SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Substances    mg/ capsule

Ibuprofen    200

Pseudoephedrine Hydrochloride    30

Excipients with known effect: Sorbitol (E420), soya lecithin, potassium.

This medicine contains 15.871 mg of potassium per capsule. For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Soft capsules (capsules).

A clear, oval, soft-gelatin capsule filled with a clear liquid and printed with 200/30 in black ink.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules are indicated for the relief of symptoms of the common cold and flu such as headache, fever, sore throat, minor aches and pain when associated with blocked nose (nasal congestion) and sinuses (sinusitis) in adults and adolescents over 15 years of age.

4.2 Posology and method of administration

For oral administration and short-term use only.

This combination product should be used where both, the decongestant action of pseudoephedrine hydrochloride and the analgesic and/or anti-inflammatory action of ibuprofen are required. If one symptom (either nasal congestion or headache and/or fever) predominates, single-agent therapy is preferable.

Posology

Adults, older people and adolescents over 15 years of age:

Take 1 capsule every 4-6 hours to a maximum of 6 capsules in any 24 hour period.

In case of more intense symptoms, 2 capsules (400 mg ibuprofen/60 mg pseudoephedrine hydrochloride) may be taken at a time. The dose can be repeated, if necessary, at six-hour intervals without exceeding a maximum dose of 6 capsules (1200 mg of ibuprofen and 180 mg of pseudoephedrine hydrochloride).

The lowest effective dose should be used for the shortest time necessary to relieve

symptoms. Maximum duration of treatment is 5 days unless instructed otherwise by a doctor.

Paediatric population

Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules are contraindicated in children under the age of 15 years.

Renal and hepatic insufficiency

No dose reduction is required in patients with mild to moderate renal or hepatic impairment, (see section 4.4) The lowest effective dose should be used.

Method of administration

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

Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, bronchospasm, rhinitis, angioedema, urticaria), in response to ibuprofen, aspirin or other non- steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, related to previous NSAID therapy.

Severe renal failure or hepatic failure (See section 4.4).

During pregnancy and breast-feeding (See section 4.6).

Children and adolescents under 15 years of age.

Patients with serious cardiovascular disease, tachycardia, hypertension, severe renal impairment, angina pectoris, hyperthyroidism, diabetes, phaeochromocytoma, closed angle glaucoma, prostatic enlargement.

Patients taking pain relievers or decongestants

Patients receiving tricyclic antidepressants.

Patients currently receiving, or who have within the last two weeks received, monoamine oxidase inhibitors.

This medicinal product MUST NOT GENERALLY BE USED in combination with:

-    oral anticoagulants,

-    other NSAIDs (including acetylsalicylic acid at high doses).

-    heparins at curative doses or in the elderly

-    lithium

-    selective serotonin reuptake inhibitors (SSRIs),

-    methotrexate (used at doses higher than 20 mg /week)

-    corticosteroids

-    antiplatelet drugs

4.4 Special warnings and precautions for use

The use of this medicinal product with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

Warnings

Due to presence of pseudoephedrine hydrochloride:

•    It is absolutely essential to comply strictly with the dosage, a 5-day treatment duration, and contra-indications (see section 4.2 and section 4.3).

•    Patients should be informed that the occurrence of hypertension, tachycardia, palpitations or cardiac arrhythmia, nausea or any neurological sign (such as occurrence or worsening of headache) requires that this treatment be discontinued.

•    Patients are advised to seek a physician's opinion in the event of:

-    hypertension, cardiac disorder, hyperthyroidism, psychosis, diabetes or enlarged prostate

-    combination with anti-migraine agents in particular ergot alkaloid-derived vasoconstrictor agents due to the sympathomimetic alpha-adrenergic activity of the vasoconstrictor component.

•    Neurological disorders such as seizures, hallucinations, behavioral disorders, agitation, and insomnia have been described, more frequently in children, after administration of vasoconstrictor agents by the systemic route, in particular during febrile episodes or in case of an overdose.

Consequently, it is necessary to observe the following:

- not to prescribe this treatment in combination with medicinal products which may lower the seizure thresholds such as terpene derivatives, clobutinol, atropin-like agents, local anesthetics, etc., or in case of a history of seizures.

- in all cases, to comply with the specified dosage and to inform the patient of overdose risk in case of combined use with other medicinal products containing vasoconstrictor agents.

• the elderly could be more sensitive in view of CNS- effects.

