Non-Drowsy Sudaplus Tablets

This variation is being submitted to implement the PRAC recommendations following the outcome of the ibuprofen / pseudoephedrine PSUSA (PSUSA/00001711/201707). These recommendations include updating Sections 4.4 and 4.8 of the Summary of Product Characteristics and to update Section 2 and 4 of the Package Leaflet accordingly

This variation is being submitted to implement the PRAC recommendations following the outcome of the ibuprofen / pseudoephedrine PSUSA (PSUSA/00001711/201707). These recommendations include updating Sections 4.4 and 4.8 of the Summary of Product Characteristics and to update Section 2 and 4 of the Package Leaflet accordingly

PSE V3 CCDS update plus incorporating paracetamol updates.

9.         Date of First Authorisation/Renewal of Authorisation

            Date of first authorisation: 30 June 2011

            Date of last renewal: 29 June 2016

10.       Date of Revision of the Text

            September 2016

Section 4.2 Added text “Posology:”

“and Children aged 12 years and over”

“Maximum daily dose: 8tablets (240 mg pseudoephedrine and 4 g paracetamol).”

“Children under 12 years:

This medicine is contraindicated in children under the age of 12 years”

“Use in the Elderly

There have been no specific studies of this medicine in the elderly.  Experience has indicated that normal adult dosage is appropriate.”

“Hepatic dysfunction:

Caution should be exercised when administering the product to patients with severe hepatic impairment.

Renal dysfunction:

Caution should be exercised when administering this medicine  to patients with mild to moderate renal impairment.

Duration of use:

Patients should be advised not to use this product for more than 5 days and to seek medical advice if symptoms persist.

Do not exceed the stated dose.

Keep out of the sight and reach of children.

Method of administration:

For oral use.”

Removed text “Adolescents aged 12 to 18 years old:

One to two tablets up to three times daily as required for relief of symptoms.

The dose should not be repeated more frequently than every four hours nor should more than three doses be given in any 24 hour period.”

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

Patients should be advised not to use this product for more than 5 days and to seek medical advice if symptoms persist.

Do not exceed the stated dose.

The tablets should be taken with water.”

“Special Populations

Pseudoephedrine is primarily excreted renally.  Pseudoephedrine should not be used by those with severe renal impairment (see Contraindications) and should be used with caution in those with moderate renal impairment (see 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetics).”

Section 4.3 Added text “excipients listed in section 6.1.

This product is contra-indicated in patients with:

·         Cardiovascular disease including hypertension

·         Diabetes mellitus

·         Phaeochromocytoma

·         Hyperthyroidism

·         Closed angle glaucoma

·         Severe renal impairment

This product should not be used concomitantly with (see Section 4.5):”

“The concomitant use of pseudoephedrine and these products may cause a rise in blood pressure or hypertensive crisis”

“Other sympathomimetic” “decongestants”

·         “Beta-blockers

This medicine is contraindicated in patients at risk of developing respiratory failure.”

Removed text “sympathomimetics” “other constituents” “Not to be used by patients taking moclobemide” “for two weeks”

“The antibiotics furazolidone and linezolid should not be taken with Non-Drowsy Sudaplus Tablets (see 4.5 Interaction with other medicinal products and other forms of interaction).”

“Not to be used by patients with the following conditions:

·              Hypertension.

·              Cardiovascular disease

·              Hyperthyroidism

·              Prostatic hypertrophy

·              Glaucoma

·              Severe renal impairment

Not to be used by patients currently receiving other sympathomimetics (such as decongestants, appetite suppressants and amfetamine-like psychostimulants).

Not to be used by patients taking beta-blockers (see 4.5 Interaction with other medicinal products and other forms of interaction).”

Section 4.4 Added text “or difficulty in urination due to prostatic enlargement”

“The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.”

“Although pseudoephedrine has virtually no pressor effects in normotensive patients, this medicine should be used with caution in patients taking other sympathomimetic agents (such as appetite suppressants and amphetamine-like psychostimulants) The physician or pharmacist should check that sympathomimetic containing preparations are not simultaneously administered by several routes i.e. orally and topically (nasal, aural and eye preparations) (see Sections 4.3 and 4.5)”

“The stated dose must not be exceeded. Patients should seek immediate medical advice in the event of overdosage, because of the risk of irreversible liver damage (see Section 4.9).”

