SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

DUEXIS® 800 mg/26.6 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains: 800 mg ibuprofen and 26.6 mg famotidine. Excipient(s): Each tablet contains 12.7 mg of lactose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Blue oval film-coated tablet embossed with “HZT” on one side. Tablet length is 19 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

DUEXIS is indicated for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in patients who require regular treatment with high dose ibuprofen administered three times a day and who are at risk of developing non-steroidal anti-inflammatory drug (NSAID) associated gastric and/or duodenal ulcers.

DUEXIS should only be used where treatment with lower doses of ibuprofen or of other NSAIDs is not considered sufficient and where treatment with a proton pump inhibitor (PPI) is not considered appropriate.

4.2 Posology and method of administration

Posology in adults

The dose is 1 tablet (ibuprofen 800 mg / famotidine 26.6 mg) administered orally three times per day (TID). No more than three DUEXIS tablets should be taken daily, resulting in a maximum daily dose of 2400 mg ibuprofen and 80 mg famotidine.

DUEXIS must be taken three times a day. Sufficient dose levels of famotidine, which protects against gastrointestinal (GI) events, are only achieved with this TID dosing. There is a risk of sub-optimal gastro-protection if a dose is not taken.

Undesirable effects may be minimised by using the shortest duration necessary to control symptoms (see section 4.4). DUEXIS should only be used in patients who require regular treatment with high dose ibuprofen administered TID and where treatment with a PPI is not considered appropriate.

In patients not treated with an NSAID previously, a lower daily dose of ibuprofen or of another NSAID should be considered. When a total daily dose of 2400 mg of ibuprofen is not considered appropriate, alternative therapeutic regimens should be prescribed.

Treatment should be continued to achieve individual treatment goals, reviewed at regular intervals and discontinued if no benefit seen.

Method of administration

DUEXIS must be swallowed whole with water, and not split, chewed, or crushed. DUEXIS can be taken without regard to food.

Special populations

Patients with renal impairment

Ibuprofen and famotidine are known to be substantially excreted by the kidney therefore the risk of toxic reactions to DUEXIS may be greater in patients with impaired renal function. In patients with mild renal impairment DUEXIS should be used cautiously and renal function should be monitored closely.

DUEXIS is contraindicated in patients with moderate to severe renal impairment (see section 4.3 and 4.4).

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment DUEXIS should be used cautiously and hepatic function should be monitored closely.

Elderly (> 65 years)

The elderly are at an increased risk of the serious consequences of adverse reactions (see section 4.4). The patient should be monitored regularly for GI bleeding during NSAID therapy. DUEXIS should be used for the shortest possible duration. When a total daily dose of 2400 mg of ibuprofen is not considered appropriate, alternative therapeutic regimens should be prescribed.

Children (< 18 years)

DUEXIS is not recommended for use in children, due to a lack of data on safety and efficacy (see section 5.1).

4.3 Contraindications

•    Known hypersensitivity to ibuprofen, famotidine or to any of the excipients.

•    NSAID s are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other NSAIDs (see section 4.4).

•    Third trimester of pregnancy (see section 4.6).

•    Severe hepatic impairment.

•    Severe heart failure (see section 4.4).

•    Severe and moderate renal impairment (creatinine clearance of less than 50 ml/minute) (see section 4.4).

•    Active peptic ulceration (see section 4.4).

•    Gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders (see section 4.4).

•    History of hypersensitivity to other H₂-receptor antagonists. Cross sensitivity in H₂-receptor antagonists has been observed.

4.4 Special warnings and precautions for use

General

The use of DUEXIS with other concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided. DUEXIS can be used with low-dose acetylsalicylic acid (aspirin) (see also section 4.5).

Undesirable effects may be minimised by using DUEXIS for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

DUEXIS should be used in patients who require regular treatment with high dose ibuprofen administered TID and where treatment with a PPI is not considered appropriate. When a total daily dose of 2400 mg of ibuprofen is considered not appropriate, alternative therapeutic regimens should be prescribed.

DUEXIS must be taken three times a day. Sufficient dose levels of famotidine, which protects against GI events, are only achieved with this TID dosing. There is a risk of sub-optimal gastro-protection if a dose is not taken.

Risk-factors to develop NSAID related GI complications include high age, concomitant use of anticoagulants, corticosteroids, other NSAIDs including low-dose aspirin, debilitating cardiovascular disease, and a history of gastric and/or duodenal ulcers.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance. Monitoring of blood count and liver function is recommended, in addition to renal function (see renal effects sub-section below).

