Indometacin Capsules BP 50mg

1. Name Of The Medicinal Product

Indometacin Capsules BP 50mg

2. Qualitative And Quantitative Composition

Indometacin BP 50.00mg

3. Pharmaceutical Form

Capsules

4. Clinical Particulars

4.1 Therapeutic Indications

Indometacin is indicated for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and other rheumatic disorders. It is indicated in the treatment of acute gout.

Indometacin is also indicated in inflammation, pain and oedema following orthopaedic procedures and the treatment of pain and associated symptoms of primary dysmenorrhoea.

4.2 Posology And Method Of Administration

Route of administration: Oral

Recommended Dose and Dosage Schedules:

The usual dose is:-

Adults:

50-100mg increasing to 150-200mg daily in divided doses.

Elderly patients:

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Children:

Contra-indicated, as paediatric dosage is not established.

To be taken preferably with or after food.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

4.3 Contraindications

Contraindicated in children as a paediatric dose has not been established.

Contraindicated in patients with an active peptic ulcer, gastro intestinal ulceration or bleeding, a recurrent history of gastro-intestinal lesions, renal disease, psychiatric disorders, epilepsy or parkinsonism.

Hypersensitivity to any of the constituents.

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 non-steroidal anti-inflammatory drugs.

Severe hepatic, renal and cardiac failure (See section 4.4 – Special warnings and precautions for use).

During the last trimester of pregnancy (See section 4.6 – Pregnancy and lactation).

Active or previous peptic ulcer.

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

Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors

(See section 4.5 Interactions). Severe heart failure

4.4 Special Warnings And Precautions For Use

Concurrent administration of Aspirin or other NSAID's should be avoided as the incidence of side effects are enhanced without additional therapeutic benefit.

Indometacin should be administered with caution to patients with impaired hepatic or cardiac function and to those with bleeding disorders, epilepsy, parkinsonism or psychiatric disorders.

Use with caution in patients with conditions predisposing to fluid retention e.g. cardiac dysfunction and hypertension. Fluid retention may occur, rarely precipitating congestive heart failure in elderly patients.

Elderly patients may be especially susceptible to the toxic effects of Indometacin.

Use with caution in patients with existing but controlled infection as Indometacin may mask the signs and symptoms of infection.

May impair ability to drive or operate machinery. In chronic rheumatoid disease opthalmological examinations at periodic intervals are recommended.

Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia). Use cautiously in patients with coagulation defects as bleeding time may be prolonged. False negative results in the dexamethasone suppression test (DST) in patients treated with Indometacin have been reported.

In all patients:

Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration.

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 – Posology and administration).

Respiratory disorders:

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

Cardiovascular, Renal and Hepatic Impairment:

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, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (See also section 4.3 – Contraindications).

Caution in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Gastrointestinal bleeding,

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.

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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 - Interactions).

When GI bleeding or ulceration occurs in patients receiving Indometacin, the treatment should be withdrawn.

NSAID's 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).

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 asceptic meningitis (See section 4.8 – Undesirable effects).

Female fertility:

The use of Indometacin 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 Indometacin should be considered.

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

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for Indometacin.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Indometacin after careful consideration.

Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Indometacin may cause blocking of the Furosemide-induced increase in plasma renin activity.

The risk of hyperkalaemia may be increased when used with potassium sparing diuretics. There have been occasional reports of decreased renal function when Indometacin was given with triamterene.

Probenecid delays excretion of Indometacin and increases the risk of toxicity.

Co-administration of Diflunisal increases the plasma level of Indometacin by about a third with concomitant decrease in renal clearance. Fatal gastrointestinal haemorrhage has occurred. The combination should not be used.

Other analgesics: Avoid concomitant use of two or more NSAID's (including aspirin) as this may increase the risk of adverse effects (see section 4.3 Contraindications).

Anti-hypertensives: Reduced anti-hypertensive effect.

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

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

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

Corticosteroids: Increased risk of GI bleeding (See section 4.4 Special warnings and precautions for use).

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4 Special warnings and precautions for use).

Quinolone antibiotics: Animal data indicate that NSAID's can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAID's and quinolones may have an increased risk of developing convulsions.

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

4.6 Pregnancy And Lactation

Pregnancy:

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 – Contraindications). 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.

Lactation:

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding. See Section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

The commonest adverse effects occurring with Indometacin are gastrointestinal disturbances (including diarrhoea, nausea and abdominal pain), headache and dizziness.

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. 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 Special warnings and precautions for use), have been reported following administration. Less frequently, gastritis has been observed.

Hypersensitivity: Hypersensitivity reactions (including angio-oedema and bronchospasm) have been reported following treatment with NSAID's. 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, pruritis, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including toxic epidermal necrolysis, erythema multiforme).

Cardiovascular: Oedema has been reported in association with NSAID treatment.

Other adverse events reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, renal failure and papillary necrosis.

Hepatic: abnormal liver function, hepatitis and jaundice.

Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of asceptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4) depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia, leucopenia and purpura.

Dematological: photosensitivity.

Other adverse effects include light headedness, insomnia , psychiatric disturbances, syncope, convulsions, coma, blurred vision and other ocular effects, oedema, weight gain, hypertension, haematuria, Stevens Johnson syndrome and alopecia.

