Octasa 800 mg MR Tablets

1. Name Of The Medicinal Product

Octasa 800 mg MR Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 800 mg mesalazine.

For a full list of excipients, see section 6.1

Excipients: Contains lactose monohydrate

3. Pharmaceutical Form

Modified-Release Tablets

Red-brown, oblong, modified-release tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Ulcerative Colitis:

For the treatment of mild to moderate acute exacerbations. For the maintenance of remission.

Crohn's ileo-colitis:

For the maintenance of remission.

4.2 Posology And Method Of Administration

Route of administration: Oral.

Swallow whole with a glass of water. Do not chew, crush or break tablets before swallowing.

ADULTS

Mild acute disease: 2.4 g (three tablets) a day in divided doses, with concomitant corticosteroid therapy where clinically indicated.

Moderate acute disease: 2.4 g to 4.8 g (three to six tablets) a day in divided doses, with concomitant corticosteroid therapy where clinically indicated.

Maintenance therapy: 1.6 g to 2.4 g (two to three tablets) taken once daily or in divided doses.

The maximum adult dose should not exceed six tablets a day.

ELDERLY

The normal adult dosage may be used unless renal function is impaired (see section 4.4).

CHILDREN

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older

• Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day.

• Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day.

It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.

4.3 Contraindications

Use in patients with a history of allergy to salicylates, or hypersensitivity to any ingredient.

Severe renal impairment (GFR less than 20 ml/min).

Severe hepatic impairment. Gastric or duodenal ulcer, haemorrhagic tendency.

4.4 Special Warnings And Precautions For Use

Patients on oral forms of mesalazine should have renal function monitored, with serum creatinine levels measured prior to the start of treatment, every three months for the first year, then six monthly for the next four years and annually thereafter.

Treatment with mesalazine should be discontinued if renal function deteriorates.

Renal disorder: Mesalazine is excreted rapidly by the kidney, mainly as its metabolite, N-acetyl-5-aminosalicylic acid. Octasa 800 mg MR Tablets are best avoided in patients with mild to moderate renal impairment but, if necessary, should be used with extreme caution.

If dehydration develops, normal electrolyte levels and fluid balance should be restored as soon as possible.

In case of lung function impairment, especially asthma, patients need to be very closely monitored.

In patients with a history of sensitivity to sulphasalazine, therapy should be initiated only under close medical supervision. Treatment must be stopped immediately if acute symptoms of intolerance occur such as cramps, abdominal pain, fever, severe headache, or rash.

Very rarely serious blood dyscrasia has been reported. Haematological investigations including a complete blood count should be performed prior to initiation and whilst on therapy according to the physician's judgement. Such tests are generally recommended within 14 days of initiation of therapy with 2-3 repeat tests each after another 4 weeks. If the results are normal, tests are recommended quarterly. In case additional signs of illness appear, further control tests are necessary. This procedure is to be followed especially if a patient develops signs and symptoms suggestive of blood dyscrasia during treatment, such as unexplained bleeding, haematoma, purpura, anaemia, persistent fever, or a sore throat. Treatment with Octasa 800 mg MR Tablets should be stopped immediately if there is a suspicion or evidence of blood dyscrasia and patients should seek immediate medical advice.

Use in the elderly should be cautious and subject to patients having normal renal function.

There is only limited documentation for an effect in children (age 6-18 years), see section 4.2.

With reference to the presence of lactose monohydrate in the formulation, 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

The concurrent use of known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions (see Section 4.4).

Mesalazine decreases the absorption of digoxin.

Mesalazine can increase the immunosuppressive effects of azathioprine and 6-mercaptopurine. A blood count, especially the leukocyte and lymphocyte cell count should be monitored repeatedly, especially at initiation of such combination therapy.

The uricosuric activity of sulfinpyrazone, and the diuretic effect of furosemide can be reduced.

4.6 Pregnancy And Lactation

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the health of the foetus/new born child. To date, no other relevant epidemiological data are available. In one single case, after long-term use of high dose mesalazine (2-4 g, orally) during pregnancy, renal failure in a neonate was reported.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects, with respect to pregnancy, embryonic/foetal development, parturition or postnatal development.

Mesalazine should only be used during pregnancy if the potential benefit outweighs the possible risk.

Lactation

N-acetyl-mesalazine and, to a lesser degree, mesalazine are excreted in breast milk. Only limited experience in women during lactation is available to date. Hypersensitivity reactions like diarrhoea cannot be excluded. Therefore, mesalazine should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the suckling neonate develops diarrhoea, the breast-feeding should be discontinued.

4.7 Effects On Ability To Drive And Use Machines

Mesalazine has no, or negligible, influence on ability to drive and use machines.

4.8 Undesirable Effects

Side-effects which occur rarely (

Side effects which occur very rarely (<1/10,000; incidence/treatment years), are listed by system organ class:

Blood and lymphatic system disorders(1)	Blood dyscrasia(1), agranulocytosis, aplastic anaemia, pancytopenia, bone marrow depression, leucopenia, neutropenia, thrombocytopenia, anaemia.
Nervous system disorders	Peripheral neuropathy, vertigo, headache.
Cardiac disorders	Myocarditis, pericarditis.
Respiratory, thoracic and mediastinal disorders	Allergic lung reactions, bronchospasm, eosinophilic pneumonia.
Gastro-intestinal disorders	Pancreatitis, exacerbation of disease, vomiting, nausea.
Hepatobiliary disorders	Hepatitis, hepatic function abnormal / abnormal liver function tests.
Skin and subcutaneous tissue disorders	Stevens Johnson syndrome, erythema multiforme, bulbous skin reactions, urticaria, rash.
Musculoskeletal, connective tissue disorders	Lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia, myalgia, arthralgia.
Renal & urinary disorders(2)	Renal failure, which may be reversible on withdrawal, nephrotic syndrome, nephritis interstitial.

⁽¹⁾ The frequency of blood dyscrasia appears smaller than the number of reported changes in individual white blood count, because reporting health professionals may have labelled several cases of blood dyscrasia not in this category

⁽²⁾ Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment

4.9 Overdose

In principle, the signs and symptoms would be expected to be similar to those observed in cases of salicylate intoxication: mixed acidosis-alkalosis, hyperventilation, pulmonary oedema, dehydration as a result of sweating and vomiting, and hypoglycaemia.