Due to the presence of ibuprofen:

•    Patients with asthma combined with chronic rhinitis, chronic sinusitis and/or nasal polyposis, are at higher risk for allergic reactions, during administration of acetylsalicylic acid and/or NSAIDs, than the rest of the population.

•    Administration of this medicinal product may lead to an acute episode of asthma, in particular in some subjects who are allergic to acetylsalicylic acid or to another NSAIDs (see section 4.3).

•    NSAIDs, by inhibiting the vasodilator action of renal prostaglandins, are likely to cause functional renal failure through a reduction in the glomerular filtration rate. This adverse effect is dose-dependent

Respiratory:	Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.
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)
Gastrointestinal effects:	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 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 patients 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 this medicinal product, the treatment should be withdrawn. 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 - undesirable effects).
Cardiovascular and cerebrovascular effects:	Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400 mg 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 daily) is associated with an increased risk of myocardial infarction. 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.
Skin reactions:	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 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. The product should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
Fertility:	The use of NSAIDs may impair female fertility (see section 4.6).

Cautions for use

Due to the presence of pseudoephedrine hydrochloride:

In case of elective surgery and in case of halogenated volatile anaesthetic agent use, it is preferable to discontinue this treatment a few days before, because of the risk of an acute hypertensive episode (see section 4.5).

Athletes must be aware that pseudoephedrine hydrochloride may induce a positive reaction in anti-doping testing.

Due to the presence of ibuprofen:

Elderly: dosage should not be modified, since age does not alter the kinetics of ibuprofen.

Caution should be observed since the elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

At the start of treatment, close monitoring of the patients' diuresis volume and renal function is necessary in patients with chronic heart failure, liver cirrhosis, impaired liver function and renal disorders, in patients receiving a diuretic treatment after major surgery which resulted in hypovolemia, and especially in the elderly.

If visual disorders develop during treatment, a complete ophthalmological examination should be performed.

Caution with regards to excipients

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules contain soya lecithin. Patients who are allergic to peanut or soya, should not use this medicinal product.

This medicine contains 15.871 mg of potassium in each capsule. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

4.5 Interaction with other medicinal products and other forms of interaction Related to the presence of pseudoephedrine hydrochloride:

Combination of pseudoephedrine with:	Possible Reaction
Contra-indicated combinations
Non-selective MAOIs (iproniazid):	Paroxysmal hypertension and hyperthermia, which may be fatal. Due to the long duration of action of MAOIs, this interaction can occur up to 15 days after discontinuation of the MAOI.

Other indirect sympathomimetic drugs and medications intended for treatment of nasal congestion whether administered by oral or nasal route (phenylpropanolamine, phenylephrine, ephedrine and methylphenidate):	Risk of vasoconstriction and/or acute hypertensive episode.
Sympathomimetic alpha agonists agents (oral and/or nasal routes):	Risk of vasoconstriction and/or acute hypertensive episode.
Combinations not recommended
Selective Reversabile MAO inhibitors of monoamine oxidase A (RIMAs), Linezolide, Methylene blue, Dopaminergic ergot alkaloids, Vasoconstrictive ergot alkaloids:	Risk of vasoconstriction and/or acute hypertensive episode
Combinations requiring precautions for use:
Halogenated volatile anaesthetics:	Perioperative acute hypertension episode. In case of elective surgery, it is recommended to discontinue treatment a few days before the procedure.
Guanethidine, reserpine and methyldopa:	Effect of pseudoephedrine may be diminished.
Tricyclic antidepressants:	Effect of pseudoephedrine may be diminished or enhanced.
Digitalis, quinidine or tricyclic antidepressants:	Increased frequency of arrhythmia.

Related to the presence of ibuprofen:

Risk related to hyperkaliemia:

Some medicinal products or therapeutic classes may promote hyperkaliemia: i.e. potassium salt, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II inhibitors, NSAIDs, heparins (low-molecular weight heparins or unfractionated heparins), ciclosporin, tacrolimus and trimethoprim.

Occurrence of hyperkaliemia may be related to concomitant risk factors.

This risk is enhanced in case of combination use with the above-mentioned medicinal products.

Risk related to the platelet-inhibiting effect:

Several substances are involved in interaction mechanisms, as a result of their platelet-inhibiting properties: acetylsalicylic acid and NSAIDs, ticlopidine and clopidogrel, tirofiban, eptifibatide and abciximab, and iloprost.

