4.1. Therapeutic indications

NON-DROWSY SINUTAB is indicated for the symptomatic relief of conditions where congestion of the mucous membranes of the upper respiratory tract, especially nasal mucosa and sinuses, is accompanied by mild to moderate pain or pyrexia, e.g: the common cold and influenza, sinusitis, nasopharyngitis, allergic rhinitis and vasomotor rhinitis.

4.2. Posology and method of administration

Posology

Adults and children aged 16 years and over:

Two tablets every four to six hours, up to four times a day. Maximum daily dose: 8 tablets (i.e. 240 mg pseudoephedrine hydrochloride, 4 g paracetamol).

Children aged 12 years to 15 years

One tablet every four to six hours, up to four times a day. Maximum daily dose: 4 tablets (i.e. 120 mg pseudoephedrine hydrochloride, 2 g paracetamol).

Children under 12 years:

NON-DROWSY SINUTAB is contraindicated in children under the age of 12 years (see section 4.3).

The Elderly:

There have been no specific studies of NON-DROWSY SINUTAB in the elderly. Experience has indicated that normal adult dosage is appropriate.

In the elderly the rate and extent of paracetamol absorption is normal but plasma half life is longer and paracetamol clearance is lower than in young adults.

Hepatic dysfunction

Caution should be exercised when administering NON-DROWSY SINUTAB to patients with severe hepatic impairment.

Renal dysfunction:

Caution should be exercised when administering NON-DROWSY SINUTAB to patients with moderate renal impairment.

Method of administration

For oral use

4.3. Contraindications

NON-DROWSY SINUTAB is contraindicated in individuals with known hypersensitivity to paracetamol, pseudoephedrine or any of the excipients listed in section 6.1.

Concomitant use of other sympathomimetic decongestants, beta-blockers or monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOI treatment (see section 4.5). The concomitant use of MAOIs may cause a rise in blood pressure and/or hypertensive crisis.

Cardiovascular disease including hypertension

Diabetes mellitus

Phaeochromocytoma

Hyperthyroidism

Closed angle glaucoma

Severe acute or chronic kidney disease/renal failure

Not to be used in children under the age of 12 years.

4.4. Special warnings and precautions for use

Patients experiencing difficulty in urination and/or enlargement of the prostate, or patients with thyroid disease who are receiving thyroid hormones should not take pseudoephedrine unless directed by a physician.

Caution should be exercised when using the product in the presence of severe hepatic impairment or moderate to severe renal impairment (particularly if accompanied by cardiovascular disease), or in occlusive vascular disease. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

If any of the following occur, this product should be stopped:

• Hallucinations

• Restlessness

• Sleep disturbances

Severe Skin reactions: Severe skin reactions such as acute generalized exanthematous pustulosis (AGEP) may occur with pseudoephedrine-containing products. This acute pustular eruption may occur within the first 2 days of treatment, with fever, and numerous, small, mostly non-follicular pustules arising on a widespread oedematous erythema and mainly localized on the skin folds, trunk, and upper extremities. Patients should be carefully monitored. If signs and symptoms such as pyrexia, erythema, or many small pustules are observed, administration of this medicine should be discontinued, and appropriate measures taken if needed.

Ischaemic colitis: Some cases of ischaemic colitis have been reported with pseudoephedrine. Pseudoephedrine should be discontinued, and medical advice sought if sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis develop.

Ischaemic optic neuropathy: Cases of ischaemic optic neuropathy have been reported with pseudoephedrine. Pseudoephedrine should be discontinued if sudden loss of vision or decreased visual acuity such as scotoma occurs.

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS)

Cases of PRES and RCVS have been reported with the use of pseudoephedrine-containing products (see section 4.8). The risk is increased in patients with severe or uncontrolled hypertension, or with severe acute or chronic kidney disease/renal failure (see section 4.3).

Pseudoephedrine should be discontinued and immediate medical assistance sought if the following symptoms occur: sudden severe headache or thunderclap headache, nausea, vomiting, confusion, seizures and/or visual disturbances. Most reported cases of PRES and RCVS resolved following discontinuation and appropriate treatment.

Taking this product with other paracetamol-containing products, could lead to overdose and should therefore be avoided.

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.

Risks of abuse

Pseudoephedrine carries the risk of abuse. Increased doses may ultimately produce toxicity. Continuous use can lead to tolerance resulting in an increased risk of overdosing. The recommended maximum dose and treatment duration should not be exceeded (see section 4.2).

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

MAOIs (see section 4.3) and/or RIMAs: Pseudoephedrine exerts its vasoconstricting properties by stimulating α-adrenergic receptors and displacing noradrenaline from neuronal storage sites. Since monoamine oxidase inhibitors (MAOIs) impede the metabolism of sympathomimetic amines and increase the store of releasable noradrenaline in adrenergic nerve endings, MAOIs may potentiate the pressor effect of pseudoephedrine. This product should not be used in patients taking monoamine inhibitors or within 14 days of stopping treatment as there is a risk of hypertensive crisis.

Moclobemide: Risk of hypertensive crisis

Sympathomimetic agents: Concomitant use of this product with tricyclic antidepressants or sympathomimetic agents (such as decongestants, appetite suppressants and amphetamine-like psychostimulants) or with monoamine oxidase inhibitors may cause a rise in blood pressure.

Antihypertensives: Because of the pseudoephedrine content, this product may partially reverse the hypotensive action of antihypertensive drugs which interfere with sympathetic activity including bretylium, betanidine, guanethedine, debrisoquine, methyldopa, adrenergic neurone blockers and beta-blockers.

Cardiac glycosides: Increased risk of dysrhythmias.