Epistaxis, hyperglycaemia, hyperkalaemia and vaginal bleeding have been reported.

Hypersensitivity reactions may also occur in Aspirin-sensitive patients.

Indometacin may provoke or worsen asthma.

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

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses 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).

4.9 Overdose

(a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely, diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

(b) Therapeutic measure

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 of prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Indometacin is a non-steroidal anti-inflammatory agent with analgesic and anti-pyretic properties. It inhibits prostaglandin synthesis. It has the property of stabilising the lysosome membrane rendering it less susceptible to breakdown and this may contribute to its anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Indometacin is readily absorbed from the gastro-intestinal tract; peak plasma concentrations are reached one half to two hours after a dose. More than 90% is bound to plasma proteins. It is metabolised in the liver and kidneys and is excreted in the urine, mainly as the glucuronide, and to a much lesser extent in the faeces. Indometacin is also excreted in milk.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose 110# BP

Starch (Maize) BP

Silicon Dioxide USP

Magnesium Stearate (E572) BP

Capsule shell components:

Erythrosine (E127)

Quinoline Yellow (E104)

Titanium Dioxide (E171)

6.2 Incompatibilities

None stated.

6.3 Shelf Life

3 years - polypropylene containers.

2 years - Blister strips.

6.4 Special Precautions For Storage

Keep tightly closed, in a dry place at or below 25^oC.

6.5 Nature And Contents Of Container

White polypropylene container with tamper evident closure.

1000, 500, 250, 100, 84, 70, 56, 42, 28, 21, 15 and 14 capsules.

Blister Strips: 84, 70, 56, 42, 28, 21, 15 and 14 capsules

6.6 Special Precautions For Disposal And Other Handling

Nothing stated.

7. Marketing Authorisation Holder

Goldshield Pharmaceuticals Limited

NLA Tower, 12-16 Addiscombe Road

Croydon, Surrey, CR0 0XT

United Kingdom

8. Marketing Authorisation Number(S)

PL 12762/0426

9. Date Of First Authorisation/Renewal Of The Authorisation

14/05/91

10. Date Of Revision Of The Text

21/02/2007

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Ibuleve Speed Relief Gel

1. Name Of The Medicinal Product

IBULEVE™ SPEED RELIEF GEL

2. Qualitative And Quantitative Composition

Ibuprofen 5.0% w/w.

Excipient

Propylene glycol 2.0% w/w

For a full list of excipients, see section List of Excipients.

3. Pharmaceutical Form

Non-greasy, fragrance-free, clear aqueous-alcoholic gel.

4. Clinical Particulars

4.1 Therapeutic Indications

For fast local relief of rheumatic pain, muscular aches, pains or swellings, such as strains, sprains and sports injuries.

4.2 Posology And Method Of Administration

Adults, including the elderly, and children over 12 years.

Apply only enough gel to thinly cover the affected area, and gently massage well into the skin, until completely absorbed. The dose is 1.0 to 2.5 g gel (quantified by appropriate means), applied up to three times daily, with individual doses administered at least 4 hours apart. Patients should not apply more than approximately 7.5 g of gel (quantified appropriately on the labelling) in any 24 hour period. Wash hands after use unless treating them. Not to be used with occlusive dressings.

Unless recommended by a doctor, advice should be sought about continued treatment if symptoms persist for more than 2 weeks.

Do not use in children under 12 years of age except on the advice of a doctor.

4.3 Contraindications

Not to be used if allergic to any of the ingredients, or in cases of hypersensitivity to aspirin, ibuprofen or related painkillers (including when taken by mouth), especially where associated with a history of asthma, rhinitis or urticaria. Not to be used on broken or damaged skin.

4.4 Special Warnings And Precautions For Use

Keep away from the eyes and mucous membranes.

Oral NSAID's, including ibuprofen, can sometimes be associated with renal impairment, aggravation of active peptic ulcers, and can induce allergic bronchial reactions in susceptible asthmatic patients. Although systemic absorption of topically applied ibuprofen is less than for oral dosage forms, these complications can occur in rare cases. For these reasons, patients with asthma, an active peptic ulcer or a history of kidney problems, should seek medical advice before using the gel, as should patients already taking other painkillers.

Patients should seek medical advice if symptoms worsen or persist.

The excipient propylene glycol may on rare occasions cause skin irritation in sensitive people. Keep out of the reach and sight of children.

For external use only.

The label will state: Do not exceed the stated dose. Not recommended for children under 12 years. For external use only. Not to be used during pregnancy or breast feeding. Do not use if you are allergic to any of the ingredients or have experienced problems with aspirin, ibuprofen or related painkillers (including when taken by mouth). If symptoms persist consult your doctor or pharmacist. Keep out of the reach and sight of children. Patients with asthma, an active peptic ulcer or a history of kidney problems should consult their doctor before use, as should patients already taking aspirin or other painkillers.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Where aspirin or other NSAID tablets are taken concurrently, it is important to bear in mind that these may increase the incidence of undesirable effects.