Use of several platelet-inhibiting agents enhances the risk of bleeding as well as their use in combination with heparin or similar compounds (hirudins), oral anti-coagulants and thrombolytic agents and must be taken into account by regular clinical and biological monitoring.

In case of simultaneous administration of ibuprofen with the following medicinal products, strict monitoring of the patients' clinical and biological condition must be performed.

Concomitant use of ibuprofen with :	Possible Reaction
Combinations not recommended
Other NSAIDs, including salicylates:	The concomitant administration of two or more NSAIDs may increase the risk of gastrointestinal ulcers and bleeding due to a synergistic effect. The concomitant use of ibuprofen with other NSAIDs should therefore be avoided (see section 4.4).
Acetylsalicylic acid at anti-inflammatory dosages (> 1 g per administered dose and/or > 3 g per day) or at analgic or antipyretic dosages (> 500 mg per administered dose and/or < 3 g per day):	Increased risk of ulcers and gastrointestinal bleeding.
Oral anti-coagulants:	Increased risk of bleeding related to the oral anti-coagulant (aggressive action on the gastro-duodenal mucosa by the NSAIDs). If such a combination cannot be avoided, strict clinical and biological monitoring is deemed necessary.
Curative doses of heparins (low-molecular weight or unfractionated heparins) or in the elderly:	Increased risk of bleeding (inhibition of platelet function and aggressive action by the NSAIDs on the gastro-duodenal mucosa). If such a combination cannot be avoided, strict clinical monitoring is deemed necessary.
Lithium:	Increased serum lithium levels which may be toxic (decreased renal excretion of lithium). If such a combination cannot be avoided, close monitoring of serum lithium and lithium dosage adjustment during this combined use and after NSAID discontinuation, is deemed necessary.
Selective serotonin reuptake inhibitors (SSRIs):	Increased risk of gastrointestinal bleeding (see section 4.4).
Methotrexate - used at doses greater than 20 mg/week:	Increased toxicity in particular hematologic toxicity of methotrexate (decrease renal clearance of methotrexate by NSAIDs). The administration of Ibuprofen/ Pseudoephedrine hydrochloride Pfizer

	200 mg/ 30 mg Capsules within 24 hours before or after administration of methotrexate may lead to elevated concentrations of plasma methotrexate and an increase in its toxic effect.
Pemetrexed (patients with a weak to moderate renal function, creatinine clearance ranging from 45 ml/min to 80 ml/min):	Increased risk of pemetrexed toxicity (NSAIDs reduce renal clearance)
Combinations requiring precautions for use:
Diuretics, ACE inhibitors, beta-receptor blockers and angiotensin-II antagonists:	NSAIDs may reduce the effect of diuretics and other antihypertensive medicinal products. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the coadministration of an ACE inhibitor, beta receptor-blockers or angiotensin-II antagonists and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible (decreased glomerular filtration (inhibition of vasodilator prostaglandins by the NSAIDs)). Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Methotrexate, used at doses lower than 20 mg/week:	Increased toxicity in particular hematologic toxicity of methotrexate (decreased renal clearance of methotrexate by the anti-inflammatory agents). A complete blood count should be performed weekly during the first weeks of such combination therapy. Patient monitoring should be increased in case of impaired renal function (even mild) as well as in the elderly. The administration of Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules within 24 hours before or after administration of methotrexate may lead to elevated concentrations of methotrexate and an increase in its toxic effect.

Ciclosporin:	The risk of a kidney-damaging effect (nephrotoxicity) due to ciclosporin is increased through the concomitant administration of certain nonsteroidal anti-inflammatory drugs. This effect also cannot be ruled out for a combination of ciclosporin with ibuprofen. Renal function should be monitored at start of the NSAIDs treatment.
Tacrolimus:	The risk of nephrotoxicity is increased if the two medicinal products are administered concomitantly, particularly in the elderly. Renal function should be monitored at start of the NSAIDs treatment.
Pemetrexed (patients with a normal renal function):	Increased risk of pemetrexed toxicity (NSAIDs reduce renal clearance). Biological monitoring of renal function.
Combinations to be taken into account
Acetylsalicylic acid (low dose):	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). Concomitant use of aspirin at a daily dose of more than 75 mg should be avoided because the risk of side effects is increased (see section 4.3 and section 4.8).
Anti platelet agents: (e.g. ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, iloprost)	Increased risk of gastrointestinal bleeding (see section 4.4).
Anticoagulants:	NSAIDs such as ibuprofen may enhance the effect of anti-coagulants (see section 4.4).
Potassium sparing diuretics:	The concomitant administration of Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules and potassium-sparing diuretics may lead to hyperkalaemia (check of serum potassium is recommended).
Beta-blockers (except esmolol):	Reduction of the antihypertensive effect (inhibition of vasodilator prostaglandines by the NSAIDs).

