1. Name Of The Medicinal Product
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets
2. Qualitative And Quantitative Composition
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets contain 60 mg Pseudoephedrine hydrochloride and 500 mg Paracetamol.
3. Pharmaceutical Form
Tablets
4. Clinical Particulars
4.1 Therapeutic Indications
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is indicated for the symptomatic relief of conditions where congestion of the mucous membranes of the upper respiratory tract, is accompanied by pain or pyrexia, e.g. the common cold and influenza, sinusitis, nasopharyngitis.
4.2 Posology And Method Of Administration
Adults and children aged 12 years and over:
Oral. One tablet every 4-6 hours up to four times a day
Maximum daily dose: 4 tablets (240 mg pseudoephedrine and 2 g paracetamol).
Children under 12 years
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets are contraindicated in children under the age of 12 years (see section 4.3).
The Elderly:
There have been no specific studies of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets in the elderly. Experience has shown 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 Sudafed Congestion, Cold & Flu Tablets to patients with severe hepatic impairment (See Pharmacokinetics in Hepatic Impairment).
Renal dysfunction:
Caution should be exercised when administering Non-Drowsy Sudafed Congestion, Cold & Flu Tablets to patients with moderate to severe renal impairment, particularly if accompanied by cardiovascular disease (See Pharmacokinetics in Renal Impairment).
Do not exceed the stated dose.
Keep out of the reach and sight of children.
4.3 Contraindications
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in individuals with known hypersensitivity to paracetamol or any other constituents of the product.
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in patients with severe hypertension or coronary artery disease.
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets is contraindicated in patients who are taking or have taken monoamine oxidase inhibitors within the preceding two weeks. The concomitant use of pseudoephedrine and this type of product may occasionally cause a rise in blood pressure.
Not to be used in children under the age of 12 years.
4.4 Special Warnings And Precautions For Use
Although pseudoephedrine has virtually no pressor effects in normotensive patients, Non-Drowsy Sudafed Congestion, Cold & Flu Tablets should be used with caution in patients suffering from mild to moderate hypertension.
As with other sympathomimetic agents Non-Drowsy Sudafed Congestion, Cold & Flu Tablets should be used with caution in patients with heart disease, diabetes, hyperthyroidism, elevated intraocular pressure or prostatic enlargement.
Caution should be exercised in the administration of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets to patients with severe hepatic impairment or moderate to severe renal impairment, (particularly if accompanied by cardiovascular disease) (See Pharmacokinetics). The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.
Concomitant use of other products containing paracetamol or decongestants with Non-Drowsy Sudafed Congestion, Cold & Flu Tablets could lead to overdose and therefore should be avoided.
The following statements will appear on packs of this product:
Keep out of the reach and sight of children.
As with all medicines, if you are pregnant or currently taking any other medicine, consult your doctor or pharmacist before taking this product.
If symptoms persist consult your doctor.
Store below 25ºC. Keep dry. Protect from light.
Warning: Do not exceed the stated dose.
Causes no drowsiness.
Contains paracetamol.
The label contains the following additional statements:
Immediate medical advice should be sought in the event of an overdose, even if you feel well.
Do not take with any other paracetamol-containing products.
Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage (leaflet).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concomitant use of Non-Drowsy Sudafed Congestion, Cold & Flu Tablets with tricyclic antidepressants, sympathomimetic agents (such as decongestants, appetite suppressants and amfetamine-like psychostimulants) or with monoamine oxidase inhibitors, which interfere with the catabolism of sympathomimetic amines, may occasionally cause a rise in blood pressure (See Contraindications).
Because of the pseudoephedrine content, Non-Drowsy Sudafed Congestion, Cold & Flu Tablets may partially reverse the hypotensive action of drugs which interfere with sympathetic activity including bretylium, betanidine, guanethidine, debrisoquine, methyldopa, alpha- and beta-adrenergic blocking agents (See Special warnings and precautions for use).
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 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.
4.6 Pregnancy And Lactation
Non-Drowsy Sudafed Congestion, Cold & Flu Tablets, like most medicines, should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs any possible risk to the developing foetus.
Pseudoephedrine and paracetamol have been in widespread use for many years without apparent ill consequence. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. The safety of pseudoephedrine during pregnancy has not been directly established.
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.
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 neonate/infant.
4.7 Effects On Ability To Drive And Use Machines
No special comment - unlikely to produce an effect.
4.8 Undesirable Effects
Pseudoephedrine
Serious side effects associated with the use of pseudoephedrine are extremely rare. Symptoms of central nervous system excitation may occur, including sleep disturbance and, rarely, hallucinations.
Skin rashes, with or without irritation, have occasionally been reported with pseudoephedrine.
Urinary retention has been reported occasionally in men receiving pseudoephedrine: prostatic enlargement could have been an important predisposing factor.
Paracetamol
Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causality related to paracetamol.
