Change to section 4.2 Posology and method of administration: update to Paediatric population, and Renal and hepatic insufficiency.

Change to section 4.4 Special warnings and precautions for use: Addition of ischemic colitis warning.

Change to section 4.8  Undesirable effects: Addition of ischemic colitis warning.

Change to section 6.1  List of excipients: addition of E numbers.

4.2       Posology and Method of Administration

 

Adults, older people, and young persons over 12 years:

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4). The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 3 days.

4.3       Contraindications

 • Patients with severe heart failure (NYHA Class IV), renal failure or hepatic failure (see section 4.4).

 

4.4     Special Warnings and Precautions for Use

Clinical studies trial and epidemiological data suggest that use of some NSAIDs (ibuprofen) (particularly at a high doses (2400 mg/day 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. 1200 mg/day daily) is associated with an increased risk of myocardial infarctionarterial thrombotic events.
Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.
Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus and , smoking), particularly if high doses of ibuprofen (2400 mg/day) are required. 

4.5       Interactions with other medicinal products and other forms of interactions

 

It is considered unsafe to take Ibuprofen in combination with warfarin or heparin unless under direct medical supervision.

 

Not recommended combinations:

 

Acetylsalicylic acid

Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects.

                        Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when
                        they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that
                        regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded.
                        No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).  

                        Refer to section 4.3 & 4.4 for more information on concomitant use of ibuprofen. with other drugs.  

4.8       Undesirable Effects

 

Clinical studies suggest that  use of ibuprofen, particularly at a high dose (2400 mg/day)may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). Oedema, hypertension, angina pectoris and cardiac failure have been reported in association with NSAID treatment.

5.1       Pharmacodynamic Properties

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Some pharmacodynamicsIn one studies show thaty, when a single doses of ibuprofen 400 mg wereas taken within 8 h before or within 30 min after immediate release aspirin (acetylsalicylic acid) dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. Although However, the limitations of these data and there are uncertainties regarding extrapolation of these ex vivo data to the clinical situation, the possibility that regular, long term imply that no firm conclusions can be made for regular use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicyclic acid cannot be excluded. use, and nNo clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

10.       DATE OF REVISION OF THE TEXT

 

February  2016.

 

- In section 2, the active substances amount has been changed to per/tablet and mg has been added after quantitive numbers of active ingredients. Also, 'with known effects' has been addes to 'Excipients with known effect: Each tablet contains 174.6 mg sucrose, 0.003 mg methyl parahydroxybenzoate (E 218), and 0.002 mg propyl parahydroxybenzoate (E 216)'.


- In section 4.1 'Advil Cold & Flu' has been added before  is '...indicated in adults and adolescents over 12 years of age'.
-In section 4.2 Paediatric population 'Advil Cold and Flu is contraindicated in'  and '(see section 4.3) have been added, 'This product should not be given to' has been removed
-In section 4.3 Contraindication 'listed in Section 6.1' has been added in the second bullet point
-In section 4.4 Special Warnings and Precautions for Use, a word 'section' has been added at the end of the sixth bullet point
In section 4.5 Interactions with other medicinal products and other forms of interactions:
 'Advil Cold and Flu' has been added 'invented name' has been removed in the fourth  and ninth, fourteenth, sixteenth, nineteenth, twentieth, square of possible reactions
 's' has been added in 'pseudoephedrine' word in the fifth and sixth square of possible reactions
-In section 4.6 Fertility, Pregnancy and Lactation 'Advil Cold & Flu' has been added, 'the use of this product' has been removed, and '(see section 4.3) has been added at the end of the sentence.
-In section 10 'partial' has been removed and date has been changed to March 2015

Multiple SmPC changes due to undergoing an MRP procedure in a number of European countries.

Includes changes to side effects, contraindications, interactions and date of revision.

4.2 Posology and Method of Administration
Posology

Adults, the elderly and young persons over 12 years:
Take 1 or 2 tablets every 4-6 hours to a maximum of 6 tablets in 24 hours.

Not to be given to children under the age of 12.

Method of administration

For oral administration only. Tablets should be taken with a glass of water.

