4.1. Therapeutic indications

For the relief of symptoms associated with colds and flu and the pain and congestion of sinusitis, including aches and pains, headache, blocked nose and sore throat, chills, lowering of temperature, and to loosen stubborn mucous and provide relief from chesty coughs.

4.2. Posology and method of administration

For oral use. Swallow whole with water, do not chew.

Adults, the elderly and children aged 16 years and over:

Two capsules every four hours as required. Do not take more than 8 capsules (4 doses) in any 24 hour period.

Do not exceed the stated dose.

Minimum dosing interval: 4 hours.

The lowest dose necessary to achieve efficacy should be used for the shortest duration of treatment.

Maximum daily dose: Eight capsules (4000 mg paracetamol, 800 mg guaifenesin, 48.8 mg phenylephrine HCl) in any 24 hour period.

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

Do not take continuously for more than 5 days without medical advice.

4.3. Contraindications

Known hypersensitivity to any of the ingredients.

Concomitant use of other sympathomimetic decongestants.

Phaeochromocytoma.

Closed angle glaucoma.

An enlargement of the prostate gland.

Hepatic or severe renal impairment, hypertension, hyperthyroidism, diabetes, heart disease or those taking tricyclic antidepressants or beta-blocking drugs and those patients who are taking or have taken within the last two weeks, monoamine oxidase inhibitors (see section 4.5).

4.4. Special warnings and precautions for use

Contains paracetamol. Do not take with any other paracetamol-containing products. The concomitant use with other products containing paracetamol may lead to an overdose. Paracetamol overdose may cause liver failure which may require liver transplant or lead to death

Concomitant use of decongestants and other cough and cold medicines should be avoided.

Medical advice should be sought before taking this product in patients with:

• Occlusive vascular disease (e.g. Raynaud's Phenomenon)

• Glutathione depletion due to metabolic deficiencies

• Chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

Use with caution in patients taking the following medications (see Interactions)

• vasoconstrictor agents such as ergot alkaloids (e.g. ergotamine and methysergide)

• digoxin and cardiac glycosides

Do not take with a cough suppressant.

This product should not be used by patients taking other sympathomimetics (such as decongestants, appetite suppressants and amphetamine-like psychostimulants) (see section 4.5).

Special label warnings

If you are taking medication or are under medical care, consult your doctor before using this medicine.

Do not exceed the stated dose.

If symptoms persist consult your doctor.

Keep out of the sight and reach of children.

Contains paracetamol. Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine, even if you feel well.

Special leaflet warnings

Contains paracetamol.

Talk to a doctor at once if you take too much of this medicine, even if you feel well.

This is because too much paracetamol can cause delayed, serious liver damage.

4.5. Interaction with other medicinal products and other forms of interaction

Paracetamol

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding. The hepato- toxicity of paracetamol may be potentiated by excessive intake of alcohol. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.

Pharmacological interactions involving paracetamol with a number of other drugs have been reported. These are considered to be of unlikely clinical significance in acute use at the dosage regimen proposed.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4).

Phenylephrine should be used with caution in combination with the following drugs as interactions have been reported:

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

Warfarin and other coumarins

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.

If urine is collected within 24 hours of a dose of this product, a metabolite may cause a colour interference with laboratory determinations of 5 hydroxyindoleacetic acid (5- HIAA) and vanillymandelic acid (VMA).

No significant interactions with other drugs have been noted for guaifenesin.

4.6. Fertility, pregnancy and lactation

This product should not be used during pregnancy without medical advice.

Human and animal studies with paracetamol have not identified any risk to pregnancy or embryo-foetal development.

No relevant data are available for products containing phenylephrine.

The safety of guaifenesin during pregnancy has not been established.

Lactation

This product should not be used whilst breast feeding without medical advice.

Human studies with paracetamol have not identified any risk to lactation or the breast-fed offspring.

Paracetamol crosses the placental barrier and is excreted in breast milk.

Phenylephrine may be excreted in breast milk.

No relevant data available for guaifenesin.

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

Adverse events from historical clinical trial data are both infrequent and from small patient exposure.

Events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by MedDRA System Organ Class.

Events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by MedDRA System Organ 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

Immune system disorders

Very rare cases of serious skin reactions have been reported.

Anaphylaxis

Cutaneous hypersensitivity reactions including skin rashes and angioedema

Metabolism and nutrition disorders

High anion gap metabolic acidosis (cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients). (Frequency not known).

Respiratory, thoracic and mediastinal disorders

Bronchospasm in patients sensitive to aspirin and other NSAIDs

Hepatobiliary disorders

Hepatic dysfunction

Gastrointestinal disorders

Acute pancreatitis

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, diarrhoea

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

Guaifenesin

The frequency of these events is unknown but considered likely to be rare.

Body System

Undesirable effect

Immune system disorders

Allergic reactions, angioedema, anaphylactic reactions

*Respiratory, thoracic and mediastinal disorders

Dyspnoea*

Gastrointestinal disorders

Nausea, vomiting, abdominal discomfort

Skin and subcutaneous disorders

Rash, urticaria

*Dyspnoea has been reported in association with other symptoms of hypersensitivity

Reporting of suspected adverse reactions

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 or search for MHRA Yellow Card in the Google Play or Apple App store.

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, even if symptoms of overdose are not present. 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 British National Formulary (BNF) overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within one hour. Plasma paracetamol concentration should be measured at four 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 eight 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 National Poisons Information Service (NPIS) or a liver unit.

Guaifenesin

Symptoms

Very large doses of guaifenesin can cause nausea and vomiting.

Treatment

Vomiting would be treated by fluid replacement and monitoring of electrolytes.

Phenylephrine

Symptoms

Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include irritability, restlessness, 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 liver toxicity.

Treatment

Treatment should be as clinically appropriate. Severe hypertension may need to be treated with an alpha blocking drug such as phentolamine.