both have non opiate-mediated cough suppressant actions and neither has any opiate mediated analgesic actions. Animal studies suggest that the main site of action of dextromethorphan is on the centrally induced cough response and studies have shown that both dextrophan and dextromethorphan are antagonists at the N-methyl-d-aspartate (NMDA) receptor in the brain. Dextromethorphan is similar in efficacy as an antitussive to codeine but without the gastrointestinal and subjective effects seen with codeine. Dextromethorphan has no addictive properties. Promethazine: Promethazine is a competitive antagonist of histamine at the H1 receptor having no influence on H2 receptor mediated events hence no influence on gastric acid secretion. It is a phenothiazine H1 antihistamine and exhibits an anticholinergic effect which forms the therapeutic basis of drying up secretions in the nose. It also exhibits local anaesthetic actions, anti-emetic effects and weak α-adrenoceptor antagonistic actions. Another major clinical effect of promethazine is sedation which is objectively apparent at doses as low as 10 mg in adults. Sedation is thus common with therapeutic doses (25 mg – 75 mg) and, between individuals, ranges in intensity from mild drowsiness to deep sleep. Within subjects, a weak correlation has been reported between promethazine blood concentrations levels and CNS effects, as reflected by impairment of rotary pursuit and simple force choice reaction time. Overall conclusions on Pharmacodynamics The pharmacodynamics is well established for the constituent medicines in the combination, and has been satisfactorily discussed.


CLINICAL EFFICACY

Introduction As a ‘well established use’ application, no new clinical studies have been performed. Paracetamol: Paracetamol is a widely used analgesic for the relief of mild to moderate pain. In headache, 2 parallel group studies in patients with episodic headache showed that paracetamol was statistically significantly better than placebo in terms of pain relief values and pain intensity over 6 hours. A crossover study looking at similar end points also showed the same. Another 3 studies are discussed but no results are given. In musculoskeletal pain, one study showed that in 90 patients with varied aetiologies, paracetamol was statistically superior over its baseline measure. In muscle ache associated with the common cold, one study using a paracetamol/pseudoephedrine combination showed that it had a statistically significant superiority over placebo with regards to general muscular ache. In sore throat relief, one double blind, placebo controlled, randomised, parallel group study a single dose of paracetamol was shown to be statistically significantly superior to placebo in relieving the sore throat pain associated with an upper respiratory tract infection. In fever, a randomised, double blind, double dummy, parallel group study in adults with fever associated with an upper respiratory tract infection found that 500mg and 1000mg of paracetamol statistically significantly reduced the patient’s temperature more than placebo. It also showed that the mean maximum reduction was greatest with 1000mg. Another study, using an endotoxin induced model of fever showed that at 8 hours paracetamol showed a statistically significant and clinically meaningful difference from placebo in temperature reduction. Dextromethorphan: In a large, double blind prospective trial, comparing placebo, codeine 15mg and dextromethorphan of varying doses in the suppression of cough showed a clear dose response for dextromethorphan. 15mg of dextromethorphan was found to have the same level of suppression as 15mg of codeine. All doses of dextromethorphan showed statistically significant reductions in cough over placebo. Promethazine: Promethazine is a classical phenothiazine histamine H1-receptor antagonist and its major action is to diminish or abolish action of histamine in the body by reversible bloackade of histamine H1-receptor sites in tissues. The clinical effects of promethazine include the drying up of nasal secreations and to some extent inhibition of sneezing (Eccles et al 1995; Howard et al 1979). In addition, promethazine also has sedating properties, which are beneficial in a product for night-time use. The precise mechanism of these effects are not fully clear as active ingredients such as promethazine have some antimuscarinic properties in addition to being antihisaminergic. A literature search has been carried out to find papers that discuss paracetamol, promethazine and dextromethorphan in combination, but no literature on the combination has been found. Although no literature on this specific combination was found the applicant has 22 years of experience with this specific combination of active ingredients from the cross-reference product Night Nurse (PL 00079/0187). It is broadly equivalent to taking paracetamol, promethazine and dextromethorphan as individual medicines as there are no documented interactions between the actives and they are metabolised in different ways.