“A variety of allergic skin reactions, with or without systemic features such as bronchospasm, angioedema have been reported following use of pseudoephedrine (see Section 4.8).

Hypersensitivity reactions, including skin rashes, angioedema and anaphylaxis have been reported very rarely with paracetamol (see Section 4.8).

Serious skin reactions such as acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported very rarely in patients receiving paracetamol. Patients should be informed about the signs of serious skin reactions when using paracetamol, and use of the product should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.”

“This product may act as a cerebral stimulant giving rise to hyperpyrexia, tremor and epileptiform convulsions.

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

·         Hallucinations

·         Restlessness

·         Sleep disturbances

Use with caution in occlusive vascular disease”

Removed text “diabetes mellitus, arrhythmias or phaeochromocytoma.”

“Use with caution in patients taking antihypertensives (see 4.5 Interaction with other medicinal products and other forms of interaction).

The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.”

“This product may give rise to insomnia and nervousness.

Care is advised in the administration of Non-Drowsy Sudaplus Tablets to patients who will be undergoing general anaesthesia within a few days.

If you are taking medication, or are under medical care consult your doctor or pharmacist.

Keep all medicines safely out of sight and reach of children.”

Section 4.5 Added text “Pseudoephedrine” “Pseudoephedrine exerts its vasoconstricting properties by stimulating α-adrenergic receptors and displacing noradrenaline from neuronal storage sites. Since 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.

MAOIs and/or RIMAs: this medicine should not be given to patients treated with MAOIs or within 14 days of stopping treatment as there is an increased risk of hypertensive crisis.

Moclobemide: risk of hypertensive crisis”

“Concomitant use” “this medicine”

“(TCAs), or with sympathomimetic agents (such as appetite suppressants and amphetamine-like psychostimulants)”

“Concomitant use of this medicine with anticholinergic drugs (such as TCAs) may enhance their effects.”

“this medicine (see section 4.3)”

“antagonise” “hypotensive” “action” “drugs which interfere with sympathetic activity, including” “bretylium, bethanidine” “methyldopa” “adrenergic neurone blockers and beta-blockers”

“Because of its pseudoephedrine content, concomitant use of this medicine with oxytocin or cardiac glycosides may cause of a risk of hypertension or an increased risk of dysrhythmias, respectively.

When used concurrently with ergot alkaloids (ergotamine & methysergide), this product can increase the risk of ergotism.

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

Paracetamol

Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged.

Alcohol can increase the hepatotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol.

Chronic ingestion of anticonvulsants or oral steroid contraceptives induces liver enzymes and may prevent attainment of therapeutic paracetamol levels by increasing first pass metabolism or clearance”

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

“Because of its paracetamol content”

Removed text “The co-administration” “Non-Drowsy Sudaplus Tablets” “the antidepressant moclobemide or with monoamine oxidase inhibitors (MAOI’s) (or within two weeks of stopping MAOI’s) which interfere with the catabolism of sympathomimetic agents”

“and may lead to hypertensive crisis in the case of moclobemide or MAOI’s.”

“inhibitor and the antibiotic linezolid is a reversible non-selective MAOI with weak MAO-inhibitory properties”

“The rate of paracetamol absorption may be reduced by colestyramine.  The interaction can be avoided by delaying administration of colestyramine by one hour, in order to maintain maximal analgesic effects.”

“Sodium bicarbonate alkalinizes the urine and may reduce the renal elimination of pseudoephedrine, a reduction in dose may be necessary.

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone”

Section 4.6 Added text “There are no adequate and well controlled clinical studies in pregnant or breast feeding women for the combination of paracetamol and pseudoephedrine”

“This medicine should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs the possible risks to the developing foetus.

Paracetamol”

“When given to the mother in labelled doses, paracetamol crosses the placenta into the foetal circulation as early as 30 minutes after ingestion and is effectively metabolised by foetal sulphate conjugation

Paracetamol has been in widespread use for many years without ill consequence. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in recommended dosage, but patients should follow the advice of their doctor regarding its use.