4.6 Pregnancy And Lactation

Not to be used during pregnancy or lactation. Although no teratogenic effects have been demonstrated, ibuprofen should be avoided during pregnancy. The onset of labour may be delayed, and the duration of labour increased. Ibuprofen appears in breast milk in very low concentrations, but is unlikely to affect breast fed infants adversely.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Very rarely, susceptible patients may experience the following side effects with ibuprofen, but these are extremely uncommon when ibuprofen is administered topically. If they occur, treatment should be discontinued:-

Hypersensitivity: hypersensitivity reactions have been reported following treatment with ibuprofen. 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, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Renal: renal impairment can occur in patients with a history of kidney problems.

Gastrointestinal: side effects such as abdominal pain and dyspepsia have been reported.

4.9 Overdose

Any overdose with a topical presentation of ibuprofen is extremely unlikely.

Symptoms of severe ibuprofen overdosage (eg following accidental oral ingestion) include headache, vomiting, drowsiness and hypotension. Correction of severe electrolyte abnormalities should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: M02A A13, Antiinflammatory preparations, non-steroids for topical use.

The gel is for topical application. It contains the active ingredient, ibuprofen, a phenylpropionic acid derivative which exerts its anti-inflammatory and analgesic effects directly in inflamed tissues underlying the site of application, mainly by inhibiting prostaglandin biosynthesis.

Because it is formulated in an aqueous/alcoholic gel, the preparation also exerts a soothing and cooling effect when applied to the affected area.

5.2 Pharmacokinetic Properties

Specially formulated for external application, the active ingredient penetrates through the skin rapidly and extensively (approximately 22% of a finite dose within 48 hours), achieving high, therapeutically relevant local concentrations in underlying soft tissues, joints and the synovial fluid, whilst producing plasma levels that are unlikely to be sufficient to cause any systemic side-effects, other than in rare individuals who are hypersensitive to ibuprofen.

Furthermore, there do not appear to be any appreciable differences between the oral and topical routes of administration regarding metabolism or excretion.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars

6.1 List Of Excipients

IMS; Carbomer; Propylene Glycol; Diethylamine; Purified Water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Membrane sealed, epoxy resin coated, collapsible aluminium tube, fitted with a screw cap containing 40 g of product.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK

8. Marketing Authorisation Number(S)

00173/0060.

9. Date Of First Authorisation/Renewal Of The Authorisation

12 January 2009.

10. Date Of Revision Of The Text

October 2010.

Ibuspray

1. Name Of The Medicinal Product

IBUSPRAY™

2. Qualitative And Quantitative Composition

Ibuprofen 5.0% w/w.

3. Pharmaceutical Form

Cutaneous spray solution.

Clear, colourless, fragrance-free, aqueous-alcoholic topical spray.

4. Clinical Particulars

4.1 Therapeutic Indications

For the topical treatment of backache, rheumatic and muscular pain, sprains, strains, and neuralgia. Ibuspray is also indicated for symptomatic relief of pain due to non-serious arthritic conditions.

4.2 Posology And Method Of Administration

Hold the bottle upright or upside down and spray approximately 4 inches to 6 inches away from the skin. After every 2 to 3 sprays, gently massage the preparation into the skin, spreading the product over a wide area around the affected site. The exact amount to be applied will vary, depending on the extent and severity of the condition, but it should normally be sufficient to apply 5 to 10 sprays (1 to 2 ml). This amount may be repeated three to four times daily, or more often if required. Do not use excessively. Hands should be washed after use, unless treating them.

Treatment should not normally continue for more than a few weeks, unless recommended to do so by a doctor.

The same dosage and dosage schedule applies to all age groups, although Ibuspray is not normally recommended for use on children below the age of 12 years unless instructed by their doctor.

4.3 Contraindications

Not to be used in cases of sensitivity to any of the ingredients, particularly if asthmatic or suffer from rhinitis or urticaria, and have previously shown hypersensitivity to aspirin or ibuprofen or related painkillers. Not to be used on broken skin.

4.4 Special Warnings And Precautions For Use

This product is flammable. Do not spray near flames, electric heaters or similar objects. Seek medical advice if symptoms worsen or persist. Oral NSAIDs, including ibuprofen, can sometimes be associated with renal impairment, aggravation of active peptic ulcers, and can induce allergic bronchial reactions in susceptible asthmatic patients. Although the systemic absorption of topically applied ibuprofen is much less than from oral dosage forms, these complications can occur in rare cases. For these reasons, patients with an active peptic ulcer, a history of kidney problems, asthma or intolerance to aspirin or ibuprofen should seek medical advice before using Ibuspray.

Keep away from the eyes and mucous membranes. For external use only.

The label will include statements to the following effect:

If symptoms persist, consult your doctor or pharmacist.

Do not use if sensitive to any of the ingredients, particularly if asthmatic, suffer from rhinitis or urticaria and have previously shown hypersensitivity to aspirin, ibuprofen or related painkillers.

Consult your doctor before use if you are taking aspirin or other painkillers.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Concurrent aspirin or other NSAIDs may result in an increased incidence of undesirable effects.

4.6 Pregnancy And Lactation

Do not use during pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Very rarely, susceptible patients may experience the following side effects with ibuprofen, but these are extremely uncommon when ibuprofen is administered topically. If they occur, treatment should be discontinued:-

Hypersensitivity: hypersensitivity reactions have been reported following treatment with ibuprofen. 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, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Renal: renal impairment can occur in patients with a history of kidney problems.