It is accepted that the combination is not new and has been in use for some time. The combination is not expected to affect the efficacy of the separate medications.

Overall conclusions on clinical efficacy The applicant has established the efficacy of paracetamol, promethazine and dextromethorphan in the required indication. CLINICAL SAFETY

Introduction The combination, as other formulations of ‘Night Nurse’ has been on the market in the UK since 1988. However, the applicant has provided no general safety review for the combination product, instead discussing each component medicine. Adverse Reactions Paracetamol: No data from published clinical studies is provided. Skin rash, allergic reactions and blood dyscrasias have all been reported in the literature. Dextromethorphan: No data from published clinical studies is provided. Other sources show that drowsiness, hypersensitivity and anaphylactic reactions have all been recorded. Promethazine: Sedation and headache are the most commonly reported adverse events in clinical trials. Also reported from other sources are CNS depression, psychomotor impairment and dizziness recognised as common adverse events with first generation antihistamines, such as promethazine. Also recognised is paradoxical central nervous excitation, more likely to occur at high doses or in children and the elderly. Also reported from the applicant’s safety database and in the BNF and Martindale are hypersensitivity and anaphylaxis. Special populations Use in the elderly: No pharmacokinetics or specific safety studies have been performed in the elderly. However, it is recognised that the elderly are more prone to the anticholinergic adverse events of sedating antihistamines. A study using promethazine as an antiemetic showed that the elderly were significantly more likely to suffer adverse events. Use in Children: Children are more likely to experience paradoxical excitation than adults. Lactation and pregnancy: Paracetamol has not been identified as a risk to pregnancy or development in human and animal studies. It is recognised to cross the placental barrier and less than 1% of the ingested dose enters breast milk. In epidemiological studies involving 342 pregnant women, no evidence of major or minor malformations were found. It is known to be excreted in breast milk. There is little information about the use of dextromethorphan in pregnancy; therefore it is recommended that pregnant women should avoid taking it.


Contraindications MAOIs: It is well recognised that use of a dextromethorphan containing medicine concurrently with an MAOI can lead to severe and sometimes fatal adverse events. This is thought to be because of serotonin syndrome. Patients at risk of respiratory failure: Both dextromethorphan and promethazine should not be used in such patients. Warnings/Precautions Promethazine, as a sedating antihistamine, has a significant antimuscarinic activity and therefore should be used with caution in prostatic hypertrophy, urinary retention, glaucoma and pyloroduodenal obstruction. Caution is also required in epilepsy. Patients with chronic or persistent cough should not self medicate with dextromethorphan containing products as this could mask significant underlying medical conditions. The use of dextromethorphan or promethazine containing medicines is also not recommended in patients with cough with excessive secretions as they may impair expectoration. Caution should be used in the use of paracetamol containing products in chromic liver disease, as it can prolong the plasma half life. In patients with renal failure the ability of the kidney to eliminate polar metabolites is limited and accumulation of paracetamol conjugates would be predicted. Thus it is appropriate to exercise caution in administering this product in patients with severe renal impairment. As promethazine is a sedating antihistamine, with its adverse effects enhanced by alcohol, it is well recognised that it should not be taken when operating machinery or driving. A number of immunological urinary pregnancy tests may give false results in the presence of promethazine. Overdose Paracetamol: Overdose of paracetamol leads to high levels of the toxic metabolite, NAPQI, after saturation of the glucoronide and sulphate pathways. NAPQI usually then reacts with glutathione but in large quantities the intrinsic stores are used and free NAPQI is left. This causes liver damage and in severe cases fulminant hepatic failure. Early treatment with N-acetylcysteine can effectively prevent hepatic and renal failure. Dextromethorphan: Symptoms of overdose are generally mild and include drowsiness and nausea and vomiting. Acute large ingestions can lead to serious toxicity, including stupor, ataxia, hyerexcitability, dystonia and psychosis. Supportive treatment is required and naloxone may be of some benefit. Promethazine: Sedation and anticholinergic effects (gastrointestinal disturbances, dry mouth, dilated pupils, tachycardia etc) are the most common features of overdose. Activated charcoal may be of use within 2 hours of ingestion otherwise management is supportive and symptomatic. Overall conclusions on clinical safety The applicant has also submitted sufficient post-marketing experience with Night Nurse products to demonstrate that the combination of active substances is safe and that the profile for this new application is not expected to differ.