4.3 Contraindications

• Use in children under 12 years of age.
• Hypersensitivity to the active substances or to any of the excipients.
• Patients with allergy to aspirin or other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or with a history of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to ibuprofen, aspirin or NSAIDs.
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
• Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
• Patients with active peptic ulceration/haemorrhage or a history of peptic ulceration/haemorrhage.
• Patients with phaeochromocytoma, closed angle glaucoma, diabetes or thyroid disease.
• Patients with kidney diseaserenal failure.
• Patients with severe liver disease.
• Patients suffering from heart disease, circulatory problems, prostatic hypertrophy, hypertension or coronary artery disease.
• Patients taking other NSAIDs, pain-relievers or decongestants.
• Patients receiving tricyclic antidepressants.
• Patients currently receiving, or who have within the last two weeks received, monoamine oxidase inhibitors.
• Patients with severe heart failure.
• Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings and Precautions for Use

• The use of Advil Cold & Flu with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
• Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms.
• If symptoms get worse or last more than 3 days or you patients experience any other symptoms not related to the original condition, treatment should be stopped unless directed otherwise by a doctor or healthcare professional.
• Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2)
• Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious 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 pPatients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low dose aspirin or other drugs likely to increase gastrointestinal risk (see below and 4.5)
• 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 oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).
• When GI bleeding or ulceration occurs in patients receiving Advil Cold & Flu, the treatment should be withdrawn.
• NSAIDs should be given with care to patients with a history of gastrointestinal disease (e.g. ulcerative colitis and, Crohn’s disease) as their condition may be exacerbated (see sections 4.8 – undesirable effects).
• In patients with cardiac or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration in renal function.
• Advil Cold & Flu should be used with caution in patients with a history of peptic ulceration or inflammatory bowel disease.
• 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 and oedema have been reported in association with NSAID therapy. Undesirable effects may be minimised using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below)
• Cardiovascular and cerebrovascular effects:
Clinical trial and epidemiological data suggest that use of some NSAIDs (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.  1200mg daily) is associated with an increased risk of myocardial infarction.
• 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 NSAIDs (see section 4.8). Patients appear to be at highest risk of 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. Advil Cold & Flu should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
• Systematic Lupus Erythematosus and mixed connective tissue disease – increase risk of aseptic meningitis (see section 4.8).
• As NSAIDs can interfere with platelet function, they should be used with caution in patients with intra-cranial haemorrhage and bleeding diathesis.
• Patients suffering from asthma, hypertension, heart disease, diabetes, liver cirrhosis, kidney diseaserenal impairment, thyroid disease or prostatic hypertrophy should consult their doctor before using this product.
• Bronchospasm may be precipitated in patients suffering from asthma or allergic disease.
• There is some 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.
• The use of NSAIDs may impair female fertility (see section 4.6).
• and is not recommended in women attempting to conceive. In women who have difficulties conceiving and who are undergoing investigation of infertility, withdrawal of the product should be considered.
• Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
• This product contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate which may cause allergic reaction (possibly delayed).
•

4.5 Interactions with other medicinal products and other forms of interactions

It is considered unsafe to take Ibuprofen in combination with warfarin or heparin unless under direct medical supervision.

Not recommended combinations:
Animal studies show that acetylsalicylic acid reduces the plasma concentrations of Ibuprofen. Ibuprofen should not be used with other pain relievers such as NSAIDs.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Combinations requiring precautions:

Care should be taken in patients treated with any of the following drugs as interactions have been reported.

Anticoagulants, antihypertensives or thiazide diuretics:
NSAIDs may enhance the effects of anticoagulants (e.g. warfarin, ticlopidine) and diminish the effects of antihypertensive or thiazide diuretics.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac Glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels. Serum digitalis concentrations should therefore be monitored in patients with decreased renal function or congestive heart failure.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

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.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increase 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.

Phenytoin: Ibuprofen may increase the pharmacologically active free phenytoin. Patients taking Ibuprofen for long-term use should be monitored.

Lithium: Decreased elimination of lithium. This may result in clinically significant increases in lithium concentrations.

