1. Name Of The Medicinal Product
Lemsip Flu 12 Hr Ibuprofen + Pseudoephedrine.
Nurofen Cold&Flu Max Sustained Release Capsules
2. Qualitative And Quantitative Composition
Each capsule contains:
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Two-thirds of the ibuprofen is in sustained-release form. All of the pseudoephedrine hydrochloride is present in sustained-release form.
3. Pharmaceutical Form
Modified release capsule.
4. Clinical Particulars
4.1 Therapeutic Indications
For the relief of symptoms of heavy cold and influenza, including relief of aches and pains, headache and sore throat, relief of nasal congestion or a runny nose, and lowering of temperature.
4.2 Posology And Method Of Administration
For oral administration and short-term use only.
Adults, the elderly and children 12 and over:
The lowest effective dose should be used for the shortest time necessary to relieve symptoms. The patient should consult a doctor is symptoms persist or worsen, or if the product is required for more than 10 days.
Two capsules. The product is taken orally with water. The capsules should not be chewed.
The dose may be repeated after 12 hours.
No more than two doses should be taken in 24 hours.
Not to be given to children under 12.
There is no indication that dosage needs to be modified in the elderly.
4.3 Contraindications
Severe coronary heart disease.
Severe hypertension.
Severe hepatic failure, renal failure or heart failure (see Section 4.4, Special warnings and precautions for use).
Current receipt, or receipt within the last two weeks, of therapy with monoamine oxidase inhibitors.
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
Hypersensitivity to ibuprofen, pseudoephedrine or any other ingredient.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs)
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Use with concomitant NSAIDs, including cyclo-oxygenase-2 specific inhibitors.
Last trimester of pregnancy (see Section 4.6, Pregnancy and lactation).
4.4 Special Warnings And Precautions For Use
The decongestant effect increases gradually after the first dose and may continue for up to 15 hours after the last dose.
To be used with caution by patients with hepatic, cardiac or renal dysfunction.
Ibuprofen: To be used with caution by patients who are asthmatic.
Pseudoephedrine: To be used with caution by patients with hypertension, heart disease, hyperthyroidism, hyperexcitability, phaeochromocytoma, prostatic enlargement, closed angle glaucoma or diabetes.
Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration necessary to control symptoms (see GI and cardiovascular risks below).
The elderly have an increased frequency of adverse reactions to NSAIDS especially gastrointestinal bleeding and perforation which may be fatal.
Respiratory:
Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.
Other NSAIDs:
The use of Lemsip Flu 12 Hr Ibuprofen + Pseudoephedrine with concomitant NSAIDS including cyclooxygenase-2-selective inhibitors should be avoided (see section 4.5)
SLE and mixed connective tissue disease:
Systemic lupus erythematosus and mixed connective tissue disease - increased risk of aseptic meningitis (see Section 4.8, Undesirable effects).
Renal:
Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)
Hepatic:
Hepatic dysfunction (see sections 4.3 and 4.8)
Cardiovascular and cerebrovascular effects:
Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of ibuprofen,particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.
Impaired female fertility:
There is limited evidence that drugs which inhibit cyclo- oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.
Gastrointestinal:
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as corticosteroids,anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see Section 4.5).
Where GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Dermatological:
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Lemsip Flu 12 Hr Ibuprofen + Pseudoephedrine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
The label will include:
Read the enclosed leaflet before taking this product.
Do not take if you:
• Have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding.
• Are allergic to ibuprofen or any other ingredient of the product, aspiring or related painkillers.
• Are taking other NSAID painkillers, or aspirin with a daily dose above 75 mg.
• Are in the last three months of pregnancy.
Speak to a pharmacist or your doctor before taking this product if you:
• Have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, liver, heart, kidney or bowel problems.
• Are pregnant.
• Are a smoker
If symptoms persist or worsen, consult your doctor.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Ibuprofen should be avoided in combination with:
Aspirin: Unless low-dose aspirin (not above 75 mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see Section 4.3, Contraindications).
Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as these may increase the risk of adverse effects (see Section 4.4,).
Ibuprofen should be used with caution in combination with:
Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see Section 4.4).
Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs.
Diuretics can increase the risk of nephrotoxicity of NSAIDs
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4)
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4)
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: There is evidence for potential increases in plasma levels of lithium.
Methotrexate: There is a potential for in an increase in plasma methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Pseudoephedrine may adversely interact with antihypertensive agents or tricyclic antidepressants, or other sympathomimetics - such as nasal decongestants, appetite suppressants or amphetamine-like psycho-stimulants, to cause a rise in blood pressure. Pseudoephedrine may partially reverse the hypotensive action of the drugs which interfere with sympathetic activity, such as bethanidine and methyldopa.
4.6 Pregnancy And Lactation
Whilst no teratogenic effects have been demonstrated in animal studies, the use of ibuprofen should, if possible, be avoided during the first six months of pregnancy.
During the third trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (See Section 4.3, Contraindications).
In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.
4.7 Effects On Ability To Drive And Use Machines
None expected at recommended doses and duration of therapy.