Gastrointestinal: side effects such as abdominal pain and dyspepsia have been reported.

4.9 Overdose

Not applicable. Any overdose with a topical presentation of ibuprofen is unlikely.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuspray is a topical preparation which has anti-inflammatory and analgesic properties. It contains the active ingredient, ibuprofen, which exerts its effects directly in inflamed tissues underlying the site of application, mainly by inhibiting prostaglandin biosynthesis. Because it is formulated in an evaporative aqueous/alcoholic solution, Ibuspray also exerts a soothing and cooling effect when applied to the affected area.

5.2 Pharmacokinetic Properties

Specially formulated for external application, the active ingredient penetrates through the skin rapidly and extensively, achieving high, therapeutically relevant local concentrations in underlying soft tissues, joints and synovial fluid, whilst producing plasma levels that are unlikely to be sufficient to cause any systemic side effects, other than in rare individuals who are hypersensitive to ibuprofen. Furthermore, there do not appear to be any appreciable differences between the oral and topical routes of administration regarding metabolism or excretion of ibuprofen.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

IMS; Macrogol 300; Cetomacrogol 1000; Purified Water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

100 ml plastic bottle incorporating a controlled dose spray pump dispenser and overcap. This is supplied as an original pack (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/0150.

9. Date Of First Authorisation/Renewal Of The Authorisation

11 August 2008.

10. Date Of Revision Of The Text

October 2007.

Ibumousse

1. Name Of The Medicinal Product

IBUMOUSSE™

2. Qualitative And Quantitative Composition

Ibuprofen 5.0% w/w.

3. Pharmaceutical Form

Non-greasy, fragrance-free, white aqueous cutaneous foam.

4. Clinical Particulars

4.1 Therapeutic Indications

For backache, rheumatic and muscular pain, and neuralgia. Ibumousse is also indicated for symptomatic relief of pain due to non-serious arthritic conditions.

4.2 Posology And Method Of Administration

Shake container before use. Hold container upright, then press nozzle to dispense the mousse into the palm of your hand. Gently massage the mousse into and around the affected areas until absorbed. The exact amount to be applied will vary, depending on the extent and severity of the condition, but it should normally be sufficient to apply 1 to 2 g (1 to 2 golf-ball sized quantities of mousse dispensed into the palm of the hand). This amount may be repeated 3 to 4 times daily, unless otherwise directed by the doctor.

Treatment should not normally continue for more than a few weeks, unless recommended by a doctor.

The same dosage and dosage schedule applies to all age groups, although the mousse is not normally recommended for children under 12 years, unless instructed by their doctor.

4.3 Contraindications

Not to be used if allergic to any of the ingredients, or in cases of hypersensitivity to aspirin, ibuprofen or related painkillers (including when taken by mouth), especially where associated with a history of asthma, rhinitis or urticaria.

Not to be used on broken or damaged skin, or where there is infection or other skin disease.

4.4 Special Warnings And Precautions For Use

This product is flammable. Do not spray near flames, burning cigarettes, electric heaters or similar objects.

Keep away from the eyes and mucous membranes.

Oral NSAIDs, including ibuprofen, can sometimes be associated with renal impairment or aggravation of active peptic ulcers, and they can induce allergic bronchial reactions in susceptible asthmatic patients. Although systemic absorption of topically applied ibuprofen is much less than for oral dosage forms, these complications can still occur in rare cases. For these reasons, patients with asthma, an active peptic ulcer or a history of kidney problems, should seek medical advice before using the mousse, as should patients already taking other painkillers.

Patients should seek medical advice if symptoms worsen or persist.

Keep out of the reach of children. For external use only. Wash hands after use unless treating them. Do not use excessively.

The label will include statements to the following effect:

Do not exceed the stated dose. Not recommended for children under 12 years without medical advice. For external use only. Not to be used during pregnancy or breastfeeding. Do not use if you are allergic to any of the ingredients or have experienced problems with aspirin, ibuprofen or related painkillers (including when taken by mouth). If symptoms persist consult your doctor or pharmacist. Keep out of the reach of children. Patients with asthma, an active peptic ulcer or a history of kidney problems should consult their doctor before use, as should patients already taking aspirin or other painkillers.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-steroidal anti-inflammatory drugs may interact with blood pressure lowering drugs, and may possibly enhance the effects of anticoagulants, although the chance of either of these occurring with a topically administered preparation is extremely remote. Concurrent aspirin or other NSAIDs may result in an increased incidence of undesirable effects.

4.6 Pregnancy And Lactation

Not to be used during pregnancy or lactation. Although no teratogenic effects have been demonstrated, ibuprofen should be avoided during pregnancy. The onset of labour may be delayed, and the duration of labour increased. Ibuprofen appears in breast milk in very low concentrations, but is unlikely to affect breast-fed infants adversely.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The cooling effect of the mousse may result in a temporary paling of the skin. Very rarely, susceptible patients may experience the following side effects with ibuprofen, but these are extremely uncommon when ibuprofen is administered topically. If they occur, treatment should be discontinued:-

Hypersensitivity: hypersensitivity reactions have been reported following treatment with ibuprofen. 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, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Renal: renal impairment can occur in patients with a history of kidney problems.