4.9 Overdose
Pseudoephedrine
Symptoms
As with other sympathomimetic agents, symptoms and signs of pseudoephedrine overdose include irritability, restlessness, tremor, convulsions, palpitations, hypertension and difficulty with micturition.
Management
Necessary 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. Acid diuresis can accelerate the elimination of pseudoephedrine, although the potential therapeutic gain of this procedure is now in dispute. The value of dialysis in overdose is not known, although four hours of haemodialysis removed approximately 20 % of the total body load of pseudoephedrine in a combination product containing 60 mg pseudoephedrine and 8 mg acrivastine.
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
• Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.
Or
• Regularly consumes ethanol in excess of recommended amounts.
Or
• 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 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 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Paracetamol
Paracetamol is an analgesic and antipyretic. The therapeutic effects of paracetamol are thought to be related to inhibition of prostaglandin synthesis, as a result of inhibition of cyclo-oxygenase. There is some evidence that it is a more effective inhibitor of central as opposed to peripheral cyclo-oxygenase. Paracetamol has only weak anti-inflammatory properties. This may be explained by the concept that inflammatory tissues have higher levels of cellular peroxides than other tissues and that cellular peroxides prevent inhibition of cyclo-oxygenase by paracetamol.
Pseudoephedrine
Pseudoephedrine has direct and indirect sympathomimetic activity and is an effective upper respiratory decongestant. Pseudoephedrine is less potent than ephedrine in producing both tachycardia and elevation of systolic blood pressure and is also less potent in causing stimulation of the central nervous system. Pseudoephedrine produces its decongestant effect within 30 minutes persisting for at least 4 hours.
5.2 Pharmacokinetic Properties
Absorption
Paracetamol
Absorption of paracetamol occurs mainly by passive transfer from the small intestine. Gastric emptying is the rate-limiting step in the absorption of orally administered paracetamol. Any drug, disease or other condition, which alters the rate of gastric emptying, will therefore influence the rate of paracetamol absorption.
Peak plasma paracetamol concentration usually occurs between 30 and 90 minutes after oral ingestion, depending on the formulation. Mean maximum plasma concentrations of paracetamol of 12.84 ug/ml were determined following the administration of Calpol Six Plus suspension (containing 1g paracetamol) to adults.
Paracetamol is incompletely available to the systemic circulation after oral administration since a variable proportion is lost through first-pass metabolism. Oral bioavailability in adults appears to depend on the amount of paracetamol administered, increasing from 63% of the administered dose after 500mg to nearly 90% of the dose after 1 or 2 g (in tablet form).
Pseudoephedrine
Pseudoephedrine is well absorbed from the gut following oral administration. After the administration of one 60 mg pseudoephedrine tablet to healthy adult volunteers, the Cmax for pseudoephedrine was approximately 180 ng/ml, with tmax occurring at approximately 1.5-2.0 hours.
Distribution
Paracetamol
Paracetamol is distributed uniformly throughout most body fluids, with an estimated volume of distribution of 0.95 l/kg. Following therapeutic doses, paracetamol is not appreciably bound to plasma proteins.
Pseudoephedrine
The apparent volume of distribution of pseudoephedrine (Vd/F) was approximately 2.8 l/kg.
Metabolism and elimination
Paracetamol
The plasma half-life of paracetamol after therapeutic doses is in the range 1.5-2.5 hours. Paracetamol is metabolised by the liver and several metabolites of paracetamol have been identified in man. The two major metabolites excreted in the urine are the glucuronide and sulphate conjugates. About 10 % of administered paracetamol is converted, via a minor pathway, by a cytochrome P-450 mixed function oxidase system to a reactive metabolite, acetamidoquinone. This metabolite is rapidly conjugated with reduced glutathione and excreted as cysteine and mercapturic acid conjugates. When large amounts of paracetamol are taken, hepatic glutathione may become depleted causing excessive accumulation within the hepatocyte of acetamidoquinone, which binds covalently to vital hepatocellular macromolecules. In overdose, this can lead to hepatic necrosis. Total body clearance of paracetamol following a single dose (1000 mg i.v) is approximately 5 ml/min/kg.
Renal excretion of paracetamol involves glomerular filtration and passive reabsorption, and the sulphate and glucuronide conjugates are subject to active renal tubular secretion. Renal clearance of paracetamol depends on urine flow rate, but not pH.
Less than 4 % of the administered drug is excreted as unchanged paracetamol. In healthy subjects, approximately 85-95% of a therapeutic dose is excreted in the urine within 24 hours.
Pseudoephedrine
The plasma t½ was approximately 5.5 hours. Pseudoephedrine is partly metabolised in the liver by N. Pseudoephedrine and its metabolite are excreted in the urine; 55% to 90% of a dose is excreted unchanged. The apparent total body clearance of pseudoephedrine (Cl/F) was 6 - 6.5 ml/min/kg. The elimination rate constant (Kel) was approximately 0.13 hr-1. The rate of urinary elimination is accelerated when the urine is acidified. Conversely, as the urine pH increases, the rate of urinary elimination is slowed.