Treatment

For mixed acidosis-alkalosis: restoration of the acid-base balance in line with the specific situation and replacement of electrolytes.

For dehydration due to sweating and vomiting: administration of fluids.

For hypoglycemia: glucose administration.

In addition gastric lavage and intravenous infusion of electrolytes to promote diuresis. There is no known antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Octasa 800mg MR Tablets contain mesalazine [ATC code: A07E C02], also known as 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine has been shown to inhibit LTB₄-stimulated migration of intestinal macrophages and thus may reduce intestinal inflammation by restricting migration of macrophages to inflamed areas. The production of proinflammatory leukotrienes (LTB₄ and 5-HETE) in the macrophages of intestinal wall is then inhibited. Under trial conditions mesalazine has also inhibited cyclooxygenase and thus, the release of thromboxane B₂ and prostaglandin E₂, but the clinical meaning of this effect is still unclear. Mesalazine also inhibits formation of the platelet activating factor (PAF). Recently, in in vitro and animal studies, mesalazine has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses. Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals. Furthermore, mesalazine inhibits secretion of water and chloride and increases the reabsorption of sodium in the intestine in experimental colitis in test animals.

5.2 Pharmacokinetic Properties

Octasa 800 mg MR Tablets are coated with a Eudragit S-based film. This copolymer allows the active principle to be released when the intraluminal pH is greater than 7, that is within the terminal ileum and colon, which are the true sites of inflammation. Octasa 800 mg MR Tablets have been designed to be weakly absorbed in the digestive tract. Absorption by the oral route is approximately 26%. Consequently, 74% of the administered dose remains within the terminal ileum and colon, being available to exert a topical anti-inflammatory effect. Mesalazine is metabolised both by the liver and the intestinal mucosa into an inactive derivative, N-acetyl-5-aminosalicylic acid. Studies show that mesalazine has an elimination half-life between nine hours (single dose) and eleven hours (steady state). A high intersubject variability has been seen in clinical trials. The elimination of mesalazine is essentially urinary and faecal, in the form of mesalazine and its N-acetyl metabolite. Following repeated administration for seven days, the quantities of mesalazine absorbed and eliminated by the urinary route in unchanged form and as the N-acetyl metabolite were 21.2 % and 20.9%, respectively.

Octasa 800 mg MR Tablets contain, in a single tablet, an equivalent quantity of mesalazine to that theoretically available from the complete azoreduction of 2 g of sulphasalazine.

5.3 Preclinical Safety Data

Preclinical data with mesalazine reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxixity, carcinogenicity or toxicity to reproduction.

Renal toxicity (renal capillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Sodium starch glycolate (Type A)

Magnesium stearate (vegetable origin)

Talc E553b

Povidone E1201

Methacrylic acid – methyl methacrylate copolymer (1:2)

Triethyl citrate

Iron oxides E172

Macrogol 6000.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Octasa 800 mg MR Tablets are available in PVC/aluminium blisters, each containing ten tablets.

The blisters are packed in cartons containing either 60, 90 or 180 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Tillotts Pharma UK Limited

960 Capability Green

Luton

Bedfordshire LU1 3PE,

United Kingdom

8. Marketing Authorisation Number(S)

PL 36633/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

17.10.2007

10. Date Of Revision Of The Text

23 June 2011

Oilatum Gel

1. Name Of The Medicinal Product

Oilatum Gel

2. Qualitative And Quantitative Composition

Light liquid paraffin 70% w/w

3. Pharmaceutical Form

Shower gel.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of contact dermatitis, atopic dermatitis, senile pruritus ichthyosis and related dry skin conditions.

4.2 Posology And Method Of Administration

Topical

Adults, children and the elderly:

Oilatum Gel may be used as frequently as necessary. Oilatum Gel should always be applied to wet skin, normally as a shower gel.

Shower as usual. Apply Oilatum Gel liberally to wet skin and massage gently. Rinse briefly and lightly pat the skin dry.

4.3 Contraindications

None.

4.4 Special Warnings And Precautions For Use

Take care to avoid slipping in the shower.

Oilatum Gel should not be used on greasy skin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None.

4.6 Pregnancy And Lactation

There is no or inadequate evidence of the safety of Oilatum Gel in human pregnancy and lactation. Topical preparations containing light liquid paraffin have been in wide use for many years without apparent ill consequence.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Light liquid paraffin exerts an emollient effect by forming an occlusive oil film on the stratum corneum. This prevents excessive evaporation of water from the skin surface and aids in the prevention of dryness.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Polyethylene 617A

2-octadodecanol

Polyethylene glycol 400 dilaurate.

Polyoxyethylene 40 sorbital septaoleate

Polyethylene glycol-2-myristyl ether propionate

Polyphenylmethyl siloxane copolymer

Floral spice

6.2 Incompatibilities

None.

6.3 Shelf Life

a) For the product as packaged for sale

3 years

b) After first opening the container

Comply with expiry date

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

High density polyethylene tubes of 15g, 25g, 30g, 50g, 60g, 65g, 70g, 75g, 125g and 150g

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for use or handling of Oilatum Gel.

7. Marketing Authorisation Holder

GlaxoSmithKline UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as Stiefel

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 19494/0062

9. Date Of First Authorisation/Renewal Of The Authorisation

7^th November 1991 / 6^th August 2004

10. Date Of Revision Of The Text

14 December 2010

Otex Ear Drops

1. Name Of The Medicinal Product

OTEX™ EAR DROPS

2. Qualitative And Quantitative Composition

Urea Hydrogen Peroxide 5.0 % w/w.

3. Pharmaceutical Form

Clear, straw coloured viscous ear drops.

4. Clinical Particulars

4.1 Therapeutic Indications

As an aid in the removal of hardened ear wax.

4.2 Posology And Method Of Administration

For adults, children and the elderly.

Instill up to 5 drops into the ear. Retain drops in ear for several minutes by keeping the head tilted and then wipe away any surplus.

Repeat once or twice daily for at least 3 to 4 days, or as required.

