This information is intended for use by health professionals

1. Name of the medicinal product

Night Nurse Capsules

2. Qualitative and quantitative composition

Active constituents

mg/capsule

Paracetamol Ph. Eur.

500.0

Promethazine hydrochloride Ph. Eur.

10.0

Dextromethorphan hydrobromide Ph. Eur.

7.5

3. Pharmaceutical form

Capsule

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

Do not exceed the stated dose

To be taken at bedtime

Maximum daily dose: Only one dose should be taken per night.

Adults and children aged 16 years and over:

Take two capsules just before bedtime.

Not to be given to children under 16 years except on medical advice.

Elderly:

The normal adult dose can be used.

Only one dose should be taken per night.

Do not take if you have already taken 4 doses of a paracetamol-containing product during the day. Other products containing paracetamol may be taken during the day but for adults 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.

Maximum duration of continued use without medical advice: 3 days.

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 persistant 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Do not exceed the stated dose.

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.

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 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 (see also section 4.5).

Special label warnings

Do not take with any other paracetamol-containing products. Do not take with other flu, cold or decongestant 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

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.

CYP2D6 inhibitors

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 20- fold, 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.

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 test to produce false 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.

This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been taken to treat a medical or dental problem and

o You have taken it according to the information provided with the medicine and

o It was not affecting your ability to drive safely.

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 of paracetamol 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. The frequency of these adverse is not known.

Body System

Undesirable effect

Blood and lymphatic system disorders

Thrombocytopenia

Agranulocytosis

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.

Reportingofsuspectedadversereactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:www.mhra.gov.uk/yellowcard.

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 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 24h from ingestion should be discussed with the NPIS or a liver unit.

PromethazineHydrochloride

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.

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-N-methylmorphinan), 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.

5.3 Preclinical safety data

Pre-clinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product and which have not already been mentioned elsewhere in this summary.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Dimeticone

Colloidal anhydrous silica

Gelatin

Patent blue V (E131)

Quinoline yellow (E104)

Titanium dioxide (E171)

Printing ink:

Shellac

Isopropyl Alcohol

Iron oxide black (E172)

N-butyl alcohol

Propylene glycol (E1520)

Ammonium hydroxide (E527)

6.2 Incompatibilities

None known

6.3 Shelf life

Three years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

The capsules are contained in a strip consisting of opaque blisters of polyvinylchloride 250 µm backed with aluminium foil 20 µm. The strips are packed in boxboard cartons. Packs contain 10 or 20 capsules (1 or 2 blister strips), or 2 capsules (trial size pack).

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

GlaxoSmithKline Consumer Healthcare (UK) Trading Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8. Marketing authorisation number(s)

PL 44673/0071

9. Date of first authorisation/renewal of the authorisation

04/03/2009

10. Date of revision of the text

February 2019