PRODUCT INFORMATION: Summary of Product Characteristics (SmPC) The approved SmPC is consistent with that for the cross-reference product and is acceptable. Patient Information Leaflet (PIL) The PIL is in line with the approved SmPC and is satisfactory. Labelling The labelling is satisfactory. Clinical Overview A satisfactory clinical overview was provided and prepared by an appropriately qualified expert. The CV of the clinical expert was supplied. CONCLUSIONS Sufficient clinical information has been submitted to support this application. The risk-benefit of the products is considered favourable from a clinical perspective. The grant of a Marketing Authorisation was therefore recommended.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY The important quality characteristics of Night Nurse Hot Lemon Menthol Powder for Oral Solutions are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for application of this type. EFFICACY No new data are submitted and none are required for this type of application. The published literature supports the efficacy of this product in the proposed indications. The safety and efficacy of paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride are well-known. The presented evidence for well-established use of the active substances is sufficient. The literature review identifies no new safety issues or concerns. The safety profile of paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride are well-known. No new or unexpected safety concerns arise from this application.

The SPC, PIL and labelling are satisfactory and consistent with those for the cross- reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride are active substances of well-known safety and efficacy. The combination of these three active substances has been used for a number of decades in the EC. Extensive clinical experience with paracetamol, dextromethorphan hydrobromide and promethazine hydrochloride is considered to have demonstrated the therapeutic value of the active substances. The benefit/risk ratio is therefore considered to be positive.



PL 00079/0671

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 18 October

2010.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 30th November 2011.

3 Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 18th March 2011, and further information relating to the clinical dossiers on 16th March 2011.

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 16th May 2011 for the clinical sections of the dossier on 3rd June 2011.

5 The application was determined on 30 August 2011.



PL 00079/0671

STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome

9th September 2011

Type IB To increase the shelf life of the finished product as marketed for sale from 12 months to 15 months.

Approved on 17th October 2011


NIGHT NURSE HOT LEMON MENTHOL POWDER FOR ORAL

SOLUTION

PL 00079/0671

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Night Nurse Hot Lemon Menthol Powder for Oral Solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active constituents mg/sachet Paracetamol 1000.0 Promethazine hydrochloride 20.0 Dextromethorphan hydrobromide Excipients Aspartame

15.0

mg/sachet 35.0

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Powder for oral solution

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

For the symptomatic relief of colds, chills and influenza at night.

4.2 Posology and method of administration Route of Administration Oral

Adults and children 16 years and over: Empty contents of one sachet into a mug. Half fill with very hot water. Stir well. Add cold water as necessary. One sachet to be taken just before going to bed. Not to be given to children under 16 years except on medical advice.

Maximum daily dose: Only one sachet should be taken per night. Do not exceed the stated dose Maximum duration of continued use without medical advice: 3 days. Other products containing paracetamol may be taken during the day but the total daily dose of paracetamol must not exceed 4000mg (including this product) in any 24 hour period. Allow at least four hours between taking any paracetamol-containing product and this product. Should not be used with other cough or cold medicines, or any other antihistamine-containing products, including those used on the skin.


4.3 Contraindications Hypersensitivity to paracetamol, dextromethorphan, promethazine or any of the other constituents. 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).

Patients taking or have taken monoamine oxidase inhibitors (MAOIs) in the last two weeks.

4.4 Special warnings and precautions for use Medical advice must be sought before taking this product in people with:

• Hepatic or renal impairment. Underlying liver disease increases the risk of paracetamol-related liver damage.

• Chronic or persistent cough, such as occurs with asthma and emphysema, or where cough

is accompanied by excessive secretions.