Pseudoephedrine”

“Although pseudoephedrine has been in widespread use for many years without apparent ill consequence, there are no specific data on its use during pregnancy.  Caution should therefore be exercised by balancing the potential benefit of treatment to the mother against any possible hazards to the developing foetus.

Breast-feeding

This medicine should not be used during lactation unless the potential benefit of treatment to the mother outweighs the possible risks to the nursing infant.

Paracetamol

Paracetamol is excreted in breast milk in low concentrations (0.1% to 1.85% of the ingested maternal dose).

Pseudoephedrine”

“Pseudoephedrine distributes into and is concentrated in breast milk”

“Fertility

There is no information on the effects of this medicine on human fertility(see Section 5.3)”

Removed text “The safe use of the combination paracetamol and pseudoephedrine has not been fully established.  Animal studies are insufficient with respect to effects on pregnancy, embryonal/fetal development and postnatal development.  The use of Non-Drowsy Sudaplus Tablets during pregnancy is therefore not recommended.

Lactation

Pseudoephedrine is excreted in breast milk in amounts leading to increased risk of effects in the infant even at therapeutic doses. Treatment with Non-Drowsy Sudaplus Tablets is not recommended during breastfeeding.”

Section 4.7 Replaced “Dizziness is one of the most frequent adverse effects.  This could affect driving or using machines.” With “This medicine has no or negligible influence on the ability to drive and use machines”

Section 4.8 Added text “The safety of pseudoephedrine and paracetamol combination from clinical trial data is based on one randomised, placebo-controlled trial in the management of symptoms attributed to the paranasal sinus associated with the common cold. In addition there were 12 randomised, placebo-controlled trials with single ingredient pseudoephedrine.

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

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’.”

“Liver damage has been reported after daily ingestion of excessive amounts.  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.

Low level transaminase elevations may occur in some patients taking labelled doses of paracetamol; these elevations are not accompanied with liver failure and usually resolve with continued therapy or discontinuation of paracetamol.

A variety of allergic skin reactions, with or without systemic features such as bronchospasm, angioedema have been reported following use of pseudoephedrine.

Hypersensitivity reactions, including skin rashes, angioedema and anaphylaxis have been reported very rarely with paracetamol.

Very rare cases of serious skin reactions have been reported”

“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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.”

Removed text “The following adverse reactions have been reported with products containing paracetamol and/or pseudoephedrine.

Blood and the lymphatic system

Very Rare (<1/10,000): blood dyscrasia, including thrombocytopenia and agranulocytosis.

Immune System disorders

Rare (>1/10,000, <1/1,000): hypersensitivity*

Psychiatric disorders

Common (>1/100, <1/10): nervousness, insomnia

Uncommon (>1/1,000, <1/100): agitation , restlessness

Rare (>1/10,000, <1/1,000): hallucinations

Nervous system disorders

Common (>1/100, <1/10): dizziness

Gastrointestinal disorders

Common (>1/100; <1/10): dry mouth, nausea, vomiting

Skin and subcutaneous tissue disorders

Rare (>1/10,000, <1/1,000): rash, dermatitis allergic*

Renal and urinary disorders

Uncommon (>1/1,000, <1/100): urinary retention**

Cardiovascular disorders

Uncommon (>1/1,000, <1/100): minor tachycardia

Rare (>1/10,000, <1/1,000): cardiac arrhythmias

Rare (>1/10,000, <1/1,000): hypertension

Hepatic disorders

Very Rare (<1/10,000): Hepatic dysfunction

Respiratory disorders

Very Rare (<1/10,000): Bronchospasm is more likely in patients sensitive to aspirin or NSAIDs.

*A variety of allergic skin reactions, with or without systemic features such as bronchospasm, angioedema have been reported following use of pseudoephedrine.  Hypersensitivity reactions, including skin rashes, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, angioedema and anaphylaxis have been reported very rarely with paracetamol.

