4.1. Therapeutic indications

DAY CAPSULE

For the relief of symptoms associated with the common cold and influenza, including relief of aches and pains, sore throat, headache, fatigue and drowsiness, nasal congestion and lowering of temperature.

NIGHT CAPSULE

For the relief of symptoms associated with the common cold and influenza, including relief of aches and pains, sore throat, headache, nasal congestion and lowering of temperature.

4.2. Posology and method of administration

This product is contraindicated in patients with severe renal impairment (see sections 4.3 and 4.4)

Paracetamol should with caution in the following situations, (see section 4.4)

4.3. Contraindications

This product is contraindicated in case of:

• Hypersensitivity to the active substances (paracetamol, phenylephrine, caffeine) or any of the other excipients listed in section 6.1.

• Patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

• Hypertension.

• Cardiovascular disorders

• Severe hepatic impairment

• Severe renal impairment

• Hyperthyroidism.

• Diabetes mellitus

• Pheochromocytoma

• Use in patients receiving therapy with tricyclic antidepressants or beta-blockers (see section 4.5)

• Angle closure glaucoma

• Use in patients who are currently receiving other sympathomimetics (such as decongestants, appetite suppressants, amphetamine-like psychostimulants)

Avoid in patients with prostatic enlargement.

4.4. Special warnings and precautions for use

Underlying liver disease increases the risk of paracetamol-related liver damage. Paracetamol should be administered with caution to patients with renal impairment and mild or moderate hepatic impairment. Patients who have been diagnosed with liver or kidney impairment must seek medical advice before taking this medication. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

This medicine should be administered only with particular caution under the following circumstances:

• Gilbert's Syndrome (familial non-haemolytic jaundice)

• Glucose-6-phosphate dehydrogenase deficiency

• Haemolytic anaemia

• Glutathione deficiency

• Dehydration

• Urinary retention

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

Hepatotoxicity at therapeutic doses of paracetamol

Cases of paracetamol induced hepatotoxicity, including fatal cases, have been reported in patients taking paracetamol at doses within the therapeutic range. These cases were reported in patients with one or more risk factors for hepatotoxicity including low body weight (<50 Kg), renal and hepatic impairment, chronic alcoholism, concomitant intake of hepatotoxic drugs and in acute and chronic malnutrition (low reserves of hepatic glutathione). Paracetamol should be administered with caution to patients with these risk factors. Caution is also advised in patients on concomitant treatment with drugs that induce hepatic enzymes and in conditions which may predispose to glutathione deficiency (see sections 4.2, 4.5 and 4.9).

Doses of paracetamol should be reviewed at clinically appropriate intervals and patients should be monitored for emergence of new risk factors for hepatotoxicity which may warrant dosage adjustment.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Precaution should be observed in patients with asthma who are sensitive to acetylsalicylic acid since mild bronchospasms are reported in association with paracetamol (cross reaction).

Patients should be advised not to take other paracetamol containing products, cold and flu medicines or cough medicines concurrently. Immediate medical advice should be sought in the event of overdosage even if the patient feels well because the risk of irreversible liver damage (see section 4.9).

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.

Excessive intake of caffeine (e.g., coffee, tea and some canned drinks) should be avoided while taking this product (see section 4.9).

Should be given with care to patients with a history of peptic ulcer. This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

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

Concomitant use of other paracetamol-containing products, cold and flu medicines or cough medicines should be avoided.

Paracetamol

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 use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Drugs which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdosage.

In concomitant treatment with probenecid, the dose of paracetamol should be reduced since probenecid reduces the clearance of paracetamol by 50% since it prevents the conjugation of paracetamol with glucuronic acid.

There is limited evidence suggesting that paracetamol may affect chloramphenicol pharmacokinetics.

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 risk factors (see section 4.4)

Phenylephrine Hydrochloride

Phenylephrine may adversely interact with below drugs. Medical advice should be sought before taking these:

• Sympathomimetics: Concomitant administration of phenylephrine with sympathomimetic amines may increase the risk of cardiovascular side effects. Concomitant use is contraindicated (see section 4.3)

• Vasodilators

• Beta blockers and other antihypertensive agents (including debrisoquin, guanethidine, reserpine, methyldopa): Phenylephrine may reduce the efficacy of beta-blockers and antihypertensive agents. The risk of hypertension and other cardiovascular side effects may be increased. Concomitant use with beta blockers is contraindicated (see section 4.3)

• Digoxin and cardiac glycosides: Concomitant use of phenylephrine may increase the risk of irregular heartbeat or heart attack.

• Monoamine oxidase inhibitors: Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine oxidase inhibitors. Concomitant use is contraindicated (see section 4.3)

• Tricyclic antidepressants (e.g., amitriptyline): Concurrent administration with phenylephrine may increase the risk of cardiovascular side effects. Concomitant use is contraindicated (see section 4.3)

• Ergot alkaloids (e.g., ergotamine and methysergide): Concomitant use of phenylephrine may cause increased risk of ergotism.

Caffeine

Caffeine, a CNS stimulant, has an antagonistic effect towards the action of sedative and tranquilizers. Caffeine may enhance the tachycardia effect of some decongestants.