Elderly

Ibuprofen: The elderly have an increased frequency of adverse reactions to NSAIDs especially GI bleeding, and perforation, which may be fatal (see sections 4.2).

Gastrointestinal effects

Ibuprofen: 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, in patients with current Helicobacter pylori infection or erosive oesophagitis and in the elderly. DUEXIS is contraindicated in patients with active peptic ulceration (see section 4.3).

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 NSAIDs with 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 DUEXIS, the treatment should be withdrawn (see section 4.3).

NSAIDs should be given with care to patients with a history of GI disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

Famotidine: In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with famotidine may alleviate symptoms and delay diagnosis.

Dyspepsia could still occur despite the addition of famotidine to the combination tablet. Ulcer complications such as bleeding, perforation and obstruction were not studied in the DUEXIS trials

(see section 5.1).

Decreased gastric acidity due to any means including H₂-receptor antagonists, increases gastric counts of bacteria normally present in the GI tract.

Cardiovascular and cerebrovascular effects

Ibuprofen: Appropriate monitoring and advice are 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 a high dose (2400 mg daily) and in long term treatment, may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration of the individual clinical circumstances. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal effects

Ibuprofen: The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Renal function should be closely monitored in these patients (see sections 4.2 and 4.5).

Famotidine: Famotidine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Hepatic effects

Borderline elevations of one or more liver tests may occur in patients taking NSAIDs. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

Haematological effects

Ibuprofen: Patients who have coagulation disorders, are receiving anticoagulation therapy or are receiving drug therapy that interferes with haemostasis should be carefully observed if ibuprofen-containing products are administered (see section 4.5).

Ibuprofen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

When active and clinically significant bleeding from any source occurs in patients receiving DUEXIS, the treatment should be withdrawn.

Eye effects

Ibuprofen: Because of adverse eye findings in animal studies with NSAIDs, it is recommended that an ophthalmic examination be carried out if any change or disturbance in vision occurs.

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

Dermatological effects

Ibuprofen:    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 the highest risk of having these reactions early in the course of therapy, the onset of the reaction occurring within the first month of treatment in the majority of cases. DUEXIS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Anaphylactic (anaphylactoid) reactions

Ibuprofen:    Hypersensitivity reactions may occur in susceptible individuals.

Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other NSAIDs or ibuprofen

containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Respiratory disorders

Ibuprofen: Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Inflammation

Ibuprofen: The anti-pyretic and anti-inflammatory activities of ibuprofen may reduce fever and other signs of inflammation, thereby diminishing their utility as diagnostic signs.

Female fertility

The use of DUEXIS, as with any drug known to inhibit cyclooxygenase / prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of DUEXIS should be considered (see section 4.6).

DUEXIS contains lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Co-administration of ibuprofen and famotidine orally did not alter the pharmacokinetics of ibuprofen or famotidine.

There is some evidence that CYP2C8 and CYP2C9 polymorphisms influence the pharmacokinetics and metabolism of ibuprofen.

Concomitant use not recommended

Other analgesics including cyclooxygenase-2 selective inhibitors:

The concomitant use of DUEXIS and other NSAIDs should be avoided, as this may increase the risk of adverse effects (see section 4.4).

Aspirin

DUEXIS can be administered with low-dose aspirin (< 325 mg/day) therapy. Concomitant use with higher doses should be avoided. While clinical trials with DUEXIS did not show increased toxicity when DUEXIS was given concomitantly with low-dose aspirin (see section 5.1), numbers of patients exposed and experience with the combination given long-term (>6 months) is limited. Patients receiving DUEXIS with low-dose aspirin should be considered to be at greater risk of NSAID related GI complications and should be monitored for symptoms and signs of GI ulceration (see sections 4.4 and 4.8).

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 suggest 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 with precaution:

Anti-coagulants

NSAIDs may enhance the effects of anti-coagulants (see section 4.4).

Antihypertensives, including ACE-Inhibitors NSAIDs may diminish the effect of these drugs.

Selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4).

Anti-platelet agents

Increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides

NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma glycoside levels.

Corticosteroids

Increased risk of GI ulceration or bleeding (see section 4.4).

Cyclosporin

Increased risk of nephrotoxicity.