4.3 Contraindications

Do not use if the eardrum is known or suspected to be damaged, in cases of dizziness, or if there is, or has been, any other ear disorder (such as pain, discharge, inflammation, infection or tinnitus).

Do not use after ill-advised attempts to dislodge wax using fingernails, cotton buds or similar implements, as such mechanical efforts can cause the ear's delicate inner lining to become damaged, inflamed or infected, whereupon the use of ear drops can be painful. For similar reasons, it is inadvisable to use Otex within 2 to 3 days of syringing.

Do not use where there is a history of ear problems, unless under close medical supervision.

Do not use if sensitive to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Keep Otex away from the eyes. For external use only. Replace cap after use, and return bottle to carton.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Otex should not be used at the same time as anything else in the ear.

4.6 Pregnancy And Lactation

No known side effects.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Due to the release of oxygen, patients may experience a mild, temporary effervescence in the ear. Stop usage if irritation or pain occurs.

Instillation of ear drops can aggravate the painful symptoms of excessive ear wax, including some loss of hearing, dizziness and tinnitus. Very rarely, unpleasant taste has been reported. If patients encounter any of these problems, or if their symptoms persist or worsen, they should discontinue treatment and consult a doctor.

4.9 Overdose

No adverse effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

After insertion of the drops into the ear, the urea hydrogen peroxide complex liberates oxygen which acts to break up the hardened wax. The hydrogen peroxide component is also a cerumenolytic. Its action as an antiseptic, especially in sites with relative anaerobiosis, is well known. The glycerol and urea assist in softening the wax, so that it may more easily be removed from the ear, either with or without syringing. The urea also acts as a mild keratolytic, helping to reduce the keratin-load in the debris. With less debris, the other components are able to reach the skin under the debris and exert their action.

5.2 Pharmacokinetic Properties

Otex is intended only for the treatment of impacted wax in the external auditory canal. The ingredients of the formulation are therefore readily available for intimate contact with the affected area, as the drops are instilled into the ear and retained therein for several minutes by tilting the head.

5.3 Preclinical Safety Data

No special information.

6. Pharmaceutical Particulars

6.1 List Of Excipients

8-Hydroxyquinoline; Glycerol.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months. Discard 4 weeks after first opening.

6.4 Special Precautions For Storage

Store upright. Do not store above 25°C. Replace cap after use.

6.5 Nature And Contents Of Container

8 ml easy squeeze plastic dropper bottle with screw cap. This is supplied as an original pack (OP).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK

8. Marketing Authorisation Number(S)

00173/0151.

9. Date Of First Authorisation/Renewal Of The Authorisation

24 June 2007.

10. Date Of Revision Of The Text

July 2010.

Osvaren 435 mg / 235 mg film-coated tablets

1. Name Of The Medicinal Product

Osvaren 435 mg / 235 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains:

Calcium acetate, 435 mg equivalent to 110 mg calcium and Magnesium carbonate, heavy 235 mg equivalent to 60 mg magnesium

Excipients: Each film-coated tablet contains max. 5.6 mg sodium and 50 mg sucrose.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet.

White to yellowish, oblong film-coated tablet with a single score line.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of hyperphosphatemia associated with chronic renal insufficiency in patients undergoing dialysis (haemodialysis, peritoneal dialysis).

4.2 Posology And Method Of Administration

Adults:

3 to 10 film-coated tablets per day, depending on the serum phosphate level. The daily dose should be subdivided according to the number of meals taken over the day (usually three a day).

The recommended starting dose is three tablets daily.

If necessary, the dosage may be raised to maximally 12 film-coated tablets per day.

To achieve the maximum phosphate binding effect, Osvaren should be taken only together with the meal and should not be crushed or chewed.

For easy swallowing, the tablets should be taken together with some liquid.

In case the tablets are too large to be swallowed by the patient, the tablets should be broken along the score line immediately before swallowing in order to avoid the development of taste of acetic acid.

Because the rate and/or extent of absorption of other oral medicinal products may vary when used concurrently with OsvaRen no other oral medicinal products should be taken within the period 2 hours before and 3 hours after administration of OsvaRen (see section 4.5).

In case of a missed dose, it should be with the next dose (no additional make up for the missed dose).

OsvaRen can be applied long-term.

Use in children and adolescents:

There is no sufficient information for the use of Osvaren in these patient groups. Therefore, the administration of OsvaRen is not recommended in children and adolescents below 18 years of age (see section 4.4)

4.3 Contraindications

Osvaren is contraindicated in patients with:

- Hypophosphataemia

- Hypercalcaemia with or without clinical symptoms, e.g. as a result of an overdose of vitamin D, a paraneoplastic syndrome (bronchial carcinoma, breast cancer, renal cell carcinoma, plasmacytoma), bone metastases, sarcoidosis or immobilisation osteoporosis

- Elevated serum magnesium levels of more than 2 mmol/l, and/or symptoms of hypermagnesaemia

- AV-block III°

- Myasthenia gravis

- Hypersensitivity to the active substances or to any of the excipients

4.4 Special Warnings And Precautions For Use

The use of phosphate binders should be preceded by a dietary consultation with the patient concerning phosphate uptake, and may depend on the kind of dialysis treatment the patient is receiving.

Osvaren should only be administered with caution (only with continuous monitoring of serum calcium, magnesium and phosphate) in case of severe hyperphosphataemia with a calcium-phosphate-product of more than 5.3 mmol2/l2 if

• refractory to therapy,

• refractory hyperkalaemia

• clinical relevant bradycardia or AV-block II° with bradycardia

Continuous monitoring of serum phosphate, serum magnesium, serum calcium and the calcium-phosphate-product should be performed, even more so in case of simultaneous intake vitamin D preparations and thiazide diuretics.

High doses and long-term administration of this medicine may result in hypermagnesaemia. Hypermagnesaemia is mostly asymptomatic, but in some cases systemic effects may be seen.

If patients with a chronic renal insufficiency receive this medicine they may develop hypercalcaemic episodes, especially in combination with the administration of metabolites of vitamin D.

Patients should be warned of the possible symptoms of hypercalcaemia.