Ergot alkaloids (ergotamine & methysergide): Increased risk of ergotism

Oxytocin: Risk of hypertension

Anticholinergic drugs: Enhances effects of anticholinergic drugs (such as tricyclic antidepressants)

Anaesthetic agents: Concurrent use with halogenated anaesthetic agents such as chloroform, cyclopropane, halothane, enflurane or isoflurane may provoke or worsen ventricular arrhythmias.

Chronic alcohol intake can increase the hepatotoxicity of paracetamol overdose and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol. Acute alcohol intake may diminish an individual's ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged.

The use of drugs which induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptive steroids, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

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.

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).

4.6. Fertility, pregnancy and lactation

There are no adequate and well-controlled clinical studies in pregnant or breast-feeding women for the combination of paracetamol and pseudoephedrine.

This product should not be used during pregnancy or lactation unless the potential benefit of treatment to the mother outweighs the possible risks to the developing foetus or breastfeeding infant.

Pregnancy

The safety of pseudoephedrine in pregnancy has not been established.

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. 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.

Breastfeeding

Pseudoephedrine is excreted in breast milk in small amounts but the effect of this on breast-fed infants is not known. It has been estimated that approximately 0.4 to 0.7% of a single 60 mg dose of pseudoephedrine ingested by a nursing mother will be excreted in the breast milk over 24 hours. Data from a study of lactating mothers taking 60 mg pseudoephedrine every 6 hours suggests that from 2.2 to 6.7% of the maximum daily dose (240 mg) may be available to the infant from a breastfeeding mother.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding. A pharmacokinetic study of paracetamol in 12 nursing mothers revealed that less than 1% of a 650 mg oral dose of paracetamol appeared in the breast milk. Similar findings have been reported in other studies, therefore maternal ingestion of therapeutic doses of paracetamol does not appear to present a risk to the infant.

Fertility

No studies have been conducted in animals to determine whether pseudoephedrine has the potential to impair fertility. There is no information of the effect of NON-DROWSY SINUTAB on fertility.

4.7. Effects on ability to drive and use machines

None known.

4.8. Undesirable effects

Adverse drug reactions identified during clinical trials and post-marketing experience with paracetamol, pseudoephedrine, or the combination are listed below by System Organ Class (SOC).

The frequencies are defined according to the following convention:

Very common ≥1/10

Common ≥1/100 and < 1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000, including isolated reports

Not known (cannot be estimated from the available data)

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence cannot be estimated, frequency category is listed as 'Not known'.

System Organ Class (SOC)

Frequency

Adverse Drug Reaction (Preferred Term)

Blood and lymphatic system disorders

Not known

Blood disorders, blood dyscrasias (including agranulocytosis and thrombocytopenia) have been reported following paracetamol use but were not necessarily causally related to the drug

Immune system disorders

Rare

Hypersensitivity (cross-sensitivity may occur with other sympathomimetics)

Psychiatric disorders

Common

Insomnia

Nervousness

Not known

Anxiety

Euphoric mood

Excitability

Hallucinations

Irritability

Paranoid delusions

Restlessness

Sleep disorder

Nervous system disorders

Very common

Headache

Common

Dizziness

Not known

Cerebrovascular accident

Paraesthesia

Posterior reversible encephalopathy syndrome (PRES) (see section 4.4)

Reversible cerebral vasoconstriction syndrome (RCVS) (see section 4.4)

Psychomotor hyperactivity

Somnolence

Tremor

Eye Disorders

Not known

Ischaemic optic neuropathy

Cardiac disorders

Not known

Dysrhythmias

Myocardial infarction/myocardial ischaemia

Palpitations

Tachycardia

Vascular disorders

Not known

Hypertension

Gastrointestinal disorders

Common

Dry mouth

Nausea

Not known

Abdominal pain

Diarrhoea

Ischaemic colitis

Vomiting

Hepatobiliary disorders

Rare

Hepatic necrosis

Skin and subcutaneous tissue disorders

Rare

Rash

Not known

Angioedema

Fixed eruption

Pruritus

Rash pruritic

Severe skin reactions, including Acute generalised exanthematous pustulosis (AGEP)

Urticaria

Renal and urinary disorders

Uncommon

Nephropathy toxic

Not known

Dysuria

Renal papillary necrosis (after prolonged administration)

Urinary retention (in men whom prostatic enlargement could have been an important predisposing factor)

Metabolism and nutrition disorders

Not known

High anion gap metabolic acidosis

Chronic hepatic necrosis has been reported in a patient who took daily therapeutic dosages of paracetamol for about a year and liver damage has been reported after daily ingestion of excessive amounts for shorter periods. A review of a group of patients with chronic active hepatitis failed to reveal differences in the abnormalities of liver function in those who were long-term users of paracetamol nor was the control of their disease improved after paracetamol withdrawal.

Very rare cases of serious skin reactions have been reported with paracetamol.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g 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, phenobarbital, 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, coma 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.

Haemolytic anaemia (in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency): Haemolysis has been reported in patients with G6PD deficiency, with use of paracetamol in overdose.

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.

Pseudoephedrine

Symptoms

Overdose may result in:

Hyperglycaemia, hypokalaemia, CNS stimulation, insomnia; irritability, restlessness, anxiety, agitation; confusion, delirium, hallucinations, psychoses, seizures, tremor, intracranial haemorrhage including intracerebral haemorrhage, drowsiness in children, mydriasis, palpitations, tachycardia, reflex bradycardia, supraventricular and ventricular arrhythmias, dysrhythmias, myocardial infarction, hypertension, vomiting, ischaemic bowel infarction, acute renal failure, difficulty in micturition.

Management

Necessary measures should be taken to maintain and support respiration and control convulsions. Catheterisation of the bladder may be necessary. If desired, the elimination of pseudoephedrine can be accelerated by acid diuresis or by dialysis.