Methotrexate: Concomitant administration of Ibuprofen with moderate and high doses of methotrexate may lead to serious and fatal methotrexate toxicity. Patients with reduced renal function may be at additional risk of toxicity from the combination even when low doses of methotrexate (20 mg/week) are used.

Antacids: Certain antacids may increase the gastrointestinal absorption of Ibuprofen. This is considered to be of clinical relevance particularly during long-term use of Ibuprofen.

Cyclosporin: Increased risk of nephrotoxicity with NSAIDs.

Corticosteroids: Increased risk of gastro-intestinal bleeding or ulceration.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Aminoglycosides: Reduction in renal function in susceptible individuals decreased elimination of aminoglycosides and increased plasma concentrations.

Sulphonylureas: There is evidence of interactions between NSAID’s and sulfonylureas. No specific interactions between ibuprofen and sulfonylureas have been described.


Pseudoephedrine:

Pseudoephedrine may interact with:
The actions of other sympathomimetic drugs.
The antibacterial agent furazolidone.

Pseudoephedrine should not be given to patients receiving MAOI therapy or within 14 days of ceasing such treatment.

The action of Pseudoephedrine may be reduced by:
Guanethidine.
Reserpine.
Methyldopa.

The action of Pseudoephedrine may be reduced or enhanced by:
Tricyclic antidepressants.

Pseudoephedrine may reduce the action of:
Guanethidine.

Pseudoephedrine may increase the possibility of arrhythmias in patients taking:
Digitalis.
Quinidine.
Tricyclic antidepressants.

4.7 Effects on Ability to Drive and Use Machines

None knownPatients who experience dizziness, hallucinations, unusual headaches and visual or hearing disturbances should avoid driving or using machinery. Single administration or short-term use of this medicine does not usually warrant the adoption of any special precautions.


5.3 Preclinical Safety Data
Repeated dose toxicity studies on combinations of ibuprofen and pseudoephedrine have not been conducted. The combination was not mutagenic.

Sub-chronic and chronic toxicity studies have been conducted on ibuprofen alone with a 6 month NOAEL of 60 mg/kg in rats. Toxicity occurred in the form of lesions and ulcerations in the gastro-intestinal tract. Ibuprofen is not mutagenic nor was it carcinogenic in chronic rodent bioassays.

Sub-chronic or chronic toxicity studies have not been performed with pseudoephedrine alone. Combination ibuprofen and pseudoephedrine was not mutagenic. A human screening study of over 3,000 pseudoephedrine users showed no increase in cancer over 7.5 years
Reprotoxicity studies in animals with individual ingredients indicated that they were not teratogenic, however use of the product in pregnancy should if possible be avoided.
None stated.

Incorrect version used when legal entity changed therefore legal entity changed to correct versioin of SmPC and re-instated.   

7.         MARKETING AUTHORISATION HOLDER

 

Pfizer Healthcare Ireland,

9 Riverwalk, National Digital Park,

Citywest Business Campus, Dublin 24.

 

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 822/164/1

 

nervousness listed twice in overdose section 4.9.

6.1 List of Excipients

Tablet Core:
Maize starch
Starch, pregelinatised
Croscarmellose sodium
Colloidal anhydrous silica
Sodium laurilsulfate
Stearic acid

Tablet Coating:   
Sucrose
Microcrystalline cellulose
Carnauba wax (yellow)
Opalux Butterscotch AS-3739:
Sucrose
Titanium Dioxide (E 171)
Iron Oxide Yellow (E 172)
Iron Oxide Red (E 172)
Povidone


Methyl Parahydroxybenzoate (E 218)
Propyl Parahydroxybenzoate (E 216)
Opaglos GS-2-0310:
Industrial Methylated Spirit
Pharmaceutical shellac
Povidone
Acetylated monoglyceride

Opacode S-1-27794 black printing ink:
Shellac glaze
Iron Oxide black (E 172)
Propylene glycol
Or
Opacode S-1-17823 black printing ink:
Shellac glaze
Iron Oxide Black (E172)
Propylene glycol
Ammonium hydroxide

Note Removed Sodium Hydroxide from tablet coating, added industrial methylated spirits to Opaglos GS-2-0310, added new black ink and its ingredients, Opaglos S 1- 17823.  