Heparins at prophylactic doses (apart from the elderly):	Increased risk of bleeding.
Deferasirox:	Increased risk of ulcers and gastrointestinal bleeding.
Glucocorticoids (except hydrocortisone as substitute treatment):	Increased risk of ulceration and gastrointestinal bleeding. (see section 4.4)
Digoxin:	The concomitant use with digoxin preparations may increase serum levels of these medicinal products. A check of serum-digoxin is not as a rule required on correct use (maximum over 5 days).
Phenytoin:	The concomitant use with phenytoin preparations may increase serum levels of these medicinal products. A check of serum-phenytoin levels is not as a rule required on correct use (maximum over 5 days).
Probenecid and sulfinpyrazone:	Medicinal products that contain probenecid or sulfinpyrazone may delay the excretion of ibuprofen.
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.
Sulphonylureas:	Clinical investigations have shown interactions between nonsteroidal antiinflammatory drugs and antidiabetics (sulphonylureas). Although interactions between ibuprofen and sulphonylureas have not been described to date, a check of blood-glucose values is recommended as a precaution on concomitant intake.
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.
Ginkgo biloba:	Increased risk of bleeding.

4.6 Fertility, pregnancy and lactation

Pregnancy

Pseudoephedrine

There is a possible association between the development of fetal abnormalities and first trimester exposure to pseudoephedrine. Therefore the use of pseudoephedrine during pregnancy should be avoided.

Ibuprofen

Whilst no teratogenic effects have been demonstrated in animal experiments, the use of ibuprofen should, if possible, be avoided during the first 6 months of pregnancy. During the 3^rd trimester, ibuprofen is contraindicated, as there is a risk of premature closure of the fetal 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.

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 upon withdrawal of treatment.

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, the use of this product is contraindicated during pregnancy and breastfeeding (see section 4.3).

4.7 Effects on ability to drive and use machines

Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules have a minor or moderate influence on the ability to drive and use machines.

Patients 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.

4.8 Undesirable effects

The most commonly-observed adverse events related to ibuprofen are gastrointestinal in nature. In general, the risk of development of adverse events (in particular the risk of development of serious gastrointestinal complications) increases with increasing dose and with increasing duration of treatment administration. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed.

Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of:

a)    Non-specific allergic reaction and anaphylaxis

b)    Breathing: Respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea

Skin: Assorted skin disorders, including rashes of various types, bruising, pruritis, urticaria, purpura, angioedema and more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

c)    Very rarely, bullous reactions including Steven’s - Johnson syndrome and toxic epidermal necrolysis.

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.

Oedema, hypertension, cardiac failure and angina pectoris have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400 mg 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).

The following list of adverse effects relates to those experienced with ibuprofen and pseudoephedrine hydrochloride at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Patients should be informed that they should stop taking Ibuprofen/ Pseudoephedrine hydrochloride Pfizer 200 mg/ 30 mg Capsules immediately and consult a doctor if they experience a serious adverse drug reaction

Infections and infestations	Ibuprofen	Very rare	Exacerbation of infectious inflammations (e.g. necrotizing fasciitis), Aseptic meningitis (stiffness of the neck, headache, nausea, vomiting, fever or disorientation in patients with pre-existent autoimmune diseases (SLE, mixed connective tissue disease))
Blood and lymphatic system disorders	Ibuprofen	Very rare	Haematopoietic disorders (anaemia, aplastic anaemia, leucopenia, thrombocytopenia, pancytopenia, haemolytic anaemia, agranulocytosis).
Immune system disorders	Ibuprofen	Uncommon	Hypersensitivity reactions with urticaria, pruritus and asthma attacks (with drop in blood pressure)
	Ibuprofen and pseudoephedrine hydrochloride	Very rare	Severe generalised hypersensitivity reactions, signs may be facial oedema, angioedema, dyspnoea, tachycardia, drop in blood pressure, anaphylactic shock
Psychiatric disorders	Ibuprofen	Very rare	Psychotic reactions, depression, nervousness.