For symptoms and management of hypermagnesaemia and hypercalcaemia please see section 4.9.

During a long-term therapy with this medicine attention must be paid to the progression or the appearance of vascular and soft tissue calcifications. The risk decreases by lowering the calcium-phosphate-product to < 4.5 mmol2/l2.

In patients receiving digitalis glycosides, this medicine should only be administered under ECG control and monitoring of the serum calcium level.

Increased intake of calcium salts may result in the precipitation of fatty acids and bile acid as calcium soap. This may lead to constipation.

Patients should be advised to seek medicinal medical advice before taking antacids containing calcium or magnesium salts to avoid adding to the calcium or magnesium load.

In case of diarrhoea the dosage of this medicine should be reduced.

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

This medicine contains sodium. This has to be taken in consideration by patients on a controlled sodium diet.

Use in children and adolescents:

There is no sufficient information for the use of this medicine in these patient groups. Therefore, the administration of this medicine is not recommended in children and adolescents below 18 years of age.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

To prevent an interaction between Osvaren and other defined medicinal products when taken concomitantly medicinal products listed in section 4.5 should not be taken within the period 2 hours before and three hours after administration of OsvaRen (see section 4.2).

OsvaRen affects the absorption of tetracyclines, doxycycline, biphosphonates, fluorides, some quinolones (gyrase inhibitors) like ciprofloxacin and norfloxacin, some cephalosporins, like cefpodoxime and cefuroxime, ketoconazole, estramustine-preparations, anticholinergics, zinc, urso- and chenodesoxycholic acids and halofantrine.

In case of an additional treatment with oral iron preparations, attention has to be paid to the fact that simultaneous intake of magnesium may influence iron absorption.

Vitamin D and derivatives increase the absorption of calcium. Thiazide diuretics reduce the renal elimination of calcium. In case of a simultaneous administration of OsvaRen and thiazides or vitamin D derivatives it is therefore necessary to control the serum calcium level (see section 4.4).

The sensitivity for glycosides and therefore the risk for arrhythmia is increased by elevated serum calcium levels (see section 4.4). The effect of calcium antagonists may be reduced. The administration of adrenalin in patients with increased serum calcium levels may lead to severe arrhythmia.

A combination of magnesium carbonate, hydroxide and aluminium hydroxide with levothyroxine may cause an increased absorption of levothyroxine.

Concurrent use of oestrogens with this medicine may increase calcium absorption.

Magnesium salts may adsorb digoxin in the gastrointestinal tract, decreasing its bioavailability. Adsorption of nitrofurantoin may occur, decreasing the bioavailability and possibly the anti-infective effect of this medicinal product. Further, the gastrointestinal absorption of penicillamine may be decreased, possibly decreasing its pharmacological effects.

4.6 Pregnancy And Lactation

For Osvaren, there are no animal and clinical data available. It is not known whether this medicine can cause foetal defects when it is administered during pregnancy or whether it can affect fertility. Therefore, this medicine should only be administered to pregnant women if the potential benefits clearly outweigh the risks.

Calcium acetate and magnesium carbonate are distributed in breast milk (see section 5.2). Breast-feeding is not recommended during treatment with this medicine .

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Very common:	(
Common:	(
Uncommon:	(
Rare:	(
Very rare:	(<1/10,000), not known (cannot be estimated from the available data)

Gastrointestinal disorders:

Common:

Soft stools, gastrointestinal irritation like nausea, anorexia, sensation of fullness, belching and constipation, diarrhoea.

Metabolism and nutrition disorders:

Common:

Hypercalcaemia either asymptomatic or symptomatic, asymptomatic hypermagnesaemia.

Uncommon:

Moderate to severe symptomatic hypercalcaemia, symptomatic hypermagnesaemia.

Very rare:

Hyperkalaemia, magnesium-induced osteal mineralisation disturbances.

For symptoms of hypercalcaemia and hypermagnesaemia see section 4.9.

4.9 Overdose

An acute hypermagnesaemia (either asymptomatic or with acute systemic toxicity) suppresses both the central and the peripheral neural activity by inhibiting acetylcholine release. Systemic toxicity is to be expected from a serum concentration of 2.5 mmol/l, severe neurotoxic side effects appear from 3 mmol/l and above. With concentrations of 2.5 – 5.0 mmol/l gastrointestinal disturbances (nausea, anorexia, constipation), cystospasm, muscle weakness, lethargy, missing deep-tendon reflexes and disturbed AV-conduction and ventricular stimulus conduction has been observed. In case of serum magnesium levels of 5 – 10 mmol/l, arterial hypotension induced by vasodilatation, paralytic ileus, flaccid paralysis and coma have been observed. At a level of more than 10 mmol/l respiratory arrest and cardiac arrest occur.

Symptoms of hypercalcaemia are initially muscle weakness and gastrointestinal disturbances (abdominal pain, constipation, nausea and vomiting). Severe hypercalcaemia is characterised by disturbances of consciousness (e.g. disorientation, stupor, in extreme cases also coma) and lethargy. In patients with a serum calcium level of more than 3.5 mmol/l a hypercalcaemic crisis is possible with the symptoms of:

- Polyuria, polydipsia

- Nausea, anorexia, constipation, pancreatitis (infrequent)

- Arrhythmia, shortening of the QT-interval, adynamia, hypertension

- Muscle weakness up to pseudo paralysis

- Psychosis, somnolence up to coma

Long-term overdosing may lead to the development of an adynamic osteopathy.

Emergency treatment:

In addition to symptomatic treatment, the therapy of hypermagnesaemia consists in lowering the magnesium-concentration of the dialysate and in a reduction of the dose of Osvaren.

If serum calcium levels increase to more than 2.5 mmol/l, a dose reduction and/or a decrease of the dialysate calcium to 1.25 mmol/l should be considered beside the symptomatic treatment. In the event of a hypercalcaemia (serum calcium > 2.75 mmol/l) the therapy with this medicine should be temporarily withdrawn. In patients with a serum calcium level of more than 3.5 mmol/l the therapeutic intervention consists of a haemodialysis treatment with calcium-free dialysate. During the treatment with a calcium-free dialysate close monitoring of serum calcium concentration is necessary in order to minimise the risk of hypocalcaemia and adverse cardiovascular reactions.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for the treatment of hyperkalaemia and hyperphosphataemia.