Gastrointestinal: side effects such as abdominal pain and dyspepsia have been reported.

4.9 Overdose

Any overdose with a topical presentation of ibuprofen is extremely unlikely.

Symptoms of severe ibuprofen overdosage (eg following accidental oral ingestion) include headache, vomiting, drowsiness and hypotension. Correction of severe electrolyte abnormalities should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The mousse is for topical application. Ibuprofen is a phenylpropionic acid derivative with analgesic and anti-inflammatory properties. It exerts its effects directly in inflamed tissues underlying the site of application, mainly by inhibiting prostaglandin biosynthesis.

Because it is formulated in an aqueous mousse, the preparation also exerts a soothing and cooling effect when applied to the affected area.

5.2 Pharmacokinetic Properties

Ibumousse has been designed for external application. The formulation delivers the active ingredient through the skin rapidly and extensively, achieving high, therapeutically relevant local concentrations in underlying soft tissues, joints and the synovial fluid, whilst producing plasma levels that are unlikely to be sufficient to cause any systemic side-effects, other than in rare individuals who are hypersensitive to ibuprofen.

There do not appear to be any appreciable differences between the oral and topical routes of administration regarding metabolism or excretion of ibuprofen.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol; Carbomer; Phenoxyethanol; Diethylamine; Butane 40; Purified Water.

(The ozone-friendly aerosol propellent is a blend of C₂ - H₅ hydrocarbons consisting primarily of propane, iso-butane and n-butane).

6.2 Incompatibilities

None known.

6.3 Shelf Life

48 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep upright and away from direct heat or sunlight. Do not expose pressurised container to temperatures higher than 50°C. Do not pierce or burn container, even when empty.

6.5 Nature And Contents Of Container

Aluminium pressurised container incorporating a spray valve and cap containing 125 g of product. This is supplied as an original pack (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Dermal Laboratories

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/0169.

9. Date Of First Authorisation/Renewal Of The Authorisation

22 May 2008.

10. Date Of Revision Of The Text

October 2007.

Ibuprofen 200mg Soft Gelatine Capsules

1. Name Of The Medicinal Product

Ibuprofen 200mg Soft Gelatine Capsules

2. Qualitative And Quantitative Composition

Ibuprofen 200 mg per capsule, soft.

For excipients see 6.1.

3. Pharmaceutical Form

Capsule, soft

Oval clear capsules printed with a logo in white.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of rheumatic or muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, symptoms of colds and influenza.

4.2 Posology And Method Of Administration

For oral administration and short-term use only. Do not chew.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Take one or two capsules (200 mg – 400 mg), up to three times a day as required (maximum dose 400 mg).

Leave at least four hours between doses and do not take more than 6 capsules (1200 mg) in any 24 hour period.

Children under 12 years:

Not recommended.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

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

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 NSAIDs therapy.

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

Last trimester of pregnancy (See section 4.6).

4.4 Special Warnings And Precautions For Use

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).

The elderly have an increased frequency of adverse reactions to NSAIDs, especially GI bleeding and perforation which may be fatal.

Respiratory:

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

Other NSAIDs:

The use of Ibuprofen 200mg Soft Gelatin Capsules with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (See section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease - increased risk of aseptic meningitis (See section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (See sections 4.3 and 4.8).

Hepatic:

Hepatic dysfunction (See sections 4.3 and 4.8).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

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

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAIDs doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (See section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as 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 ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of 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.

Ibuprofen 200mg Soft Gelatin Capsules should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Patients with rare hereditary problems of fructose intolerance should not take this medicine because of the presence of sorbitol.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

• are in the last 3 months of pregnancy

Speak to a pharmacist or your doctor before taking this product if you

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• are a smoker

• are in the first 6 months of pregnancy

If symptoms persist or worsen, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (See section 4.4).

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).

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).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs.

Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (See section 4.4).

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

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

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

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

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal experiments, the use of Ibuprofen 200mg Soft Gelatin Capsules should, if possible, be avoided during the first 6 months of pregnancy.

During the 3rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (See section 4.3).

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

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of:

(a) Non-specific allergic reactions and anaphylaxis

(b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea

(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

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

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (See section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Dermatological:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Jonhson syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4).

Cardiovascular and Cerebrovascular:

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

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (See section 4.4).

4.9 Overdose

In children ingestion of more than 400 mg/kg ibuprofen may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-inflammatory and antirheumatic products, ATC code: M01AE01.

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

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.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

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

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance additional to that contained elsewhere in the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule contents

Macrogol 600

Potassium hydroxide

Purified water

Capsule shell

Gelatin

Sorbitol

Purified water

Opacode WB white NS-78-18011 (titanium dioxide (E171), hypromellose, propylene glycol)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

A blister pack consisting of opaque, white polyvinyl chloride (PVC)/polyethylene (PE)/polyvinylidene chloride (PVDC), heat sealed to aluminium foil. The blisters are packed into cardboard cartons.