Pharmacokinetics in Renal Impairment
Paracetamol
The mean plasma half-life of paracetamol is similar in normal and renally impaired subjects between 2-8hrs, but from 8-24hrs paracetamol is eliminated less rapidly. Marked accumulation of the glucuronide and sulphate conjugates occurs in chronic renal failure.
There may be some extra renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. An increase in the interval between doses of paracetamol has been recommended for adults with chronic renal failure. Haemodialysis may result in reduced plasma levels of paracetamol. Supplementary doses of paracetamol may be necessary in order to maintain therapeutic blood levels.
Pseudoephedrine
Following the administration of a single dose of Duact Capsules
(60 mg pseudoephedrine + 8 mg acrivastine) to patients with varying degrees of renal impairment, the Cmax for pseudoephedrine increased approximately 1.5 fold in patients with moderate to severe renal impairment when compared to the Cmax in healthy volunteers. The tmax was not affected by renal impairment. The t½ increased 3 -12 fold in patients with mild to severe renal impairment respectively, when compared to the t½ in healthy volunteers.
Pharmacokinetics in Hepatic Impairment
Paracetamol
The mean plasma paracetamol half-life is similar in normal subjects and those with mild liver disease, but is significantly prolonged (approximately 75%) in patients with severe liver disease. However, the clinical significance of the increase in half-life is unclear, since there is no evidence of drug accumulation or hepatotoxicity in patients with liver disease, and glutathione conjugation is not impaired. The administration of 4g paracetamol daily for 13 days to 20 subjects with chronic stable liver disease, resulted in no deterioration of liver function, and in mild liver disease, there is no evidence that paracetamol is harmful when taken at recommended doses. However, in severe liver disease, the plasma paracetamol half-life is significantly prolonged.
Pseudoephedrine
There have been no specific studies of pseudoephedrine in hepatic impairment.
Pharmacokinetics in the Elderly
Paracetamol
Differences in pharmacokinetic parameters observed between fit young and fit elderly subjects are not thought to be of clinical significance. However, there is some evidence to suggest that serum paracetamol half-life is markedly increased (by approximately 84%) and clearance of paracetamol is decreased (by approximately 47%) in frail, immobile, elderly subjects when compared to fit young subjects.
Pseudoephedrine
In elderly volunteers, following the administration of Duact Capsules (60 mg pseudoephedrine + 8 mg acrivastine) the t½ for pseudoephedrine was 1.4 fold that seen in healthy volunteers. The apparent Cl/F was 0.8 fold that seen in healthy volunteers, and the Vd/F was essentially unchanged.
5.3 Preclinical Safety Data
Mutagenicity
Paracetamol
In vivo mutagencicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man.
Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2 hr).
Pseudoephedrine
The results of a wide range of tests indicate that pseudoephedrine does not pose a mutagenic risk to man.
Carcinogenicity
Paracetamol
There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the urethra (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma.
There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in mice and liver and bladder carcinomas can be detected in rats, following chronic feeding of 500mg/kg/day paracetamol.
Pseudoephedrine
There is insufficient information available to determine whether pseudoephedrine has carcinogenic potential.
Teratogenicity
Paracetamol
There is no information relating to the teratogenic potential of paracetamol. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol is not associated with teratogenic effects in humans.
Paracetamol has been found to be fetotoxic to cultured rat embryos.
Pseudoephedrine
Systemic administration of pseudoephedrine, up to 50 times the human daily dosage in rats and up to 35 times the human daily dosage in rabbits did not produce teratogenic effects.
Fertility
Paracetamol
There is no information relating to the effects of paracetamol on human fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg body weight/day) orally for 70 days.
Pseudoephedrine
Systemic administration of pseudoephedrine to rats, up to 7 times the human daily dosage in females and 35 times the human daily dosage in males, did not impair fertility or alter foetal morphological development and survival.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Pregelatinised maize starch
Povidone
Crospovidone
Stearic acid
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
Store below 25°C. Keep dry and protect from light
6.5 Nature And Contents Of Container
Blister packs (12 tablets) consisting of a white, opaque PVC/PVdC film and either:
Aluminium foil blister lidding
Or
Paper/aluminium foil child resistant blister lidding
6.6 Special Precautions For Disposal And Other Handling
None applicable.
Administrative Data
7. Marketing Authorisation Holder
McNeil Products Limited
Foundation Park
Roxborough Way
Maidenhead
Berkshire SL6 3UG
United Kingdom
8. Marketing Authorisation Number(S)
PL 15513/0025
9. Date Of First Authorisation/Renewal Of The Authorisation
28th October 1997
10. Date Of Revision Of The Text
21 APRIL 2009
No comments:
Post a Comment