V03AE04 – Calcium Acetate and Magnesium Carbonate.

As calcium acetate and magnesium carbonate are phosphate-binding compounds they lead together with the phosphate contained in food to the formation of low solubility calcium and magnesium phosphate-salts in the gut, which then will be excreted with the faeces. Calcium acetate reaches its maximal phosphate-binding capacity at a pH of 6 – 8. Therefore, Osvaren is also suitable for phosphate binding in patients with hypo- or anacidity of the stomach.

5.2 Pharmacokinetic Properties

Absorption

Provided that no precipitation to magnesium complexes is caused by dietary phosphate or other nutrients, the dissolved magnesium ions are bioavailable and are absorbed in the intestine.

The absorption of orally administered magnesium in healthy humans depends on the supply. Experiments have shown that the rate of absorption in patients who received 1.5 mmol magnesium per day was 65 %, and in patients who received 40 mmol per day it was only 11 %.

The dissolved calcium ions are bioavailable and can be absorbed via the intestinal route as long as calcium does not form insoluble calcium complexes with the phosphate contained in food or other nutrients. Absorption of calcium is governed by hormonal regulatory mechanisms. The ratio of absorption increases with higher doses and with hypocalcaemic states and decreases with increasing age. Depending on the vitamin D status and the doses taken, a fractional absorption of 10-35 % can be expected. Administration of higher doses will only result in a smaller increase of the amount absorbed. The normal daily intake with food amounts to approx. 1000 mg.

Distribution

Total body magnesium is about 20 – 28 g. In healthy adults about 53% of total body magnesium is in bone, 27% in muscle, 19% in soft tissue and less than 1% extracellular. The majority of intracellular magnesium is found in bound form.

Total body calcium is about 1,250 g (31 mol) in a person weighting 70 kg, of which 99% is located in bones and teeth. About 1 g is in the plasma and the extracellular fluid, and 6 to 8 g in the tissues themselves. Reference values for serum total calcium vary among clinical laboratories, depending on the methods of measurement, within a normal range of 2.15-2.57 mmol/l. About 40 to 45% of this quantity is bound to plasma proteins, about 8 to 10% is complexed with ions such as citrate, and 45 to 50% is dissociated as free ions.

Excretion

Orally administered magnesium salts are eliminated in the urine (absorbed fraction) and the feaces (unabsorbed fraction). Small amounts are distributed into breast-milk. Magnesium crosses the placenta.

Under physiologic conditions calcium is excreted in approximately equal amounts in urine and endogenous intestinal secretion. Parathyroid hormone, vitamin D and thiazide diuretics decrease urinary excretion of calcium, whereas other diuretics (loop diuretics), calcitonin and growth hormone promote renal excretion. Urinary calcium excretion decreases in early stages of renal failure. Urinary calcium excretion increases during pregnancy. Calcium is also excreted by the sweat glands. Calcium crosses the placenta and is distributed into breast-milk.

5.3 Preclinical Safety Data

Standard genotoxicity studies have not been performed with Osvaren. Based on available data no genotoxic or carcinogenic potential have to be assumed.

No reproductive toxicity studies have been performed with this medicine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Starch, pregelatinised, from maize

maize starch

sucrose

gelatine

croscarmellose sodium

magnesium stearate

Film coating:

Castor oil, refined

hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

After first opening of the container: 3 months

6.4 Special Precautions For Storage

Keep the container tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

HDPE container with LDPE cap: Pack size of 180 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Fresenius Medical Care Nephrologica Deutschland GmbH

61346 Bad Homburg v.d.H., Germany

8. Marketing Authorisation Number(S)

PL 29386/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

03/01/2011

10. Date Of Revision Of The Text

03/01/2011

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

Oxis 6 Turbohaler inhalation powder

Oxis Turbohaler 6 micrograms per dose Inhalation Powder

Formoterol fumarate dihydrate

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Oxis Turbohaler is and what it is used for


• 2. Before you use Oxis Turbohaler


• 3. How to use Oxis Turbohaler


• 4. Possible side effects


• 5. How to store Oxis Turbohaler


• 6. Further information

What Oxis Turbohaler is and what it is used for

Oxis Turbohaler is an inhaler. It contains a medicine called formoterol. This belongs to a group of medicines called ‘long-acting beta-agonists’ or ‘bronchodilators’.

It works by relaxing the muscles in your airways. This helps you to breathe more easily. It starts to work within 1 to 3 minutes and the effects last up to 12 hours.

Your doctor has prescribed this medicine to treat asthma or chronic obstructive pulmonary disease (COPD).

Asthma

For asthma, your doctor will prescribe two asthma inhalers: Oxis Turbohaler and a separate ‘corticosteroid’ inhaler. These should be used together.

• Oxis Turbohaler is used to help prevent asthma symptoms from happening.


• Some people also use Oxis Turbohaler when they need extra doses for relief of asthma symptoms, to make it easier to breathe again.


• Oxis Turbohaler can also be used before exercise to prevent asthma symptoms caused by exercise.

Chronic obstructive pulmonary disease (COPD)

Oxis Turbohaler can also be used to treat the symptoms of COPD in adults. COPD is a long-term disease of the airways in the lungs, which is often caused by cigarette smoking.

Before you use Oxis Turbohaler

Do not use Oxis Turbohaler if:

• You are allergic (hypersensitive) to formoterol, or the other ingredient, lactose (which contains small amounts of milk proteins).

Take special care with Oxis Turbohaler

Before you use Oxis Turbohaler, tell your doctor or pharmacist if:

• You are diabetic. You may need some additional blood sugar tests while you are using Oxis Turbohaler.


• You have high blood pressure or you have ever had a heart problem.


• You have problems with your thyroid gland.


• You have low levels of potassium in your blood. Your doctor may take blood samples to check the levels of potassium in your blood.


• You have severe liver problems such as liver cirrhosis.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before using Oxis Turbohaler.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because Oxis Turbohaler can affect the way some medicines work and some medicines can have an effect on Oxis Turbohaler.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

• Beta-blocker medicines (such as atenolol or propranolol for high blood pressure), including eyedrops (such as timolol for glaucoma).