4.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients.
• . Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings and Precautions for Use
• If symptoms get worse or last more than 3 days or you experience any other symptoms not related to the original condition, treatment should be stopped unless directed otherwise by a doctor or healthcare professional.

• Patients suffering from liver cirrhosis, kidney disease, should consult their doctor before using this product.

4.6 Fertility, Pregnancy and Lactation

Pregnancy:

Ibuprofen:
Whilst no teratogenic effect has been demonstrated in animal experiments, use of ibuprofen during pregnancy should be avoided during the first 6 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 duration of labour increased with an increased bleeding tendency in both mother and child (see Section 4.3).

Pseudoephedrine:
Data on pregnancy outcomes after maternal exposure to pseudoephedrine are limited. Two analyses of health maintenance organisation pharmacy data identified 9 malformed infants among 902 first-trimester pseudoephedrine exposures suggesting no specific association with birth defects overall. However the related compounds epinephrine, ephedrine and phenylephrine have been associated with haemorrhages and cardiovascular and limb malformations in animal models. The vasoconstrictive effects of these drugs may indicate that their use in early pregnancy might increases the risk of vascular disruption defects.

Lactation:

Ibuprofen:
In limited studies, ibuprofen appears in the breast milk in very low concentrations, and is unlikely to affect the breast fed infant adversely.

Pseudoephedrine:
Pseudoephedrine is excreted in breast milk in small quantities, but the effect of this on breast-fed infants is not known. It is estimated that 0.4% to 0.7% of a single dose of pseudoephedrine ingested by the mother will be excreted in breast milk over 24 hours.

In summary, caution should be exercised by balancing the potential benefit of treatment against any possible risks.
 
4.8 Undesirable Effects

Effects added;  
abdominal distension, mouth ulcerations, angina pectoris haemolytic anaemia, leukopenia, agitation, irritability, nervousness, restlessness, tinnitus, vertigo, visual disturbances, tachycardia, psychomotor hyperactivity, meningitis and aseptic meningitis.

4.9 Overdose

Overdosage may result in nervousness, agitation, anxiety, irritability, nervousness, restlessness, dizziness, tremor, vertigo, insomnia, nausea, abdominal pain, vomiting, epigastric pain, diarrhoea, bradycardia, palpitation, tachycardia, tinnitus, headache and gastrointestinal bleeding. Hyperkalemia, metabolic acidosis, hypertension or hypotension are also possible signs of overdose. Toxicity may manifest as drowsiness, excitation, disorientation or coma. The patient may develop convulsions. Hepatic function may be abnormal. Metabolic acidosis may occur and the prothrombin time/INR may be prolonged. Acute renal failure and liver damage may occur. In asthmatics, exacerbation of asthma is possible.

5.1 Pharmacodynamic Properties

Ibuprofen
Pharmacotherapeutic group: Propionic acid derivatives.
ATC code: M01AE51

Pseudoephedrine Hydrochloride
Pharmacotherapeutic group: Nasal decongestants for systemic use, sympathomimetrics.
ATC code: R01BA52

10. DATE OF (PARTIAL) REVISION OF THE TEXT

May 2011.

7.         MARKETING AUTHORISATION HOLDER

 

Pfizer Consumer Healthcare Ltd

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

 

 

(Note: MAH, Wyeth - DELETED) 

The last renewal date is the 08 Sept 2009, as part of the Section 6, the excipients were separated clearly out into tablet core, tablet coating and printing ink. No medical changes were made at renewal.  

Section 4.5 Interactions with other medicinal products.
Now mentions that experimental data suggests that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However there are limitations to this data in relation to regular ibuprofen use. No clinically revelant effect is considered to be likely in occasional use. 

Section 5.1 Pharmacodynamic Properties
Now mentions that experimental data suggests that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 mins after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet agggregation occurred. 
However there are limitations to this data in relation to regular ibuprofen use. No clinically revelant effect is considered to be likely in occasional use.