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. During concomitant therapy with DUEXIS, the patient should be observed closely for signs of renal failure (see section 4.4), as well as to assure diuretic efficacy.

Lithium

There is evidence with ibuprofen for potential increases in plasma levels of lithium.

Methotrexate

There is a potential with ibuprofen for an increase in plasma methotrexate.

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.

Atazanavir

Famotidine may decrease the absorption of atazanavir, due to an increase in gastric

pH.

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.

Anti-fungals

The absorption of ketoconazole and itraconazole could be reduced by concomitant use with famotidine. Ketoconazole should be given 2 hours before DUEXIS administration.

Antacids

Antacids may decrease the absorption of famotidine and lead to lower plasma concentrations of famotidine. DUEXIS should therefore be taken 1-2 hours before the application of an antacid.

Probenecid

The administration of probenecid can delay the elimination of famotidine. Concomitant use of probenecid and famotidine should be avoided.

Sucralfate

The concomitant use of sucralfate should be avoided within two hours of the famotidine dose.

4.6 Fertility, Pregnancy and lactation

Pregnancy

DUEXIS is contraindicated during the third trimester of pregnancy (see section 4.3). DUEXIS should be used during the first and second trimester of pregnancy only if the potential benefit justifies the potential risk to the foetus.

Animal reproduction studies have not been conducted with DUEXIS.

Ibuprofen:

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. 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). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Famotidine:

Famotidine is not recommended for use in pregnancy. Lactation

Ibuprofen:

In the limited studies so far available, ibuprofen appears in the breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

Famotidine:

Famotidine is secreted in human milk.

Because of the potential for serious adverse reactions in nursing infants from DUEXIS, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Fertility

The use of NSAIDs like ibuprofen may impair female fertility. The use of DUEXIS is not recommended in women attempting to conceive (see section 4.4).

4.7 Effects on ability to drive and use machines

In clinical trials with DUEXIS, there has been no observed impairment of the ability to drive or operate machinery.

When taking famotidine, a component of DUEXIS, some patients have experienced adverse reactions such as dizziness and headache. Patients should be informed that they should avoid driving vehicles or operating machinery or doing activities which require prompt vigilance if they experience these symptoms (see section 4.8 undesirable effects).

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high dose (2400 mg daily), and in long term treatment may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Gastrointestinal disorders: 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, 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: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome).

DUEXIS

The safety of DUEXIS was evaluated in 1022 patients in controlled clinical studies, including 508 patients treated for at least 6 months and 107 patients treated for approximately 1 year. Provided below is the incidence of adverse drug reactions considered related to DUEXIS reported in controlled clinical studies where DUEXIS was administered to more than 1000 subjects. The most frequent adverse events are gastrointestinal in nature.

System Organ Class	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)
Infections and infestations	upper respiratory tract infection, bronchitis, nasopharyngitis, sinusitis, influenza, urinary tract infection	viral, fungal and bacterial infections
Blood and lymphatic system disorders	anaemia		haemorrhagic diathesis, neutropenia
Immune system disorders		Hypersensitivity reactions (including systemic reactions and bronchospasm)
Endocrine disorders		hypothyroidism
Metabolism and nutrition disorders		hyperlipidaemia, anorexia, hypercholesterolaemia, dehydration, electrolyte disturbances, blood glucose metabolism disturbances hypocalcaemia
Psychiatric disorders	insomnia	depression, anxiety, schizoaffective disorder	aggression, hallucination
Nervous system disorders	headache, dizziness	migraine, somnolence, syncope, restless legs syndrome, neuralgia, paraesthesia, sciatica, transient ischaemic attack	ageusia, dysgeusia
Eye disorders		conjunctivitis, vision blurred