• Medicines for a fast or uneven heart beat (such as quinidine).


• Medicines like digoxin, often used to treat heart failure.


• Diuretics, also known as ‘water tablets’ (such as furosemide). These are used to treat high blood pressure.


• Steroid medicines that you take by mouth (such as prednisolone).


• Xanthine medicines (such as theophylline or aminophylline). These are often used to treat asthma.


• Erythromycin (used to treat infections).


• Anti-histamines (such as terfenadine).


• Other substances that dilate the airways (bronchodilators, such as salbutamol).


• Ephedrine (used to treat asthma or as a decongestant).


• Tricyclic anti-depressants (such as amitriptyline).

If any of the above applies to you, or if you are not sure, talk to your doctor or pharmacist before using Oxis Turbohaler.

Also tell your doctor or pharmacist if you are going to have a general anaesthetic for an operation or for dental work.

Pregnancy and breast-feeding

• If you are pregnant, or planning to get pregnant, talk to your doctor before using Oxis Turbohaler - do not use Oxis Turbohaler unless your doctor tells you to.


• If you get pregnant while using Oxis Turbohaler, do not stop using Oxis Turbohaler but talk to your doctor immediately.


• If you are breast-feeding, talk to your doctor before using Oxis Turbohaler.

Driving and using machines

Oxis Turbohaler is not likely to affect you being able to drive or use any tools or machines.

Important information about some of the ingredients of Oxis Turbohaler

Oxis Turbohaler contains lactose, which is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before using this medicine. The amount of lactose in this medicine does not normally cause problems in people who are lactose intolerant.

The excipient lactose contains small amounts of milk proteins, which may cause allergic reactions.

How to use Oxis Turbohaler

• Always use Oxis Turbohaler exactly as your doctor, nurse or pharmacist has told you. Ask one of them for advice if you are not sure.


• Do not increase the dose of Oxis Turbohaler prescribed by your doctor without talking to your doctor first.


• If you are using Oxis Turbohaler regularly for asthma or COPD you should continue to use your medicine, even if you have no symptoms.

Important information about your asthma or COPD symptoms

If you feel you are getting breathless or wheezy while using Oxis Turbohaler, you should continue to use Oxis Turbohaler but go to see your doctor as soon as possible, as you may need additional treatment.

Contact your doctor immediately if:

• Your breathing is getting worse or you often wake up at night with asthma.


• You start getting chest tightness.


• You are not getting relief from your current dose.


• You need to take more than your usual dose for more than two days in a week.


• You need to use your Turbohaler more often than usual before exercise.

These signs could mean that your asthma or COPD is not being properly controlled and you may need different or additional treatment immediately.

Asthma

Oxis Turbohaler should not be used in children under 6 years of age.

Adults (18 years and above)

• The usual dose is 1 or 2 inhalations, once or twice a day.



• Your doctor may increase this to 4 inhalations, once or twice a day.



• Some people also use Oxis Turbohaler as a ‘reliever inhaler’. If you get asthma symptoms, the usual dose is 1 or 2 inhalations when they happen.



• A total daily dose of more than 8 inhalations is not normally needed. This includes the inhalations that you take every day, when you get asthma symptoms and before exercise. However, your doctor may allow you to take up to 12 inhalations a day. Do not use more than 12 inhalations in total in 24 hours.



• Do not take more than 6 inhalations at any one time.

Children and adolescents (6 to 17 years)

• The usual dose is 2 inhalations, once or twice a day.



• Some children also use Oxis Turbohaler as a ‘reliever inhaler’. If your child gets asthma symptoms, the usual dose is 1 or 2 inhalations when they happen.



• A total daily dose of more than 4 inhalations is not normally needed. This includes the inhalations that your child takes every day, when they get asthma symptoms and before exercise. However, your doctor may allow your child to take up to 8 inhalations a day. Your child should not use more than 8 inhalations in total in 24 hours.



• Your child should not have more than 2 inhalations at any one time.

Asthma caused by exercise

If you or your child have asthma symptoms caused by exercise, your doctor may advise you or your child to use Oxis Turbohaler before exercise as well. Oxis Turbohaler should not be used in children under 6 years of age.

Adults (18 years and above)

• The usual dose is 2 inhalations before exercise.



• A total daily dose of more than 8 inhalations is not normally needed. This includes the inhalations that you take every day, when you get asthma symptoms and before exercise. However, your doctor may allow you to take up to 12 inhalations a day. Do not use more than 12 inhalations in total in 24 hours.



• Do not take more than 6 inhalations at any one time.

Children and adolescents (6 to 17 years)

• The usual dose is 1 or 2 inhalations before exercise.



• A total daily dose of more than 4 inhalations is not normally needed. This includes the inhalations that your child takes every day, when they get asthma symptoms and before exercise. However, your doctor may allow your child to take up to 8 inhalations a day. Your child should not use more than 8 inhalations in total in 24 hours.



• Your child should not have more than 2 inhalations at any one time.

Chronic obstructive pulmonary disease (COPD)

• Only to be used by adults (aged 18 years and above).



• The usual dose is 2 inhalations once or twice a day.



• Your doctor may advise you to take extra doses for relief of your COPD symptoms.



• You should not have more than 8 inhalations a day.



• Do not take more than 4 inhalations at any one time.

How to take an inhalation

Every time you need to take an inhalation, follow the instructions below.

• 1. Unscrew the white cover and lift it off.

• 2. Hold your Turbohaler upright with the turquoise grip at the bottom.

• 3. Do not hold the mouthpiece when you load your Turbohaler. To load your Turbohaler with a dose, turn the turquoise grip as far as it will go in one direction. Then turn it as far as it will go in the other direction (it does not matter which way you turn it first). You should hear a click sound. Your Turbohaler is now loaded and ready to use. It is not possible to overload your Turbohaler even if you turn the grip several times. Only load your Turbohaler when you need to use it.
  
  



• 4. Hold your Turbohaler away from your mouth. Breathe out gently (as far as is comfortable). Do not breathe out through your Turbohaler.
  