Package size(s): 4, 10 or 16 capsules per carton. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

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

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

103-105 Bath Road

Slough

SL1 3UH

8. Marketing Authorisation Number(S)

PL 00063/0651

9. Date Of First Authorisation/Renewal Of The Authorisation

30/06/2010

10. Date Of Revision Of The Text

11/03/2011

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

IF APPLICABLE

INVEGA 1.5 mg, 3 mg, 6 mg, 9 mg, 12 mg prolonged-release tablets

1. Name Of The Medicinal Product

INVEGA^® 1.5 mg prolonged-release tablets

INVEGA^®

INVEGA^®

INVEGA^®

INVEGA^®

2. Qualitative And Quantitative Composition

Each prolonged-release tablet contains 1.5 mg of paliperidone.

Each prolonged-release tablet contains 3 mg of paliperidone.

Each prolonged-release tablet contains 6 mg of paliperidone.

Each prolonged-release tablet contains 9 mg of paliperidone.

Each prolonged-release tablet contains 12 mg of paliperidone.

FOR THE 3 mg TABLET:

Excipient: Each tablet contains 13.2 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablet

1.5 mg: Trilayer capsule-shaped orange brown tablets printed with “PAL 1.5”

3 mg: Trilayer capsule-shaped white tablets printed with “PAL 3”

6 mg: Trilayer capsule-shaped beige tablets printed with “PAL 6”

9 mg: Trilayer capsule-shaped pink tablets printed with “PAL 9”

12 mg:Trilayer capsule-shaped dark-yellow tablets printed with “PAL 12”.

4. Clinical Particulars

4.1 Therapeutic Indications

INVEGA is indicated for the treatment of schizophrenia.

INVEGA is indicated for the treatment of psychotic or manic symptoms of schizoaffective disorder. Effect on depressive symptoms has not been demonstrated.

4.2 Posology And Method Of Administration

Adults

INVEGA is for oral administration. The administration of INVEGA should be standardised in relation to food intake (see section 5.2). The patient should be instructed to always take INVEGA in the fasting state or always take it together with breakfast and not to alternate between administration in the fasting state or in the fed state.

Schizophrenia

The recommended dose of INVEGA for the treatment of schizophrenia is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.

Schizoaffective disorder

The recommended dose of INVEGA for the treatment of schizoaffective disorder is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses within the recommended range of 6 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 4 days. Maintenance of effect has not been studied.

INVEGA must be swallowed whole with liquid, and must not be chewed, divided, or crushed. The active substance is contained within a non absorbable shell designed to release the active substance at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Patients with hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

Patients with renal impairment

For patients with mild renal impairment (creatinine clearance

For patients with moderate to severe renal impairment (creatinine clearance

Elderly

Dosing recommendations for elderly patients with normal renal function (

Paediatric population

Schizophrenia and schizoaffective disorders: There is no relevant use of INVEGA in children aged less than 12 years. The safety and efficacy of INVEGA in children aged 12 to 18 years has not been established: no data are available.

Other special populations

No dose adjustment for INVEGA is recommended based on gender, race, or smoking status. (For pregnant women and breast-feeding mothers, see section 4.6)

Switching to other antipsychotic medicinal products

There are no systematically collected data to specifically address switching patients from INVEGA to other antipsychotic medicinal products. Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.

4.3 Contraindications

Hypersensitivity to the active substance, risperidone, or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Patients with schizoaffective disorder treated with paliperidone should be carefully monitored for a potential switch from manic to depressive symptoms.

QT interval

Caution should be exercised when INVEGA is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines thought to prolong the QT interval.

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotics, including INVEGA, should be discontinued.

Tardive dyskinesia

Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including INVEGA, should be considered.

Hyperglycemia

Rare cases of glucose related adverse reactions, e.g., increase in blood glucose, have been reported in clinical trials with INVEGA. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Orthostatic hypotension

Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.

Based on pooled data from the three, placebo-controlled, 6-week, fixed-dose trials with INVEGA (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGA compared with 0.8% of subjects treated with placebo. INVEGA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia).

Seizures

INVEGA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Potential for gastrointestinal obstruction

Because the INVEGA tablet is non-deformable and does not appreciably change shape in the gastrointestinal tract, INVEGA should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines in non-deformable controlled-release formulations. Due to the controlled-release design of the dosage form, INVEGA should only be used in patients who are able to swallow the tablet whole.

Conditions with decreased gastro-intestinal transit time

Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe diarrhoea, may result in a reduced absorption of paliperidone.

Renal impairment

The plasma concentrations of paliperidone are increased in patients with renal impairment and, therefore, dosage adjustment may be required in some patients (see section 4.2 and 5.2). No data are available in patients with a creatinine clearance below 10 ml/min. Paliperidone should not be used in patients with creatinine clearance below 10 ml/min.

Hepatic impairment

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.

Elderly patients with dementia

INVEGA has not been studied in elderly patients with dementia. The experience from risperidone is considered valid also for paliperidone.

Overall mortality

In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.

Cerebrovascular adverse reactions

An approximately 3-fold increased risk of cerebrovascular adverse reactions have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known. INVEGA should be used with caution in elderly patients with dementia who have risk factors for stroke.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing INVEGA to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including risperidone) with α-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance priapism has also been reported with paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 3-4 hours.

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing INVEGA to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Venous Thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with INVEGA and preventive measures undertaken.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.

Lactose content (pertains only to the 3 mg tablets)

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

Caution is advised when prescribing INVEGA with medicines known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g., mefloquine).