System Organ Class	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)
Ear and labyrinth disorders		tinnitus, vertigo
Cardiac disorders			palpitations, atrioventricular block second degree
Vascular disorders	hypertension
Respiratory, thoracic and mediastinal disorders	cough, pharyngolaryngeal pain	asthma, dyspnoea, bronchospasm	allergic sinusitis, increased upper airway secretion, pleural fibrosis, pleurisy
Gastrointestinal disorders	nausea, dyspepsia, diarrhoea, constipation, abdominal pain upper, vomiting, gastrooesophageal reflux disease, stomach discomfort, abdominal pain, flatulence	gastritis (including rare haemorrhagic courses), abdominal distension, abdominal tenderness, dry mouth, abdominal discomfort, eructation, haematochezia, rectal haemorrhage, oesophagitis, irritable bowel syndrome	aphthous stomatitis, colitis, duodenitis, dysphagia, lip swelling, mouth ulceration, oesophageal ulcer, proctitis ulcerative, retching
Hepatobilary disorders		cholecystitis, abnormal liver function tests including transaminases increased	blood alkaline phosphatase increased
Skin and subcutaneous tissue disorders		pruritus, rash, dermatitis, urticaria, alopecia, dry skin, eczema, skin lesion	photosensitivity reaction, swelling face
Musculoskeletal and connective tissue disorders	back pain, pain in extremity, arthralgia	musculoskeletal pain, joint swelling, myalgia, tendonitis
Renal and urinary disorders		renal failure, haematuria, fluid retention, blood urea increase, creatinine increased
Reproductive system and breast disorders		prostatitis, menorrhagia
General disorders and administration site conditions	oedema peripheral	chest pain, fatigue, influenza like illness, pyrexia, oedema, pain, asthenia, thirst

System Organ Class	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)
Investigations		weight changes, blood calcium decreased, blood chloride increased

Ibuprofen

The list of the following adverse effects relates to those experienced with marketed ibuprofen. In chronic conditions, under long-term treatment, additional adverse effects may occur. The most commonly-observed adverse events are gastrointestinal in nature.

System Organ Class	Very common (>1/10)	Commo n (>1/100 to <1/10	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Blood and lymphatic system disorders				decrease of haemoglobin and haematocrit levels, inhibition of thrombocyte aggregation, prolonged bleeding time	haematopoieti c disorders (anaemia, hemolytic anemia, aplastic anemia), neutropenia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis. First signs may be: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding

System Organ Class	Very common (>1/10)	Commo n (>1/100 to <1/10	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Immune system disorders			hypersensitivit y reactions such as urticaria, pruritus, exanthema, asthma attacks (sometimes with concomitant hypotension)		severe hypersensitivity reactions, such as: facial edema, swelling of the tongue, pharyngeal swelling with obstruction of the airway, dyspnea, tachycardia, sudden hypotension which may lead to life-threatening shock
Psychiatri c disorders		agitation 5 insomni a, irritabili ty, anxiety		depression, confusion, hallucination s	nervousness

System Organ Class	Very common (>1/10)	Commo n (>1/100 to <1/10	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Nervous system disorders		headach e, altered state of conscio usness, vertigo, fatigue,			aseptic meningitis (especially in patients with existing autoimmune disorders such as SLE, mixed connective tissue disease) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation; see section 4.4), stroke, optic neuritis, paraesthesia
Eye disorders			blurred vision	toxic amblyopia
Ear and labyrinth disorders					Tinnitus, hearing impaired
Cardiac disorders					cardiac failure, angina pectoris, myocardial infarction, palpitations
Vascular disorders					hypertension
Respirato thoracic and mediastin al disorders			rhinitis, bronchospasm		Asthma, dyspnoea

System Organ Class	Very common (>1/10)	Commo n (>1/100 to <1/10	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Gastroint estinal disorders	gastrointes -tinal disorders such as heartburn, dyspepsia, abdominal pain and nausea, vomiting, flatulence, diarrhoea, constipatio n	gastroint es-tinal ulcers, sometim es with bleeding and perforati on, occult bleeding , which may lead to anaemia 5 melaena 5 hemato ma, ulcerativ e stomatiti s, colitis, aggravat ed inflamm atory bowel disease, complic ations of the colonic divertic ula (perforat ion, fistulas)	Gastritis, abdominal distension		peptic ulcer, perforation or gastrointestina l haemorrhage, melaena, haematemesis (sometimes fatal, particularly in the elderly), exacerbation of ulcerative colitis and Crohn’s disease, oesophagitis, pancreatitis, intestinal strictures

System Organ Class	Very common (>1/10)	Commo n (>1/100 to <1/10	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Hepatobil iary disorders				elevated transminases and alkaline phosphatases	hepatic impairment, liver damage, especially with longterm treatment, liver failure, acute hepatitis, jaundice
Skin and subcutane ous tissue disorders			Photosensitivit y, skin rashes		severe forms of skin reaction (erythema multiforme, exfoliative dermatitis, blisterforming reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, necrotizing fasciitis
Renal and urinary disorders			development of oedema, especially in patients with hypertension or renal impairment, nephrotic syndrome, interstitial nephritis which may be associated with renal failure	elevation of urea level in the blood	renal papillary necrosis especially with longterm treatment, acute renal failure, haematuria, proteinuria

Famotidine

The list of the following adverse effects relates to those experienced with marketed famotidine. The following adverse experiences have been reported in patients taking famotidine during clinical trials and through post marketing reports.

