Variation assessment report for Beechams Breathe Clear Hot ... · mhra par; beechams breathe clear...

MHRA PAR; BEECHAMS BREATHE CLEAR HOT HONEY & LEMON MENTHOL FLAVOUR POWDER FOR ORAL SOLUTION, PL 00079/0674

1

Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution

PL 00079/0674

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 9

Summary of product characteristics

0

Patient information leaflet

Page 17

Labelling Page 18


2

BEECHAMS BREATHE CLEAR HOT HONEY & LEMON MENTHOL FLAVOUR POWDER FOR ORAL SOLUTION

PL 00079/0674

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation (licence) for the medicinal product Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution (product licence number: PL 00079/0674) on 29 July 2011. Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution is available from pharmacies and other outlets without prescription. Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution is used for the short term relief of the symptoms of flu, colds and chills. These symptoms include headache, shivers, aches and pains, blocked nose and painful sinuses, catarrh and sore throat. This medicine contains two active ingredients: paracetamol, a painkiller that reduces the body temperature of someone with a fever, and phenylephrine hydrochloride, a decongestant which unblocks the nose and sinuses, helping breathing. This product also contains 40 mg of vitamin C. Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using this product outweighs the risk; hence a Marketing Authorisation has been granted.


3


PL 00079/0674

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 6

Clinical assessment

Page 7

Overall conclusions and risk benefit assessment Page 8


4

INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution to Beecham Group plc (trading as GlaxoSmithKline Consumer Healthcare) on 29 July 2011. This is an abridged application submitted under Article 10(c) of EC Directive 2001/83, last paragraph. The applicant claims that this product is identical to Beechams Hot Lemon with Honey (PL 00079/0283) which was licensed for use in the UK on 18 December 1991 to Beecham Group Plc. No new data were submitted, nor was it necessary for this simple application, as the data are identical to those of the previously licensed cross-reference product. Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution is indicated for the relief of symptoms of influenza, feverishness, chills and feverish colds, including headache, throat pain, aches and pains, nasal congestion, sinusitis and its associated pain, and acute nasal catarrh. This product is on the General Sales List.


5

PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCES: PARACETAMOL PHENYLEPHRINE HYDROCHLORIDE The paracetamol and phenylephrine hydrochloride used in this product comply with their respective Ph. Eur. monographs and are, therefore, satisfactory. DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution is an off-white to beige, free-flowing, heterogeneous powder with an odour of honey, lemon and menthol. The product contains the pharmaceutical excipients ascorbic acid, sucrose, sodium citrate, citric acid, maize starch, menthol, honey flavour, honey Flav-o-lok, lemon flavour, caramel SCS (E 150), aspartame and saccharin sodium. This formulation was identical to that of the reference product at the time of assessment of this Marketing Authorisation application. The product is packed in laminate sachets comprising paper / polythene / aluminium foil / polythene. Five or ten sachets may be contained in a box board carton. There appears to be no difference between the composition and packaging of the proposed products and those of the already licensed reference product. The proposed shelf-life (36 months) and storage condition (Store below 25°C) are consistent with the details registered for the reference product.

ADDITIONAL DATA REQUIREMENTS The active ingredient specification, manufacturing process, and finished product specification are in line with those for the reference product and are satisfactory. The applicant is also the Marketing Authorisation Holder of the reference product. A Letters of Access is, therefore, not required EXPERT REPORTS Satisfactory expert reports in the form of quality, non-clinical and clinical overall summaries are provided, with signed declarations from each expert confirming that the applicant’s product is identical to the reference product in all particulars. Expert CVs are also submitted and are acceptable. PRODUCT LITERATURE The proposed SmPC, PIL and labels are identical to those for the reference product and are satisfactory. ASSESSOR’S OVERALL CONCLUSIONS A Marketing Authorisation may be granted for this product.


6

PRECLINICAL ASSESSMENT

No new preclinical data have been supplied with this application and none is required for an application of this type.


7

CLINICAL ASSESSMENT

OVERVIEW The clinical particulars for Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution are identical to those for the already licensed product; Beechams Hot Lemon with Honey (PL 00079/0283) and are, therefore, satisfactory.

BIOAVAILABILITY AND BIOEQUIVALENCE No bioequivalence study has been performed to support this application and none is needed. PRODUCT LITERATURE All product literature is medically satisfactory. ASSESSOR’S OVERALL CONCLUSIONS It is recommended that a Marketing Authorisation can be granted.


8

OVERALL CONCLUSION AND BENEFIT: RISK ASSESSMENT

QUALITY Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution is identical to the already licensed reference product. This product is, therefore, pharmaceutically satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY The efficacy of paracetamol and phenylephrine hydrochloride is well established. The SmPC, PIL and labelling are satisfactory and consistent with those for the cross-reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable, no significant preclinical or clinical safety concerns were identified, and benefit has been shown to be associated with paracetamol and phenylephrine hydrochloride. The benefit: risk ratio is, therefore, considered to be acceptable.