4.8 Undesirable Effects
Hypersensitivity reactions have been reported and these may consist of:
(a) Non-specific allergic reactions and anaphylaxis.
(b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea.
(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
The following list of adverse effects relates to those experiences with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.
Hypersensitivity reactions
Uncommon: Hypersensitivity reactions with urticaria and pruritus.
Very rare: Severe hypersensitivity reactions. Symptoms could be facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).
Exacerbation of asthma and bronchospasm.
Gastrointestinal
The most commonly-observed adverse events are gastrointestinal in nature.
Uncommon: Abdominal pain, nausea and dyspepsia.
Rare: Diarrhoea, flatulence, constipation and vomiting.
Very rare: Peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly.
Exacerbation of ulcerative colitis and Crohn's disease (see Section 4.4).
Nervous system
Uncommon: Headache.
Very rare: Aseptic meningitis – single cases have been reported very rarely
Renal
Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.
Hepatic
Very rare: Liver disorders.
Haematological
Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). The first signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.
Dermatological
Uncommon: Various skin rashes.
Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.
Immune system
In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see Section 4.4, Special warnings and precautions for use).
Cardiovascular and Cerebrovascular:
Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).
Pseudoephedrine: Adverse reactions are uncommon, but dry mouth, anorexia, urinary retention in men, skin rashes and symptoms of CNS excitation, such as tension, restlessness, sleep disturbance or hallucinations, may occur rarely.
4.9 Overdose
The product consists of sustained-release capsules and effects may be prolonged.
Symptoms of either or both components may be present.
Ibuprofen: In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.
Symptoms
Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management
Management should always be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.
Pseudoephedrine: Features may include irritability, palpitations, hypertension, convulsions, tremor, hyperactivity, hyperpyrexia, dryness of the skin and mucous membranes, and the possible effects given in Section 4.8. Treatment includes early gastric lavage and symptomatic and supportive measures. Elimination can be accelerated by acid diuresis or by dialysis. Hypertensive effects may be treated with an i.v. alpha-receptor blocking agent. Convulsions may be treated with an anticonvulsant.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Ibuprofen: Ibuprofen is an aryl-propionic acid structurally related to other non-steroidal anti-inflammatory drugs. It has analgesic, antipyretic and anti-inflammatory activity. Its mechanism of action is attributed to the inhibition of cyclo-oxygenase to prevent the production of prostaglandins. Furthermore, ibuprofen reversibly inhibits platelet aggregation.
Pseudoephedrine: Pseudoephedrine is an adrenergic agonist acting at both α-and β-adrenoreceptors. It is reported to have less tachycardiac and pressor activity, and fewer effects on the central nervous system than ephedrine. It is a recognised, orally-acting, nasal decongestant, and acts by vasoconstriction to reduce oedema and nasal swelling.
5.2 Pharmacokinetic Properties
Ibuprofen: Ibuprofen is well absorbed after oral administration. Absorption may be slowed after food, but without an appreciable decrease in bioavailability. It is extensively metabolised (>90%) to two major metabolites and excreted by kidney as free and conjugated metabolites and free drug. Ibuprofen is extensively protein bound in plasma and the plasma half-life is in the range 1.9-2.2 hours.
In this product, two-thirds of the ibuprofen is in the form of sustained-release pellets, resulting in a plateau of ibuprofen plasma levels lasting several hours after dosing, with plasma elimination half-life of approximately 5 hours. These characteristics allow twice-daily dosing.
Pseudoephedrine: Pseudoephedrine, from standard release formulations, is rapidly and completely absorbed after oral administration. Up to about 90% of a dose is excreted in the urine within 24 hours of dosing. The half-life is between 5 and 8 hours, but may be increased when the urine is alkaline and reduced when it is acid. Onset of nasal decongestant action occurs approximately 30 minutes after an oral dose of 60 mg and continues for at least 4 hours.
In the capsules all of the pseudoephedrine is in sustained-release form.
The sustained-release pellets in this presentation result in maximum pseudoephedrine levels approximately 7 hours after dosing, with plasma elimination half-life of approximately 7-8 hours. These characteristics allow twice-daily dosing.
5.3 Preclinical Safety Data
None stated.
6. Pharmaceutical Particulars
6.1 List Of Excipients
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6.2 Incompatibilities
Not known.
6.3 Shelf Life
Two years.
6.4 Special Precautions For Storage
Store at 25°C or below in a dry place.
6.5 Nature And Contents Of Container
Laminate blister containing four or five unit doses (eight or ten capsules). The blisters are packed into an outer carton.
6.6 Special Precautions For Disposal And Other Handling
See Section 4.2.
ADMINISTRATIVE DATA
7. Marketing Authorisation Holder
Reckitt Benckiser Healthcare (UK) Limited,
Dansom Lane,
Hull,
HU8 7DS,
United Kingdom.
8. Marketing Authorisation Number(S)
PL/00063/0098
9. Date Of First Authorisation/Renewal Of The Authorisation
26/10/2005
10. Date Of Revision Of The Text
14/05/2009
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