System Organ Class	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Blood and lymphatic disorders				pancytopenia, leucopenia, thrombocytopenia, agranulocytosis, neutropenia
Immune system disorders				hypersensitivity reactions (anaphylaxis, angioneurotic oedema, bronchospasm)
Metabolism and nutrition disorders		anorexia
Psychiatric disorders				reversible psychic disturbances including depression, anxiety disorders, agitation, disorientation, confusion and hallucinations, reduced libido, insomnia
Nervous system disorders	headache, dizziness	taste disorder		convulsions, grand mal seizures (particularly in patients with impaired renal function), paraesthesia, somnolence

System Organ Class	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,000 to <1/1,000)	Very rare (<1/10,000)
Cardiac disorders				A-V block with H2 receptor antagonists administered intravenously, prolonged QT interval (particularly in patients with impaired renal function)
Respiratory, thoracic, and mediastinal disorders				interstitial pneumonia sometimes fatal
Gastrointestinal disorders	constipation, diarrhoea	dry mouth, nausea and/or vomiting, abdominal discomfort or distension, flatulence
Hepatobiliary disorders				liver enzyme abnormalities, hepatitis, cholestatic jaundice
Skin and subcutaneous tissue disorders		rash, pruritus, urticaria		alopecia, Stevens Johnson Syndrome/toxic epidermal necrolysis sometimes fatal
Musculoskeletal and connective tissue disorders				arthralgia, muscle cramps
Reproductive system and breast disorders				impotence
General disorders and administration site conditions		fatigue		chest tightness

4.9 Overdose

No data are available with regard to overdose of DUEXIS. Findings related to the individual active substances are listed below.

Ibuprofen:

Symptoms:    Symptoms include headache, nausea, vomiting, epigastric pain,

gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, drowsiness, dizziness, tinnitus, fainting, depression of the CNS and respiratory system, coma, occasionally convulsions and rarely, loss of consciousness. In cases of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures: Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

Famotidine:

The adverse reactions in overdose cases with famotidine are similar to the adverse reactions encountered in normal clinical experience (see section 4.8). Patients with Zollinger-Ellison syndrome have tolerated doses up to 800 mg daily for more than a year without the development of significant adverse effects. The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed. There is no specific antidote.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: NSAID, ATC code: M01AE01, associated with a H₂ receptor antagonist.

Mechanism of action

DUEXIS is an immediate release, fixed dose combination tablet of ibuprofen and famotidine.

Ibuprofen possesses analgesic, anti-inflammatory and antipyretic activities. Its mode of action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.

Famotidine is a competitive inhibitor of histamine H₂-receptors.    The primary

clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

Systemic effects of famotidine in the CNS, cardiovascular, respiratory, or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.

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 400 mg was taken within 8 hours before or within 30 min after immediate release aspirin dosing (81 mg), a decreased effect of aspirin 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.

Clinical safety and efficacy

The safety and efficacy of DUEXIS was evaluated in two multicentre, double-blind, active-controlled, randomised, 24-week studies for the reduction of the risk of development of ibuprofen-associated, upper gastrointestinal ulcers. Patients who were expected to require daily administration of an NSAID for at least the coming 6 months for conditions such as the following: osteoarthritis, rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome and chronic soft tissue pain were enrolled into the studies. All patients enrolled tested negative for Helicobacter pylori.

Patients were assigned randomly, in approximately a 2:1 ratio, to treatment with either DUEXIS or ibuprofen (800 mg) three times a day. A total of 1533 patients, 1022 patients on DUEXIS and 511 patients on ibuprofen alone, were enrolled and ranged in age from 39 to 80 years (median age 55 years) with 68% females. Race was distributed as follows: 79% Caucasian, 17% Black, and 4% other.

The proportion of patients with endoscopic evidence of an upper gastrointestinal ulcer at week 24 is presented in Table 1.