9


PL 00079/0674

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation application on 26 October

2010 2 Following standard checks and communication with the applicant the MHRA

considered the application valid on 26 November 2010 3 Following assessment of the application the MHRA requested further

information relating to the dossier on 19 April 2011 4 The applicant responded to the MHRA’s request, providing further information

on the dossier on 11 May 2011 5 Following assessment of the application the MHRA requested further

information relating to the dossier on 23 May 2011 6 The applicant responded to the MHRA’s request, providing further information

on the dossier on 7 June 2011 7 Following assessment of the application the MHRA requested further

information relating to the dossier on 13 June 2011 8 The applicant responded to the MHRA’s request, providing further information

on the dossier on 20 June 2011 9 The application was determined on 29 July 2011


10

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Beechams Breathe Clear Hot Honey & Lemon Menthol Flavour powder for oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Constituents mg / 6 g powder Paracetamol 600.00 Phenylephrine Hydrochloride 10.00 Excipients Vitamin C (Ascorbic Acid) 40.00 Sucrose 3802 For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for Oral Solution. Off-white to beige, free-flowing, heterogeneous powder with an odour of honey, lemon and menthol.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The relief of symptoms of influenza, feverishness, chills and feverish colds including headache, sore throat pain, aches and pains, nasal congestion, sinusitis and its associated pain, and acute nasal catarrh.

4.2 Posology and method of administration

Directions for use Empty contents of sachet into beaker. Half fill with very hot water. Stir well. Add cold water as necessary and sugar if desired. Recommended Dose and Dosage Schedule Adults (including elderly) and children aged 12 years and over: One sachet to be taken every four hours, if necessary, up to a maximum of six sachets in any 24 hours. Do not take continuously for more than 7 days without medical advice. Not to be given to children under 12 years of age except on medical advice.

4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients. Concomitant use of other sympathomimetic decongestants. Phaeochromocytoma. Closed angle glaucoma. Hypertensive patients or those taking of have taken in the last two weeks


11

monoamine oxidase inhibitors, tricyclic antidepressants or beta-blockers (see section 4.5). Hepatic or renal impairment, diabetes, hyperthyroidism and cardiovascular disease.

4.4 Special warnings and precautions for use

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Medical advice should be sought before taking this product in patients with these conditions:

o An enlargement of the prostate gland

o Occlusive Vascular disease (e.g. Raynaud’s Phenomenon) This product should not be used by patients taking other sympathomimetics (such as decongestants, appetite suppressants and amphetamine-like psychostimulants).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Do not exceed the stated dose. Patients should be advised not to take other paracetamol-containing or any other cold, flu or decongestant products concurrently. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Special label warnings Do not take with other flu, cold or decongestant products. 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.

4.5 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding, occasional doses have no significant effect. Phenylephrine should be used with caution in combination with the following drugs as interactions have been reported.


12

Monoamine oxidase inhibitors (including moclobemide)

Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine oxidase inhibitors (see contraindications).

Sympathomimetic amines Concomitant use of phenylephrine with other sympathomimetic amines can increase the risk of cardiovascular side effects.

Beta-blockers and other antihypertensives (including debrisoquine, guanethidine, reserpine, methyldopa)

Phenylephrine may reduce the efficacy of beta-blocking drugs and antihypertensive drugs. The risk of hypertension and other cardiovascular side effects may be increased.

Tricyclic antidepressants (e.g. amitriptyline)

May increase the risk of cardiovascular side effects with phenylephrine.

Ergot alkaloids (ergotamine and methylsergide) increased risk of ergotism

Digoxin and cardiac glycosides Increase the risk of irregular heartbeat or heart attack

4.6 Fertility, Pregnancy and Lactation

Due to the phenylephrine content this product should not be used in pregnancy or whilst breast-feeding without medical advice. Phenylephrine may be excreted in breast milk.

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if affected by dizziness.

4.8 Undesirable effects

Undesirable effects 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 Agranulocytosis These are not necessarily causally related to paracetamol


13

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

Respiratory, thoracic and mediastinal disorders

Bromchospasm*

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. Phenylephrine The following adverse events have been observed in clinical trials with phenylephrine and may therefore represent the most commonly occurring adverse events.

Body System Undesirable effect

Psychiatric disorders Nervousness, irritability, restlessness, and excitability

Nervous system disorders Headache, dizziness, insomnia

Cardiac disorders Increased blood pressure

Gastrointestinal disorders Nausea, Vomiting.

Adverse reactions identified during post-marketing use are listed below. The frequency of these reactions is unknown but likely to be rare.

Eye disorders Mydriasis, acute angle closure glaucoma, most likely to occur in those with closed angle glaucoma

Cardiac disorders Tachycardia, palpitations

Skin and subcutaneous disorders

Allergic reactions (e.g. rash, urticaria, allergic dermatitis). Hypersensitivity reactions – including that cross-sensitivity may occur with other sympathomimetics

Renal and urinary disorders Dysuria, urinary retention. This is most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy.