	Pseudoephedrine hydrochloride	Not known	Agitation*, hallucination*, anxiety, abnormal behaviour*, insomnia*, excitability, restlessness, nervousness, irritability.
Nervous system disorders	Ibuprofen	Uncommon	Central nervous disturbances such as headache, dizziness, sleeplessness, agitation, irritability or tiredness,
	Ibuprofen	Not Known	Cerebrovascular accident (stroke)
	Pseudoephedrine hydrochloride	Not known	Haemorrhagic stroke (in rare instances, hemorrhagic stroke has occurred in patients who used medicinal products containing pseudoephedrine hydrochloride. Such cases of stroke in particular have occurred in case of an overdose, misuse and/or in patients presenting with vascular risk factors), ischemic stroke, convulsion headache, seizures*, dizziness, psycomotor hyperactivity.
*particularly in chile an overdose, or the c threshold or contribu occurrence of such e	ren after administration of vasoconstrictor agents. Factors such as, fever, ombination use with a medicinal product which may decrease the seizure ite to an overdose were often found and appear to predispose the ffects (see sections 4.3 and 4.4).
Eye disorders	Ibuprofen	Uncommon	Visual disturbances
	Pseudoephedrine	Not known	Closed-angle glaucoma (acute episode)
Ear and labyrinth disorders	Ibuprofen	Rare	Tinnitus
	Ibuprofen	Not known	Vertigo
Cardiac disorders	Ibuprofen	Very rare	Palpitations, heart failure, myocardial infarction
	Pseudoephedrine hydrochloride	Not known	Palpitations, tachycardia, chest pain, arrythmia, myocardial infarction
Vascular disorders	Ibuprofen	Very rare	Arterial hypertension
	Ibuprofen	Not known	Angina pectoris

	Pseudoephedrine hydrochloride	Not known	Hypertension
Gastrointestinal disorders **	Ibuprofen	Common	Dyspepsia, abdominal pain, nausea, vomiting, flatulence, diarrhoea, constipation, minor gastrointestinal blood loss in rare cases leading to anaemia
	Ibuprofen	Uncommon	Gastric ulcer with bleeding and/or perforation, gastritis, ulcerous stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4)
	Ibuprofen	Very rare	Oesophagitis, pancreatitis, intestinal diaphragm-like stricture
	Pseudoephedrine hydrochloride	Not known	Dry mouth, thirst, nausea, vomiting
**The above gastrointestinal effects are all more frequent when dosage used is high and in case of treatment for an extended duration
Hepatobiliary disorders	Ibuprofen	Very rare	Hepatic dysfunction, hepatic damage, particularly in long-term therapy, hepatic failure, acute hepatitis, acute jaundice.
Skin and subcutaneous tissue disorders	Ibuprofen	Uncommon	Various skin rashes
	Ibuprofen	Very rare	Bullous exanthema such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome), alopecia, severe skin infections, soft-tissue complications in a varicella infection.
	Ibuprofen	Not known	Angioedema, erythema multiforme, skin eruption, rash, purpura, pruritus, urticaria.
	Pseudoephedrine hydrochloride	Not known	Rash (exanthema), urticaria, pruritus, hyperhidrosis, sweating.
Renal and Urinary disorders	Ibuprofen	Rare	Kidney-tissue damage (papillary necrosis) and elevated uric acid concentrations in the blood

	Ibuprofen	Very rare	Oedemas (particularly in patients with arterial hypertension or renal insufficiency), nephrotic syndrome, interstitial nephritis, acute renal insufficiency
	Ibuprofen	Not known	Hematuria, renal failure, proteinuria, oliguria
	Pseudoephedrine hydrochloride	Not known	Difficulty in micturition (dysuria, urinary retention in particular in patients with urethroprostatic disorders)
Investigations	Ibuprofen	Not Known	Transaminases increased (transient), Hematocrit decreased, and haemoglobin decreased
Respiratory, thoracic and mediastinal disorders	Ibuprofen	Not Known	Bronchospasm, dyspnea, wheezing, asthma (- acute episode, in some subjects may be related to acetylsalicylic acid or NSAID allergy (see section 4.3))
General disorders and administration site conditions	Ibuprofen	Not known	Edema, swelling, peripheral edema

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

An overdose may result in the following: acute hypertension, cardiac arrhythmia, seizures, illusions, hallucinations, agitation, anxiety, irritability, nervousness, restlessness, vertigo, behavioral disorders, insomnia, mydriasis, stroke, nausea, vomiting, convulsions, dizziness, tremor, abdominal pain, hepatic function abnormality, hyperkalemia, metabolic acidosis, headaches, loss of consciousness, renal failure, dyspnea, respiratory depression, hypotension epigastric pain, diarrhoea, tinnitus, gastrointestinal bleeding. excitation, disorientation, coma, exacerbation of asthma is possible and somnolence.