4.6. Fertility, pregnancy and lactation

Pregnancy

This medicinal product is contraindicated during pregnancy. Based on human experience, phenylephrine hydrochloride causes congenital malformation when administered during pregnancy. It has also been shown to have possible associations with foetal hypoxia.

Phenylephrine should not be used during pregnancy.

A large amount of data on pregnant women indicates no malformative nor feto/neonatal toxicity of paracetamol. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results.

If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

The safety of this medicine during pregnancy has not been established but in view of a possible association of foetal abnormalities with exposure to phenylephrine, the product should be avoided during pregnancy. In addition, because phenylephrine may reduce placental perfusion, the product should not be used in patients with a history of preeclampsia.

Taken during pregnancy, it appears that the half-life of caffeine is prolonged. This is a possible contributing factor in hyperemesis gravidarum (morning sickness). In pregnancy a total daily consumption above 200 mg caffeine per day could possibly increase the risk of spontaneous abortion and low birth weight.

Lactation

The safety of this medicine during lactation has not been established.

This medicinal product should not be used whilst breastfeeding without medical advice.

Phenylephrine may be excreted in breast milk. Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

Caffeine appears in breast milk. Irritability and poor sleeping pattern in the infant have been reported.

Fertility

There are no available human data regarding the influence of this medicine on fertility.

4.7. Effects on ability to drive and use machines

This medicinal product has minor influence on the 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 reactions reported from extensive post-marketing experience are tabulated below by System Organ Class and frequency. The following convention has been utilised for the classification of undesirable effects: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from available data).

Paracetamol

System Organ Class

Undesirable effect

Frequency

Blood and lymphatic system disorders

There have been reports of blood dyscrasias including thrombocytopenia, leukopenia, pancytopenia, neutropenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Very rare

Immune system disorders

Anaphylaxis

Very rare

Allergies (not including angioedema)

Rare

Respiratory, thoracic and mediastinal disorders

Bronchospasms in patients sensitive to aspirin and other NSAIDs

Very rare

Hepatobiliary disorders

Hepatic dysfunction

Very rare

Skin and subcutaneous tissue disorders

Cutaneous hypersensitivity reactions including skin rashes, pruritus, sweating, purpura, urticaria and angioedema.

Very rare

Very rare cases of serious skin reactions have been reported.

Very rare

Toxic epidermal necrolysis (TEN), drug-induced dermatitis, Stevens-Johnson syndrome (SJS), Acute Generalized exanthematous pustulosis (AGEP)

Renal and urinary disorder

Sterile pyuria

Very rare

Metabolism and nutrition disorders

High anion gap metabolic acidosis

Not known

Description of selected adverse reactions

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.

Caffeine (Day capsules only)

System Organ Class

Undesirable effect

Frequency

Psychiatric disorders

Insomnia

Not known

Nervous system disorders

Nervousness

Dizziness

Not known

Gastrointestinal disorders

Nausea

Not known

Phenylephrine Hydrochloride

System Organ Class

Undesirable effect

Frequency

Immune system disorders

Allergic reactions

Rare

Psychiatric disorders

Nervousness, insomnia

Not Known

Nervous system disorders

Headache, dizziness

Not known

Eye disorders

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

Rare

Cardiac disorders

Palpitations, tachycardia or reflex bradycardia

Rare

Elevated blood pressure, cardiac arrythmias

Not known

Gastrointestinal disorders

Nausea, vomiting, diarrhoea

Not known

Skin and subcutaneous disorders

Rash, urticaria, allergic dermatitis

Rare

Tingling and coolness of the skin

Not known

Renal and urinary disorders

Dysuria, urinary retention. This is most likely to occur in men with an enlarged prostate.

Not known

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

There is a risk of poisoning, particularly in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition. Overdosing may be fatal in these cases. Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor, and abdominal pain.

An overdose of paracetamol, administered as a single dose, in adults or children can induce complete and irreversible liver cell necrosis resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy, which may lead to coma and death.

Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.

Liver damage is likely in adults who have taken more than the recommended amounts of paracetamol. It is considered that excess quantities of toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Some patients may be at increased risk of liver damage from paracetamol toxicity.

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 British National Formulary (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 National Poison Information Service (NPIS) or a liver unit.

Caffeine (Day capsules only)

Overuse of this product, defined as consumption of quantities in excess of the recommended dose, or consumption for a prolonged period of time, may lead to physical or psychological dependency. Doses over 1g are probably necessary to induce toxicity, 2 – 5g to produce severe toxicity and 5 – 10g is likely to be lethal. It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol related toxicity.

Symptoms include: epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors, convulsions).

No specific antidote is available, reduce or stop dosage and avoid excessive intake of coffee or tea.

Phenylephrine Hydrochloride

Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include irritability, restlessness, hypertension and possibly reflex bradycardia.

Severe overdosage may produce confusion, hallucinations, seizures and arrythmyias, hypertension and associated reflex bradycardia. However, the amount required to produce serious phenylephrine toxicity would be greater than required to cause paracetamol-related liver toxicity.

Symptoms should be treated according to established guidelines, as appropriate. Severe hypertension may be treated with an alpha-receptor blocking agent (such as phentolamine mesylate 6 – 10 mg) given intravenously.