• Narrow-angle glaucoma

• Cardiovascular problems

• Prostatic hypertrophy

• Urinary retention

• Epilepsy

Use with caution in the elderly, who are more likely to experience anticholinergic adverse effects including confusion and paradoxical excitation. Avoid use in elderly patients with confusion. Children are more likely to experience paradoxical excitation with sedating antihistamine. Medical advice should be sought if symptoms persist, or are accompanied by high fever, skin rash or persistent headache. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Patients should be advised not to take other paracetamol-containing products or decongestant-containing medicines concurrently. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Avoid alcoholic drink. Special label warnings Do not take with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if you feel well. Special leaflet warnings Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage. Contains a source of phenylalanine equivalent to 20 mg per sachet. May be harmful to people with phenylketonuria.Each sachet contains 122 mg sodium. This should be taken into account by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction Medical advice should be sought before taking paracetamol-promethazine-dextromethorphan in combination with these drugs:

Monoamine-oxidase inhibitors (MAOIs) Severe reactions, including serotonin syndrome (see below), may occur when this product is taken


concomitantly, or within two weeks of taking, an MAOI. MAOIs may prolong and intensify the anticholinergic effects of antihistamines.

Selective serotonin re-uptake inhibitors (SSRIs), tricylic antidepressants or MAOIs

Concomitant use of dextromethorphan with selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, or MAOIs may result in serotonin syndrome with changes in mental status, hypertension, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering and tremor.

Anticholinergic drugs such as atropine, MAOIs and tricyclic antidepressants

As promethazine has some anticholinergic activity, the effects of some anticholinergic drugs may be potentiated.

Alcohol Concomitant use of alcohol with dextromethorphan and promethazine may increase the CNS depressant effects of these drugs.

CNS depressant drugs such as antipsychotics, hypnotics or anxiolytics

Promethazine may potentiate the sedative effects of other CNS depressant drugs.

Warfarin and other coumarins The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increase risk of bleeding; occasional doses have no significant effect.

Inhibitors of cytochrome P450 2D6 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.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Promethazine may interfere with immunologic urine pregnancy tests to produce false positive or negative results.

4.6 Fertility, Pregnancy and lactation Pregnancy This product should not be used during pregnancy without medical advice. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. No relevant data are available for products containing dextromethorphan. Human and animal studies with promethazine are insufficient to establish the safety of this drug during pregnancy. It should only be used when considered essential by the doctor. Lactation This product should not be used whilst breast feeding without medical advice. Paracetamol is excreted in breast milk but not in a clinically significant amount. Promethazine may be excreted in breast milk. It should only be used when considered essential by a doctor.

4.7 Effects on ability to drive and use machines This product may cause drowsiness, dizziness, blurred vision, cognitive and psychomotor impairment which can seriously affect the ability to drive and use machinery. If affected do not drive or operate machinery.

4.8 Undesirable effects

The following convention has been utilized for the classification of undesirable effects: very common (≤ 1/10), common (≤ 1/100, <1/10), uncommon (≤ 1/1000, < 1/100), rare (≤ 1/10,000, < 1/1000), very rare (<1/10,000), not known (cannot be estimated from available data). Paracetamol Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at


therapeutic/labelled dose and considered attributable are tabulated below by system class. Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but post-marketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.

Body System Undesirable effect Blood and lymphatic system disorders Thrombocytopenia

Immune system disorders Anaphylaxis

Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson syndrome/toxic epidermal necrolysis

Respiratory thoracic and mediastinal disorders

Bronchospasm*

Hepatobiliary disorders Hepatic dysfunction *There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Dextromethorphan The following adverse events have been observed in published clinical studies and are likely to represent uncommon adverse reactions to dextromethorphan. Body system Undesirable effect Nervous system disorders Drowsiness, dizziness Gastrointestinal disorders Gastrointestinal disturbance, nausea,

vomiting, abdominal discomfort Adverse reaction identified during post-marketing use with dextromethorphan are listed below. The frequency of these reactions is unknown but likely to be very rare. Body system Undesirable effect Immune system disorders Allergic reactions (e.g. rash, urticaria,

angiodema) Nervous system disorders 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

Promethazine

Adverse reactions which been observed in published clinical studies with promethazine and which are considered to be common or very common are listed below by MedDRA system Organ Class. The frequency of other reactions identified during post-marketing use is not known, but these reactions are likely to be uncommon or rare.