Management

Management should be symptomatic and supportive and include the maintainance of a clear airway and monitoring of cardiac and vital signs until stable.

-    Patient should be immediately transferred to a hospital department.

-    The ingested medicinal product should be rapidly evacuated by gastric lavage.

-    Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount.to decrease ibuprofen absorption.

-    Symptomatic therapy should be administered.

-    If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma

5 PHARMACOLOGICAL PROPERTIES

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

Ibuprofen is a non steroidal anti-inflammatory agent belonging to the Propionic Acid class of drugs that has demonstrated its efficacy by inhibition of prostaglandin synthesis. It has analgesic, antipyretic and anti-inflammatory properties. Pseudoephedrine Hydrochloride is a sympathomimetic agent which causes vasoconstriction of nasal mucosa, thereby reducing rhinorrhoea and nasal congestion.

Experimental data suggest 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 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. 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.

5.2 Pharmacokinetic properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Absorption

Ibuprofen is rapidly absorbed from the gastrointestinal tract following administration. Maximum plasma concentrations occur about 1 to 2 hours after ingestion. Time for peak plasma concentrations to be reached may vary depending on dosage form and whether taken with food.

In an oral bioavailability study comparing solubilised ibuprofen (in the ibuprofen + pseudoephedrine soft capsules formulation) was shown to be bioequivalent to the ibuprofen plus pseudoephedrine tablet, and ibuprofen soft capsule for ibuprofen extent of exposure (AUC). The combination soft capsule formulation had greater peak exposure (Cmax) to ibuprofen than the tablet formulation. In addition, median time to peak exposure (Tmax) was comparable between ibuprofen + pseudoephedrine soft capsules (39 min) and comparator ibuprofen soft capsules (45 min), and was 2030 minutes shorter than comparator ibuprofen + pseudoephedrine tablets (67.5 min).

The solubilized ibuprofen (as present in ibuprofen +pseudoephedrine soft capsules) displays a faster systemic absorption rate versus the comparator combination ibuprofen + pseudoephedrine tablet formulation.

Pseudoephedrine (in immediate release formulations) is readily absorbed from the gastrointestinal tract with peak plasma levels at 1-3 hours.

Distribution

Ibuprofen is primarily metabolized in the liver to primary metabolites 2-Hydroxyibuprofen and 2-Carboxyibuprofen. Ibuprofen is 90 to 99% bound to plasma proteins. In limited studies, Ibuprofen appears in the breast milk at very low concentrations.

Pseudoephedrine is thought to cross the placenta and to enter cerebrospinal fluid Pseudoephedrine distributes into breast milk; about 0.5% of an oral dose is distributed into breast milk over 24 hours.

Elimination

Ibuprofen has a plasma half-life of about 2 hours. It is rapidly excreted in the urine mainly as metabolites and their conjugates. About 1% is excreted in the urine as unchanged ibuprofen and about 14% as conjugated ibuprofen.

Pseudoephedrine is excreted largely unchanged in the urine with small amounts of its hepatic metabolite. It has a half-life of about 5 to 8 hours; elimination is enhanced and half-life accordingly shorter in acid urine. Small amounts are distributed into breast milk.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Liquid Fill:

Potassium hydroxide Macrogol 600 Purified water Gelatine Capsule:

Sorbitol liquid, partially dehydrated (E 420)

Gelatine

Black printing ink [Macrogol 400, Polyvinyl Acetate Phthalate, Propylene Glycol, Iron Oxide Black (E172)]

Soya lecithin in Triglycerides, medium chain

6.2 Incompatibilities

No information is available

6.3 Shelf life

2 years

Special precautions for storage

Store below 30°C

6.5 Nature and contents of container

Capsules are packed in to a white, opaque, PVC/PVdC heat sealed to Glassine/Aluminium foil blister strips,

or

white, opaque, PVC/PE/PVdC heat sealed to Glassine/Aluminium foil blister strips Blister strips packed in outer cardboard carton

Pack sizes: 2, 4, 8, 10, 12, 16, 20, 24

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Pfizer Consumer Healthcare Ltd

Ramsgate Road

Sandwich

Kent

CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00165/0389

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/01/2016

10    DATE OF REVISION OF THE TEXT

20/01/2016