Potential for INVEGA to affect other medicines

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicines that are metabolised by cytochrome P-450 isozymes. In vitro studies indicate that paliperidone is not an inducer of CYP1A2 activity.

Given the primary CNS effects of paliperidone (see section 4.8), INVEGA should be used with caution in combination with other centrally acting medicines, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.

Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential, e.g., other antipsychotics, tricyclics.

Caution is advised if paliperidone is combined with other medicines known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, clozapine, tricyclics or SSRIs, tramadol, mefloquine, etc.).

No interaction study between INVEGA and lithium has been performed, however, a pharmacokinetic interaction is unlikely to occur.

Co-administration of INVEGA 12 mg once daily with divalproex sodium prolonged-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate. Co-administration of INVEGA with divalproex sodium prolonged-release tablets increased the exposure to paliperidone (see below).

Potential for other medicines to affect INVEGA

In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of INVEGA with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone. In vitro studies have shown that paliperidone is a P-glycoprotein (P-gp) substrate.

Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of INVEGA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if necessary. It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer the effect wears off over a similar time period. Other medicinal products or herbals which are inducers, e.g. rifampicin and St John´s wort (Hypericum perforatum) may have similar effects on paliperidone.

Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone, e.g., metoclopramide.

Co-administration of a single dose of INVEGA 12 mg with divalproex sodium prolonged-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for INVEGA should be considered when INVEGA is co-administered with valproate after clinical assessment.

Concomitant use of INVEGA with risperidone

Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

4.6 Pregnancy And Lactation

There are no adequate data from the use of paliperidone during pregnancy. Paliperidone was not teratogenic in animal studies, but other types of reproductive toxicity were observed (see section 5.3). Neonates exposed to antipsychotics (including paliperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. INVEGA should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

Paliperidone is excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if therapeutic doses are administered to breast-feeding women. INVEGA should not be used while breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to INVEGA is known.

4.8 Undesirable Effects

The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were headache, akathisia, somnolence, dizziness, sedation, tremor, nausea, agitation, constipation, dyspepsia, tachycardia, extrapyramidal disorder, hypertonia, dry mouth, vomiting, weight increased, sinus tachycardia, dystonia, nasopharyngitis, and fatigue.

The ADRs that appeared to be dose-related included weight increased, dyskinesia, extrapyramidal disorder, hypertonia, parkinsonism, tachycardia, salivary hypersecretion, vomiting, dystonia, headache, breast discharge, gynaecomastia, bradycardia, constipation, dyspepsia, stomach discomfort, asthenia, nasopharyngitis, rhinitis, upper respiratory tract infection, back pain, muscle twitching, myalgia, akathisia, bradykinesia, dysarthria, dystonia, somnolence, restlessness, sleep disorder, breast engorgement, breast pain, galactorrhoea, cough, pharyngolaryngeal pain, and orthostatic hypotension.

The following are all ADRs that were reported in clinical trials and postmarketing. The following terms and frequencies are applied: very common (common (uncommon (rare (very rare (< 1/10,000), and not known (cannot be estimated from the available clinical trial data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The data described in this section are derived from the following clinical trial databases in subjects with schizophrenia, schizoaffective disorder, and bipolar disorder:

- 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA at fixed doses ranging from 3 mg to 12 mg once daily.

- 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA: 6 mg with the option to reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the other study, 214 subjects received flexible doses of INVEGA (3 mg to 12 mg once daily). Both studies included subjects who received INVEGA either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants.

- three double-blind placebo-controlled studies in subjects with bipolar disorder. In these three studies, a total of 1257 subjects were evaluable for safety, of which a total of 739 subjects were treated with INVEGA.

System Organ Class	Adverse Drug Reaction
Frequency
	Very common	Common	Uncommon	Rare	Not Known
Infections and infestations		upper respiratory tract infection, nasopharyngitis	urinary tract infection, rhinitis
Immune system disorders				anaphylactic reaction, hypersensitivity
Endocrine disorders				hyperprolactinaemiaa
Metabolism and nutrition disorders		weight increased, increased appetite	hyperglycaemia, decreased appetite
Psychiatric disorders		agitation	nightmare, sleep disorder
Nervous system disorders	headache	dystoniab, parkinsonismb, dysarthria, akathisia, dyskinesiab extrapyramidal disorderb, tremorb, dizziness, sedation, somnolence	syncope, dizziness postural, lethargy	transient ischaemic attack, grand mal convulsion, convulsion, tardive dyskinesia	cerebrovascular accident, neuroleptic malignant syndrome
Eye disorders		vision blurred
Cardiac disorders		sinus tachycardia, tachycardia	bundle branch block, atrioventricular block first degree, bradycardia, palpitations, electrocardiogram abnormal, sinus arrhythmia	bundle branch block left, electrocardiogram QT prolonged
Vascular disorders		orthostatic hypotension	hypotension	ischaemia
Respiratory, thoracic and mediastinal disorders		cough, pharyngolaryngeal pain, nasal congestion			pneumonia aspiration
Gastrointestinal disorders		vomiting, abdominal discomfort/abdominal pain upper, stomach discomfort, nausea, dyspepsia, dry mouth, constipation	flatulence	small intestinal obstruction	swollen tongue
Skin and subcutaneous tissue disorders			rash, pruritus	angioedema, rash papular
Musculoskeletal, connective tissue and bone disorders		arthralgia, back pain, pain in extremity	musculoskeletal pain, myalgia
Renal and urinary disorders			urinary retention	urinary incontinence
Pregnancy, puerperium and perinatal conditions					drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders			erectile dysfunction, galactorrhoea, amenorrhoea,	gynaecomastia, breast discharge, menstruation irregular, breast engorgement, breast pain, breast tenderness, retrograde ejaculation	priapism
General disorders		asthenia, fatigue	oedema peripheral	oedema

^a Hyperprolactinaemia can in some cases lead to gynaecomastia, menstual disturbances, amenorrhoea, and galactorrhoea.

