Pfizer Consumer Healthcare

Advil Cold & Flu Coated Tablets

Ibuprofen 200 mg

Pseudoephedrine Hydrochloride 30 mg

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).

For a full list of excipients, see section 6.1.

Coated tablets.

Oval shaped, butterscotch coloured, sugar coated tablets and imprinted '200/30' in black ink on one face.

Symptomatic relief of nasal/sinus congestion with headache, fever and pain associated with the common cold and flu. Advil Cold & Flu is indicated in adults and adolescents over 12 years of age.

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.

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.

Posology

Adults, older people and young persons over 12 years:

Take 1 or 2 tablets every 4-6 hours to a maximum of 6 tablets in any 24 hour period.

Paediatric population

Advil Cold & Flu is contraindicated in children under the age of 12 (see section 4.3).

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. Tablets should be taken with a glass of water.

• Use in children under 12 years of age.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

• Patients with allergy to aspirin or other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or with a history of hypersensitivity reactions (e.g. asthma, bronchospasm, rhinitis, angioedema or 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 phaeochromocytoma, closed angle glaucoma, diabetes or thyroid disease.

• Patients with history of haemorrhagic stroke.

• Patients suffering from heart disease, circulatory problems, prostatic hypertrophy, hypertension, coronary artery disease, angina pectoris, tachycardia or haemorrhagic diathesis.

• Patients taking other NSAIDs including cyclooxygenase-2 selective inhibitors, 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 (NYHA Class IV), renal failure or hepatic failure (see section 4.4).

• During pregnancy and breast-feeding. (see section 4.6).

• The use of Advil Cold & Flu with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.3 and 4.5).

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

• If symptoms get worse or last more than 3 days or 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 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 section 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 section 4.8 – undesirable effects).

• In patients with cardiac or renal dysfunction, caution is required since the use of NSAIDs may result in deterioration in renal function.

• Cardiovascular and cerebrovascular effects:

Clinical studies suggest that use of some NSAIDs (ibuprofen) particularly at a high dose (2400 mg/day) 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) is associated with an increased risk of arterial 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.

• 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.

• Systemic 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, renal or hepatic impairment, thyroid disease or prostatic hypertrophy should consult their doctor before using this product (see section 4.3 and 4.8).

• There is a risk of renal impairment in dehydrated adolescents or young persons, between the age of 12 and 17 years.

• Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

• The use of NSAIDs may impair female fertility (see section 4.6). 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.

• Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

• Consumption of alcohol should be avoided during treatment.

• Pseudoephedrine hydrochloride may cause a positive reaction in tests conducted during anti-doping checks.

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).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Combinations requiring precautions:

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

Advil Cold & Flu has no or negligible influence on the ability to drive and use machines at recommended doses and duration of therapy.

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.

The most common observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, abdominal distension, mouth ulcerations, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) 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, angiodema and, less commonly, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

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

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.

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 Advil Cold & Flu tablets immediately and consult a doctor if they experience a serious adverse drug reaction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

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

Over dosage may result in nervousness, agitation, anxiety, irritability, 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.

Management

Due to the rapid absorption of the two active ingredients from the gastro-intestinal tract, emetics and gastric lavage must be instituted within four hours of overdosage to be effective. Charcoal is effective only if given within one hour. Cardiac status should be monitored and the serum electrolytes measured.

If there are signs of cardiac toxicity, propanolol may be administered intravenously. A slow infusion of a dilute solution of potassium chloride should be initiated in the event of a drop in the serum potassium level. Despite hypokalaemia, the patient is unlikely to be potassium depleted, therefore overload must be avoided. Continued monitoring of the serum potassium is advisable for several hours after administration of the salt. For delirium or convulsions, intravenous administration of diazepam is indicated.

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. 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 competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400 mg were 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 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 acetylsalicyclic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

In adults, Ibuprofen from solid oral dosing is absorbed from the gastrointestinal tract and peak plasma concentrations occur about 1 to 2 hours after ingestion. Ibuprofen is primarily metabolised in the liver to 2-Hydroxyibuprofen and 2- carboxyibuprofen. Ibuprofen is 90 to 99% bound to plasma proteins and 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.

In limited studies, ibuprofen appears in the breast milk at very low concentrations.

Pseudoephedrine Hydrochloride is rapidly absorbed from the gasto-intestinal tract with peak plasma levels at 1-3 hours. It is partly metabolised in the liver like most sympathomimetics, but is mainly excreted unchanged in the urine.

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.

Tablet Core:

Maize starch

Starch, pregelinatised (maize)

Croscarmellose sodium

Colloidal anhydrous silica

Sodium laurilsulfate

Stearic acid

Tablet Coating:

Sucrose

Microcrystalline cellulose

Carnauba wax (yellow)

Opalux Butterscotch AS-3739:

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

Not Applicable

3 years

Do not store above 25°C.

uPVC/ Aluminium blister packs in cardboard cartons containing 2, 4, 10, 12, 20 and 24 tablets.

Not all pack sizes may be marketed.

No special requirements.

Pfizer Healthcare Ireland,

9 Riverwalk,

National Digital Park,

Citywest Business Campus,

Dublin 24

Ireland.

PA 0822/164/001

Date of first authorisation: 08 September 1994

Date of last renewal: 08 September 2009

February 2016.