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.

Posology

Each blister contains 6 red/yellow Day capsules and 2 dark blue/light blue Night Capsules.

For all indications:

Adults, the elderly and children aged 16 years and over: 2 red/yellow capsules every 4 to 6 hours during the day, followed by 2 dark blue/light blue capsules at bedtime.

Leave at least 4 to 6 hours between doses.

Do not take more than 8 capsules (4 doses) in any 24 hour period.

Paediatric population:

Not recommended for use in children under 16 years of age.

Elderly patients

Elderly patients, especially those who are frail or immobile, may require a reduced dose or frequency of dosing.

Renal impairment

Patients who have been diagnosed with kidney impairment must seek medical advice before taking this medication. It is recommended, when giving paracetamol to patients with renal failure, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours.

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

Hepatic impairment

Patients who have been diagnosed with hepatic impairment or Gilbert's Syndrome must seek medical advice before taking this medication. The medicinal product should be used with caution in patients with mild or moderate hepatic impairment (see section 4.4). The medicinal product is contraindicated in patients with severe hepatic impairment (see section 4.3).

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

• Dehydration,

• Malnutrition,

• Chronic alcoholism.

Note: Does not contain a sleep aid.

Method of administration

Route of administration: Oral. Swallow whole with water. Do not chew.

The recommended daily dosage or the specified number of doses should not be exceeded because of the risk of liver damage (see sections 4.4 and 4.9).

Minimum dosing interval: 4 hours.

Dosage should not be continued for longer than 3 days without consulting a doctor.

If pain or fever persist for more than 3 days or gets worse, or if any other symptoms occur, treatment should be discontinued, and a physician should be consulted.

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.

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).

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5- oxoproline, is recommended.

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'.

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, 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.

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.

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

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

Caffeine (Day capsules only)

Phenylephrine Hydrochloride

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.

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.

Pharmacotherapeutic Group: Other analgesics and antipyretics Anilides, paracetamol combinations excluding psycholeptics.

Paracetamol

Analgesic:

The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting a prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent through a peripheral action by blocking pain- impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Antipyretic:

Paracetamol probably produces antipyresis by acting on the hypothalamic heat- regulating centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

Caffeine (Day capsules only)

Central nervous system stimulant – Caffeine stimulates all levels of the CNS, although its cortical effects are milder and of shorter duration than those of amphetamines. Caffeine possesses a weak diuretic action.

Analgesia Adjunct:

Caffeine constricts cerebral vasculature with an accompanying decrease in cerebral blood flow and in the oxygen tension of the brain. It is believed that caffeine helps to relieve headache by providing a more rapid onset of action and/or enhanced pain relief with lower doses of analgesic. Recent studies with ergotamine indicate that the enhancement of effect by the addition of caffeine may also be due to improved gastrointestinal absorption of ergotamine when administered with caffeine.

Phenylephrine Hydrochloride

Sympathomimetic amines, such as phenylephrine, act on alpha-adrenergic receptors of the respiratory tract to produce vasoconstriction, which temporarily reduces the swelling associated with inflammation of the mucous membranes lining the nasal and sinus passages. This allows the free drainage of the sinusoidal fluid from the sinuses.

In addition to reducing mucosal lining swelling, decongestants also suppress the production of mucus, therefore preventing a build up of fluid within the cavities which could otherwise lead to pressure and pain.

Paracetamol

Absorption

Paracetamol is rapidly absorbed from the gastro-intestinal tract with peak plasma concentrations occurring between 10 and 60minutes after oral administration depending on pharmaceutical form.

Distribution

Paracetamol is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding.

Metabolism

Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours.

Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated metabolite, N-acetyl-p-benzoquinoneimine, which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdose and cause liver damage.

Elimination

Less than 5% is excreted as unmodified paracetamol; the elimination half-life varies from 1 to 4 hours. Elimination is essentially through the urine. 90% of the ingested dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60- 80%) and sulphate conjugates (20-30%). In cases of renal failure (GFR≤ 50ml/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times slower in subjects with severe renal impairment than in healthy subjects.

Caffeine (Day capsules only)

Absorption

Caffeine is absorbed readily after oral administration and is widely distributed throughout the body. Maximum plasma concentrations are achieved within one hour and the plasma half-life is about 4.9 hours, but there are large inter-individual and intra-individual differences ranging between 1.9 – 12.2 hours.

Distribution

Caffeine administered orally is practically fully bioavailable and distributes into all body fluids. The mean plasma protein binding of caffeine is 35%. Maximum plasma concentrations are reached after 30 – 40 minutes.

Biotransformation

Caffeine is metabolised almost completely in the liver via oxidation, demethylation, and acetylation, and is excreted in the urine as 1-methyluric acid, 1-methylxanthine, 7-methylxanthine, 1,7-dimethylxanthine (paraxanthine), 5-acetylamino-6- formylamino-3methyluracil (AFMU), and other metabolites with only about 1% unchanged.

Elimination

Caffeine and its metabolites are primarily eliminated by the kidneys.

Phenylephrine Hydrochloride

Absorption

Phenylephrine has reduced bioavailability from the gastro-intestinal tract owing to irregular absorption and the first-pass metabolism (see below).

Metabolism

Phenylephrine undergoes first-pass metabolism by monoamine oxidase in the gut and liver.

Elimination

Phenylephrine hydrochloride is excreted in the urine almost entirely as the sulphate conjugate.

This medicine has a well-established safety profile. For paracetamol, conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

Day Capsule

Maize starch

Croscarmellose sodium

Sodium laurilsulfate

Magnesium stearate

Talc

Night Capsule

Maize starch

Croscarmellose sodium

Sodium laurilsulfate

Magnesium stearate

Talc

None known.

36 months.

Do not store above 25° C.

Blister packs of white opaque 250 micron PVC/30 micron hard temper pyramidal aluminium foil, heat-seal coated, contained in an outer cardboard carton.

Pack sizes:

16 capsules comprising two blisters each containing 6 red/yellow Day capsules and 2 light blue/dark blue Night capsules.

None.