^b Extrapyramidal disorder may occur: Parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, muscle spasms, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor (includes tremor and parkinsonian rest tremor). It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.

In the schizoaffective disorder studies, a greater proportion of subjects in the total INVEGA dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with INVEGA monotherapy.

Elderly

In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen in non-elderly subjects. INVEGA has not been studied in elderly patients with dementia. In clinical trials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidents have been reported (see section 4.4).

Events of particular interest to the class

Extrapyramidal Symptoms (EPS). In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6 mg doses of INVEGA. Dose dependence for EPS was seen with the two higher doses of INVEGA (9 and 12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher rate than placebo in all dose groups without a clear relationship to dose. EPS included a pooled analysis of the following terms: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor.

Weight Gain. In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of

In schizoaffective disorder clinical trials, a higher percentage of INVEGA-treated subjects (5%) had an increase in body weight of

Laboratory Tests: Serum Prolactin. In schizophrenia clinical trials, increases in serum prolactin were observed with INVEGA in 67% of subjects. Adverse events that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, gynaecomastia) were reported overall in 2% of subjects. Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of treatment, but remained above baseline levels at study endpoint.

Class effects

QT prolongation, ventricular arrythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown.

Paliperidone is the active metabolite of risperidone. The safety profile of risperidone may be pertinent.

4.9 Overdose

In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in association with overdose. In the case of acute overdosage, the possibility of multiple medicinal product involvement should be considered.

Consideration should be given to the prolonged-release nature of the product when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacologic group: Psycholeptics, other antipsychotics ATC code: N05AX13

INVEGA contains a racemic mixture of (+)- and (-)-paliperidone.

Mechanism of Action

Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alfa1-adrenergic receptors and blocks, to a lesser extent, H1-histaminergic and alfa2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.

Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions to a lesser extent than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.

Pharmacodynamic Effects

Clinical Efficacy

Schizophrenia

The efficacy of INVEGA in the treatment of schizophrenia was established in three multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA doses, which varied across the three studies, ranged from 3 to 15 mg once daily. The primary efficacy endpoint was defined as a decrease in total Positive and Negative Syndrome Scale (PANSS) scores as shown in the following table. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. All tested doses of INVEGA separated from placebo on day 4 (p<0.05). Predefined secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression – Severity (CGI-S) scale. In all three studies, INVEGA was superior to placebo on PSP and CGI-S. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score

Schizophrenia Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End Point- LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set

	Placebo	INVEGA 3 mg	INVEGA 6 mg	INVEGA 9 mg	INVEGA 12 mg
R076477-SCH-303 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE)	(N=126) 94.1 (10.74) -4.1 (23.16)		(N=123) 94.3 (10.48) -17.9 (22.23) <0.001 -13.7 (2.63)	(N=122) 93.2 (11.90) -17.2 (20.23) <0.001 -13.5 (2.63)	(N=129) 94.6 (10.98) -23.3 (20.12) <0.001 -18.9 (2.60)
R076477-SCH-304 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE)	(N=105) 93.6 (11.71) -8.0 (21.48)		(N=111) 92.3 (11.96) -15.7 (18.89) 0.006 -7.0 (2.36)		(N=111) 94.1 (11.42) -17.5 (19.83) <0.001 -8.5 (2.35)
R076477-SCH-305 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE)	(N=120) 93.9 (12.66) -2.8 (20.89)	(N=123) 91.6 (12.19) -15.0 (19.61) <0.001 -11.6 (2.35)		(N=123) 93.9 (13.20) -16.3 (21.81) <0.001 -12.9 (2.34)

Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the PANSS was used. A 15 mg dose was also included in Study R076477-SCH-305, but results are not presented since this is above the maximum recommended daily dose of 12 mg.

Schizophrenia Studies: Proportion of Subjects with Responder Status at LOCF End Point Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set
	Placebo	INVEGA 3 mg	INVEGA 6 mg	INVEGA 9 mg	INVEGA 12 mg
R076477-SCH-303 N Responder, n (%) Non-responder, n (%) P value (vs Placebo)	126 38 (30.2) 88 (69.8) --		123 69 (56.1) 54 (43.9) <0.001	122 62 (50.8) 60 (49.2) 0.001	129 79 (61.2) 50 (38.8) <0.001
R076477-SCH-304 N Responder, n (%) Non-responder, n (%) P value (vs Placebo)	105 36 (34.3) 69 (65.7) --		110 55 (50.0) 55 (50.0) 0.025