4.9 Overdose

Paracetamol


14

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 established treatment guidelines, see BNF overdose section. 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 24 hours from ingestion should be discussed with the NPIS or a liver unit. Phenylephrine Hydrochloride Symptoms and signs: Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include hypertension and possibly reflux bradycardia. In severe cases confusion, hallucinations, seizures and arrythmias may occur. However the amount required to produce serious phenylephrine toxicity would be greater than required to cause paracetamol-related toxicity.


15

Treatment Treatment should be as clinically appropriate. Severe hypertension may need to be treated with an alpha blocking drug such as phentolamine. Ascorbic Acid Symptoms and signs High doses of ascorbic acid (>3000 mg) may cause transient osmotic diarrhoea and gastrointestinal effects such as nausea and abdominal discomfort. Effects of overdose of ascorbic acid would be subsumed by severe liver toxicity caused by paracetamol overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Paracetamol provides the analgesic and antipyretic actions. Phenylephrine Hydrochloride is a sympathomimetic agent and provides relief from nasal congestion due to its vasoconstrictor action. Ascorbic Acid is commonly included in combination cold products to compensate for vitamin C losses that may occur in the initial stages of acute viral infections, including the common cold.

5.2 Pharmacokinetic properties

Paracetamol - Is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine, mainly as glucuronide and sulphate conjugates. Ascorbic Acid - Is readily absorbed from the GI tract and is widely distributed in the body tissues, 25% bound to plasma proteins. Ascorbic acid in excess of the body's needs is eliminated in the urine as metabolites. Phenylephrine Hydrochloride -Due to irregular absorption and first pass metabolism by monoamine oxidase in the gut and liver, phenylephrine has reduced bioavailability from the gastrointestinal tract. It is excreted in the urine almost entirely as the sulphate conjugate.

5.3 Preclinical safety data

None stated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ascorbic acid, Sucrose, Sodium citrate, Citric acid, Maize starch, Menthol, Honey flavour, Honey Flav-o-lok, Lemon flavour, Caramel SCS (E 150), aspartame, saccharin sodium.

6.2 Incompatibilities

None stated. 6.3 Shelf life

36 months.


16

6.4 Special precautions for storage Store below 25°C.

6.5 Nature and contents of container

The product is packed in laminate sachets comprising paper / polythene / aluminium foil / polythene. Five or ten sachets may be contained in a box board carton.

6.6 Special precautions for disposal

No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

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 00079/0674 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 29/07/2011 10 DATE OF REVISION OF THE TEXT

29/07/2011


17

PATIENT INFORMATION LEAFLET


18

LABELLING Sachet (front):


19

Sachet (back):


20

Cartons:


21


22

Module 6

Steps taken after initial procedure - Summary

The following table lists some non-safety updates to the Marketing Authorisation for this product that have been approved by the MHRA since the product was first licensed. The table includes updates that are detailed in the annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

Date submitted

Application type

Scope Outcome

13/06/2012 VAR Medical Type IB

To update sections 4.9, 5.1 and 5.2 of the SPC in line with the reference product.

Granted 15/08/2012


23

Annex 1 Reference: PL 00079/0674, application 0007 Product: Beechams Breathe Clear Hot Honey & Lemon Menthol

Flavour powder for oral solution MAH: Beecham Group plc Active Ingredient: Phenylephrine hydrochloride and paracetamol Reason: To update sections 4.9, 5.1 and 5.2 of the SPC in line with the reference product. Supporting evidence: The applicant has submitted the following updated documents: Sections 4.9, 5.1 and 5.2 of the SPC. Evaluation The updated SmPC fragments are satisfactory. Conclusion The variation was approved on 15th August 2012 and the following updated SmPC, has been incorporated into this Marketing Authorisation.

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


24

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 established treatment guidelines, see BNF overdose section. 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 24 hours from ingestion should be discussed with the NPIS or a liver unit. Phenylephrine Hydrochloride Symptoms and signs: Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include hypertension and possibly reflux bradycardia. In severe cases confusion, hallucinations, seizures and arrythmias may occur. However the amount required to produce serious phenylephrine toxicity would be greater than required to cause paracetamol-related toxicity. Treatment Treatment should be as clinically appropriate. Severe hypertension may need to be treated with an alpha blocking drug such as phentolamine.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Paracetamol provides the analgesic and antipyretic actions.

Phenylephrine Hydrochloride is a sympathomimetic agent and provides relief from nasal congestion due to its vasoconstrictor action.

5.2 Pharmacokinetic properties

Paracetamol - Is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine, mainly as glucuronide and sulphate conjugates.


25

Phenylephrine Hydrochloride - Due to irregular absorption and first pass metabolism by monoamine oxidase in the gut and liver, phenylephrine has reduced bioavailability from the gastrointestinal tract. It is excreted in the urine almost entirely as the sulphate conjugate.

10 DATE OF REVISION OF THE TEXT

15/08/2012

Variation assessment report for Beechams Breathe Clear Hot ... · mhra par; beechams breathe clear...

Documents

Transcript of Variation assessment report for Beechams Breathe Clear Hot ... · mhra par; beechams breathe clear...