  



• 5. Place the mouthpiece gently between your teeth. Close your lips. Breathe in as deeply and as hard as you can through your mouth. Do not chew or bite on the mouthpiece.

• 6. Remove your Turbohaler from your mouth. Then breathe out gently. The amount of medicine that is inhaled is very small. This means you may not be able to taste it after inhalation. If you have followed the instructions, you can still be confident that you have inhaled the dose and the medicine is now in your lungs.
  
  



• 7. If you are to take a second inhalation, repeat steps 2 to 6.
  
  



• 8. Replace the cover tightly after use.

Do not try to remove or twist the mouthpiece. It is fixed to your Turbohaler and must not be taken off. Do not use your Turbohaler if it has been damaged or if the mouthpiece has come apart from your Turbohaler.

Cleaning your Turbohaler

Wipe the outside of the mouthpiece once a week with a dry tissue. Do not use water or liquids.

When to start using a new Turbohaler

• The Turbohaler contains 60 doses (inhalations). The dose indicator tells you how many doses are left in the Turbohaler.



• When you first see a red mark at the edge of the indicator window, there are approximately 20 doses left. When the red mark reaches the bottom of the indicator window, you must start using your new Turbohaler.

Note:

• The grip will still twist and ‘click’ even when your Turbohaler is empty.



• The sound that you hear as you shake your Turbohaler is produced by a drying agent and not the medicine. Therefore the sound does not tell you how much medicine is left in your Turbohaler.

If you use more Oxis Turbohaler than you should

If you use more Oxis Turbohaler than you should, contact your doctor or pharmacist for advice immediately. The following effects may happen: trembling, headache or a rapid heart beat.

If you forget to use Oxis Turbohaler

• If you forget to take a dose, take it as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose.



• Do not take a double dose to make up for a forgotten dose.

If you stop using Oxis Turbohaler

Do not stop using Oxis Turbohaler without talking to your doctor.

If you have any further questions on using your Turbohaler, ask your doctor, nurse or pharmacist.

Possible side effects

Like all medicines, Oxis Turbohaler can cause side effects, although not everybody gets them.

If the following happens to you, stop using Oxis Turbohaler and talk to your doctor immediately:

• Bronchospasm (tightening of the muscles in the airways which causes sudden wheezing) after inhaling your medicine. This happens very rarely, affecting less than 1 in 10,000 people.

Other possible side effects:

Common (affects less than 1 in 10 people)

• Palpitations (awareness of your heart beating), trembling or shaking. If these effects occur, they are usually mild and usually disappear as you continue to use Oxis Turbohaler.


• Headache.

Uncommon (affects less than 1 in 100 people)

• Feeling restless or agitated.


• Disturbed sleep.


• Fast heart beat.


• Muscle cramps.

Rare (affects less than 1 in 1,000 people)

• Uneven heart beat.


• Nausea (feeling sick).


• Low or high levels of potassium in your blood.


• Allergic reactions such as rash, itching and bronchospasm.

Very rare (affects less than 1 in 10,000 people)

• Chest pain or tightness in the chest (angina pectoris).


• An increase in the amount of sugar (glucose) in your blood.


• Taste changes, such as an unpleasant taste in the mouth.


• Changes in your blood pressure.


• Feeling dizzy.

If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Oxis Turbohaler

• Keep out of the reach and sight of children.


• Do not store above 30°C.


• When not in use, Oxis Turbohaler should be stored with the cover tightened.


• Do not use Oxis Turbohaler after the expiry date printed on the carton or on the side of your Turbohaler. The expiry date refers to the last day of that month.


• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. This will help to protect the environment.

Further information

What Oxis Turbohaler 6 contains

The active substance is formoterol fumarate dihydrate.

Each dose contains 6 micrograms of formoterol fumarate dihydrate of which you can inhale 4.5 micrograms..

The other ingredient is lactose monohydrate (which contains milk proteins).

What Oxis Turbohaler 6 looks like and contents of the pack

Oxis Turbohaler 6 is an inhaler containing your medicine. The inhalation powder is white in colour. Each Turbohaler contains 60 doses and has a white body with a turquoise turning grip.

Oxis Turbohaler 6 is available in packs of 1, 3, 10, 18 or 20 Turbohalers.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for Oxis Turbohaler 6 is held by

AstraZeneca UK Ltd

600 Capability Green

Luton

LU1 3LU

UK

Oxis Turbohaler 6 is manufactured by

AstraZeneca AB

S-151 85 Södertälje

Sweden

Oxis Turbohaler is authorised in the Member States of the EEA under the following names:

Austria: Oxis Turbohaler 6 μg – Dosier - Pulverinhalator

Belgium: Oxis Turbohaler 4,5 μg/dose

Denmark: Oxis Turbuhaler

Finland: Oxis Turbuhaler

France: Oxis Turbuhaler 6 μg par dose

Germany: Oxis Turbohaler 6 Mikrogramm Pulver zur Inhalation

Greece: Oxez Turbuhaler

Ireland: Oxis Turbohaler 6, inhalation powder

Italy: Oxis Turbohaler 4.5

Luxembourg: Oxis Turbohaler 4.5 μg/dose

The Netherlands: Oxis 6 Turbuhaler

Portugal: Oxis Turbohaler

Spain: Oxis Turbuhaler 4.5 microgramos polvo para inhalación

Sweden: Oxis Turbuhaler

UK: Oxis Turbohaler 6, inhalation powder

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name
Oxis Turbohaler 6

Reference number
17901/0154

This is a service provided by the Royal National Institute of Blind People.

This leaflet was last approved in 2008-09-18

© AstraZeneca 2008

Oxis and Turbohaler are trade marks of the AstraZeneca group of companies.

RSP 08 0001a

Oruvail 200mg Capsules

1. Name Of The Medicinal Product

Oruvail 200

2. Qualitative And Quantitative Composition

Ketoprofen 200mg

3. Pharmaceutical Form

Controlled release capsules

4. Clinical Particulars

4.1 Therapeutic Indications

Oruvail is recommended in the management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and peri-articular disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low back pain (strain, lumbago, sciatica, fibrositis), painful musculo-skeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery.