Table 1:    Proportion of Patients Who Developed at Least One Upper GI

Ulcer during the 24-Week Treatment Period

Study	Number of Patients a (N)	Treatment Group	Proportionb (%) of Patients with Upper GI Ulcer c	P-valued
HZ-CA-301	380	DUEXIS	13.8%	0.0304
	190	Ibuprofen	22.6%
HZ-CA-303	550	DUEXIS	14.7%	0.0002
	262	Ibuprofen	29.1%

^a Patients with at least one post baseline endoscopy from week 6.7 through week 26.7

^b Week 24 proportions are estimated from a life table analysis that included a covariate for treatment

^c Unequivocal depth and >3 mm in diameter

^d    P-value is the difference of the Week 24 estimated proportions of subjects

developing at least one upper gastrointestinal ulcer.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with DUEXIS in all subsets of the paediatric population in chronic pain due to arthropathies. See 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Ibuprofen and famotidine are rapidly absorbed after a single dose administration of DUEXIS. Mean C_max values for ibuprofen are 45 pg/mL and are reached approximately 1.9 hours after oral administration of DUEXIS. The C_max and AUC_0-24_hours values for the 800 mg of ibuprofen contained in a DUEXIS tablet are bioequivalent to the values for 800 mg of ibuprofen administered alone. C_max values for famotidine were 61 ng/mL and are reached at approximately 2 hours after oral administration of DUEXIS.

A food-effect study involving administration of DUEXIS to healthy volunteers under fasting conditions and with a high-fat meal indicated that the bioavailability of the ibuprofen and famotidine components is not affected by food.

Ibuprofen is extensively bound to plasma proteins. Fifteen to 20% of famotidine in plasma is protein bound.

Ibuprofen is present in this product as a racemate, and following absorption it undergoes interconversion in the plasma from the R-isomer to the S-isomer. Both the R- and S- isomers are metabolized to two primary metabolites: (+)-2-4'-(2-hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2-carboxypropyl) phenyl propionic acid, both of which circulate in the plasma at low levels relative to the parent. The only metabolite of famotidine identified in man is the S-oxide.

Ibuprofen is eliminated from the systemic circulation with half-life (ti_/2) values 2 hours following administration of a single dose of DUEXIS. Ibuprofen is rapidly metabolised and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. Studies have shown that following ingestion of ibuprofen, 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite A (25%), (+)-2-[p-(2-hydroxymethyl-propyl) phenyl] propionic acid and metabolite B (37%), (+)-2-[p-(2-carboxypropyl)phenyl] propionic acid; the percentages of free and conjugated ibuprofen were approximately i% and i4%, respectively.

Famotidine is eliminated from the systemic circulation with t_1/2 values 3 hours following administration of a single dose of DUEXIS. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound.

Renal Impairment: There is a close relationship between creatinine clearance values and the elimination t_1/2 of famotidine, which is a component of DUEXIS. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 ml/min, the elimination t_1/2 of famotidine may exceed 20 hours. DUEXIS is contraindicated in moderate and severe renal failure (creatinine clearance < 50mL/min) (see section 4.3).

5.3 Preclinical safety data

No non-clinical data on the combination of the active substances are available. There are no known interactions between ibuprofen and famotidine that would indicate any novel or synergistic adverse pharmacology, pharmaco/toxicokinetics, toxicity, physical/chemical interaction or tolerability issues as a result of their combination.

Ibuprofen:

In acute animal toxicity studies, ibuprofen did not show particular toxicity. In subchronic and chronic toxicity studies, gastrointestinal damages and ulcers were seen. Ulcers were noted in animal studies in mice at doses of 300 mg/kg, in rats at doses of 180 mg/kg and in dogs at doses of 8mg/kg. These findings should be seen in the context of systemic effects and the higher susceptibility of dogs is explained by the high and long term plasma levels in this species.

Famotidine:

No relevant information.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core Tablet

Microcrystalline cellulose Lactose anhydrous Croscarmellose sodium Silica, colloidal anhydrous Magnesium stearate Opadry white contains:

Titanium Dioxide (E171)

Hypromellose Macrogol 400 Polysorbate 80

Outer Tablet

Microcrystalline cellulose Povidone

Magnesium stearate Silica, colloidal anhydrous Croscarmellose sodium Film-coating Opadry II blue contains:

Poly (Vinyl Alcohol)

Titanium Dioxide (E171)

Macrogol 3350 Talc

Indigo Carmine Aluminium Lake (E132) Brilliant Blue FCF Aluminium Lake (E133)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 Years.

10