**Urinary retention is most likely to occur in those with bladder outlet obstruction such as prostatic hypertrophy.”

Section 4.9 Added text “Please refer to local guidance for the treatment of paracetamol overdose.”

“and adolescents” “7.5 to” “over a period of 8 hours or less. Fatalities are infrequent (less than 3-4% of untreated cases) and have rarely been reported with overdoses of less than 15g. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue”

Liver damage may not become apparent until 48 to 72 hours after ingestion. This may include hepatomegaly, liver tenderness, jaundice, acute hepatic failure and hepatic necrosis.Blood bilirubin, hepatic enzymes, INR, prothrombin time, blood phosphate and blood lactate may be increased. These clinical events associated with paracetamol overdose are considered expected, including fatal events due to fulminant hepatic failure or its sequelae.”

“The following sequelae to acute hepatic failure associated with paracetamol overdose (adults and adolescents: ≥ 12 years of age: > 7.5g within 8 hours) are considered expected and may be fatal

Expected Sequelae to Acute Hepatic Failure Associated with Paracetamol Overdose”

“*Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may also develop, even in the absence of severe liver damage.”

“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.

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 local centres and/or experts that provide advice on poisons and overdoses or a liver unit.”

“Overdosage may result in:

Metabolism and nutrition disorders: hyperglycaemia, hypokalaemia

Psychiatric disorders: CNS stimulation, insomnia; irritability, restlessness, anxiety, agitation; confusion, delirium, hallucinations, psychoses

Nervous system disorders: convulsions, tremor, intracranial haemorrhage including intracerebral haemorrhage, drowsiness in children

Eye disorders: mydriasis

Cardiac disorders: palpitations, tachycardia, reflex bradycardia, supraventricular and ventricular arrhythmias, dysrhythmias, myocardial infarction

Vascular disorders: hypertension, hypertensive crisis

Gastrointestinal disorders: nausea, vomiting, ischaemic bowel infarction

Musculoskeletal and connective tissue disorders: rhabdomyolysis

Renal and urinary disorders: acute renal failure, difficulty in micturition”

“Measures should be taken to maintain and support respiration and control convulsions.  Gastric lavage should be performed if indicated.  Catheterisation of the bladder may be necessary.  If desired, the elimination of pseudoephedrine can be accelerated by acid diuresis or by dialysis.”

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

“Abnormalities of glucose metabolism and metabolic acidosis may occur.  Clinical symptoms of liver damage are usually evident initially after 2 days, and reach a maximum after 4 to 6 days

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.  Other non-hepatic symptoms that have been reported following paracetamol overdosage include myocardial abnormalities and pancreatitis.

In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death”

“Immediate treatment is essential in the management of paracetamol overdose. 

Despite a lack of 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.

Paracetamol concentrations in blood should be measured not less than 4 hours after overdose in order to be able to assess the risk of developing liver damage (using the paracetamol overdose nomogram).  However, N-acetylcysteine (NAC) treatment should be started immediately when massive overdose is suspected.

The administration of activated charcoal may be beneficial when performed within one hour of the overdose but can be considered for up to four hours after the overdose.

Intravenous (IV) infusion (or oral administration if IV infusion is not possible) of the antidote N-acetylcysteine should be started if possible before the 8th hour.  The effectiveness of the antidote declines sharply after this time.  N-acetylcysteine can, however, give some degree of protection even after 8 hours, and up to 24 hours, but in these cases prolonged treatment is given.   If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Symptomatic treatment should be implemented.”

“As with other sympathomimetics pseudoephedrine overdose will result in symptoms due to central nervous system and cardiovascular stimulation e.g. excitement, irritability, restlessness, tremor, hallucinations, hypertension, palpitations, arrhythmias and difficulty with micturition.  In severe cases, psychosis, convulsions, coma and hypertensive crisis may occur.  Serum potassium levels may be low due to extracellular to intracellular shifts in potassium.”

“Treatment should consist of standard supportive measures.  Beta-blockers should reverse the cardiovascular complications and the hypokalaemia.”

Section 6.6 removed text “of a used medicinal product or waste materials   derived from such medicinal product” “of the product”

Section 10 Removed “(Partial)” and replaced date with “16 March 2016”