Body System Undesirable effect Immune system disorders Not known: Hypersensitivity reactions

including rash, urticaria, angiodema and anaphylaxis, photosensitivty

Psychiatric disorders Not known: Confusion*, disorientation*, paradoxical excitation*, **(e.g. increased energy, irritability, restlessness, nervousness, sleep disturbance) *The elderly are more susceptible to confusion, disorientation and paradoxical excitation **Children are more susceptible to paradoxical excitation

Nervous system disorders Very common: Drowsiness


Common: Psychomoto impairment, disturbance in attention, dizziness, headache.

Eye disorders Common: Blurred vision Gastrointestinal disorders Common: Dry mouth

Not Known: Gastrointestinal disturbance Renal and urinary disorders Not known: Urinary retention

The elderly are more susceptible to anticholinergic effects of promethazine.

4.9 Overdose Paracetamol Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors If the patient a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes. or b) Regularly consumes ethanol in excess of recommended amounts. or c) Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with current best practice guidelines – see current BNF. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.


Promethazine Hydrochloride Symptoms Promethazine overdose is likely to result in effects similar to those listed under Adverse Reactions. Additional symptoms may include delirium, agitation, hallucinations, dystonic reactions, hypotension, and ECG changes. Large overdose may cause convulsions, toxic psychosis, arrythmias, coma and cardiorespiratory depression. Management Treatment is supportive with attention to maintenance of adequate respiratory and circulatory status. Convulsions and marked CNS stimulation should be treated with parenteral diazepam or other suitable anti-convulsants. Dextromethorphan The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms

Dextromethorphan overdose is likely to result in effects similar to those listed under Adverse Reactions. Following large overdoses, additional symptoms may include excitation, mental confusion ,restlessness, nervousness and irritability, stupor, ataxia, dystonia, hallucinations, psychosis and respiratory depression. Management This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg. Give naloxone if overdose is severe and if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Paracetamol - an analgesic and antipyretic. Promethazine hydrochloride – an antihistamine with anticholinergic activity. Dextromethorphan hydrobromide - an antitussive.

5.2 Pharmacokinetic properties

Paracetamol - is readily absorbed from the upper gastrointestinal tract. It is metabolised predominantly in the liver and excreted in the urine, mainly as glucuronide and sulphate conjugates. Promethazine hydrochloride - is readily absorbed from the gastrointestinal tract, but undergoes extensive first pass metabolism in the liver, with only 25% of the oral dose reaching the systemic circulation unchanged. After oral therapy therapeutic effects are identifiable at 15-30 minutes and peak plasma concentrations at 2 to 3 hours. Estimates of terminal half life in blood plasma are in the range of 4-6 hours. It is extensively plasma protein bound. It is eliminated mainly as metabolites, predominantly by the faecal (via biliary) route, with < 1% of the parent compound and ca. 10% as the sulphoxide metabolite being excreted in the urine over a 72 hour period. Dextromethorphan hydrobromide - is well absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted as demethylated metabolites including dextrorphan, 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.


5.3 Preclinical safety data None stated.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Maltodextrin Sucralose Citric acid Tartaric acid Sodium citrate Acesulfame potassium E 950 Aspartame E 951 Powdered menthol flavour Lemon flavour Quinoline yellow E 104

6.2 Incompatibilities

Not known 6.3 Shelf life

15 months 6.4 Special precautions for storage

Do not store above 25°C. 6.5 Nature and contents of container

Pack sizes of five sachets are available. The sachet laminate comprises: ‘Surlyn’ 25 gm-2 (product contact layer)/aluminium foil 15 microns/low density polyethylene 12 gm-2 /bleached paper 45 gm-2 (outer layer).

6.6 Special precautions for disposal

No special requirements for disposal and handling.

7 MARKETING AUTHORISATION HOLDER Beecham Group Plc 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom Trading as GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8 MARKETING AUTHORISATION NUMBER(S) PL 00079/0671

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 30/08/2011 10 DATE OF REVISION OF THE TEXT

17/10/2011



PL 00079/0671

PATIENT INFORMATION LEAFLET



PL 00079/0671

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