Oruvail reduces joint pain and inflammation and facilitates increase in mobility and functional independence. As with other non-steroidal anti-inflammatory agents, it does not cure the underlying disease.

4.2 Posology And Method Of Administration

Adults: 100 - 200mg once daily, depending on patient weight and on severity of symptoms.

The maximum daily dose is 200mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200mg daily, and higher doses are not recommended (see also section 4.4).

Elderly: 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.

Paediatric dosage not established.

Oruvail capsules are for oral administration. 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

Ketoprofen is contraindicated in patients who have a history of hypersensitivity reactions such as bronchospasm, asthmatic attacks, rhinitis, angioedema, urticaria or other allergic-type reactions to ketoprofen, any other ingredients in this medicine, ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8 Undesirable effects).

Ketoprofen is contraindicated in patients with hypersensitivity to any of the excipients of the drug.

Ketoprofen is also contraindicated in the third trimester of pregnancy.

Ketoprofen is contraindicated in the following cases:

- severe heart failure

- 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

- haemorrhagic diathesis

- severe hepatic insufficiency

- severe renal insufficiency

- third trimester of pregnancy

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 section 4.2 Posology and method of administration, and GI and cardiovascular risks below).

The use of ketoprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5 Interactions).

Elderly:

The elderly have an increased risk of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2 Posology and method of administration).

Cardiovascular, Renal and Hepatic impairment:

At the start of treatment, renal function must be carefully monitored in patients with heart impairment, heart failure, liver dysfunction, cirrhosis and nephrosis, in patients receiving diuretic therapy, in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decomposition. (see Section 4.3 Contra-indications)

NSAIDs have also been reported to cause nephrotoxicity in various forms and this can lead to interstitial nephritis, nephrotic syndrome and renal failure.

In patients with abnormal liver function tests or with a history of liver disease, transaminase levels should be evaluated periodically, particularly during long-term therapy. Rare cases of jaundice and hepatitis have been described with ketoprofen.

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 ketoprofen.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ketoprofen after careful consideration. Similar consideration should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Respiratory disorders:

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to aspirin or NSAIDs (see section 4.3).

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.

Some epidemiological evidence suggests that ketoprofen may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially at high doses (see also section 4.2 and 4.3).

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAlD doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

NSAIDs should only be given with care to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8 Undesirable effects).

Patients with a history of gastrointestinal 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 corticosteroids, or 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 ketoprofen, the treatment should be withdrawn.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosis (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis (see Section 4.8 Undesirable effects).

Female fertility:

The use of ketoprofen, as with other NSAIDs, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of ketoprofen should be considered.

Skin reactions:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Infectious disease:

As with other NSAIDs, in the presence of an infectious disease, it should be noted that the anti-inflammatory, analgesic and the antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever.

Visual disturbances:

If visual disturbances such as blurred vision occur, treatment should be discontinued.

Patients with active or a past history of peptic ulcer.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel):

Increased risk of bleeding (see section 4.4)

If coadministration is unavoidable, patient should be closely monitored.

Lithium:

Risk of elevation of lithium plasma levels, sometimes reaching toxic levels due to decreased lithium renal excretion. Where necessary, plasma lithium levels should be closely monitored and the lithium dosage levels adjusted during and after NSAIDs therapy.

Other analgesics/NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates:

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects, particularly gastrointestinal ulceration and bleeding. (see Section 4.4 Special warnings and precautions for use).

Methotrexate:

Serious interactions have been recorded after the use of high dose methotrexate with NSAIDs, including ketoprofen, due to decreased elimination of methotrexate. At doses greater than 15mg/week:

Increased risk of haematologic toxicity of methotrexate, particularly if administered at high doses (> 15 mg/week), possibly related to displacement of protein-bound methotrexate and to its decreased renal clearance. At doses lower than 15mg/week: During the first weeks of combination treatment, full blood count should be monitored weekly. If there is any alteration of the renal function or if the patient is elderly, monitoring should be done more frequently.

Mifepristone:

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

Pentoxifylline:

There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.

Antihypertensive agents (beta-blockers, angiotensin converting enzyme inhibitors, diuretics):

Risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs).

Diuretics:

Risk of reduced diuretic effect. Patients and particularly dehydrated patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated before initiating coadministration therapy and renal function monitored when the treatment is started (see section 4.4 Special warnings and precautions for use).

Cardiac glycosides:

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

Ciclosporin:

Increased risk of nephrotoxicity, particularly in elderly subjects.

Corticosteroids:

Increased risk of gastrointestinal ulceration or bleeding. (see Section 4.4 Special warnings and precautions for use).

Quinolone antibiotics:

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

Tacrolimus:

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus, particularly in elderly subjects.

Thrombolytics:

Increased risk of bleeding.

Probenecid:

Concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen.

Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs):

Increased risk of gastrointestinal bleeding (section 4.4 Special warnings and precautions for use).

ACE inhibitors and Angiotensin II Antagonists:

In patients with compromised renal function (e.g. dehydrated patients or elderly patients the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure.

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.

4.6 Pregnancy And Lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, ketoprofen should not be given unless clearly necessary. If ketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of the pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- Inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, ketoprofen is contraindicated during the third trimester of pregnancy.

Lactation

No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned about the potential for somnolence, dizziness or convulsions, drowsiness, fatigue and visual disturbances and be advised not to drive or operate machinery if these symptoms occur.

4.8 Undesirable Effects

The following CIOMS frequency rating is used, when applicable:

Very common (

The following adverse reactions have been reported with Ketoprofen in adults:

Blood and lymphatic system disorders

- rare: haemorrhagic anaemia, anaemia due to bleeding

- not known: agranulocytosis, thrombocytopenia, bone marrow failure, neutropenia

Immune system disorders

- rare: anaphylactic reactions (including shock)

Psychiatric disorders

- not known: mood altered

Nervous system disorders

- uncommon: headache, dizziness, somnolence

- rare: paraesthesia

- not known: convulsions, dysgeusia, depression, confusion, hallucinations, vertigo, malaise, drowsiness, reports of aseptic meningitis (especially in patients with existing auto-immune disorders such as systemic lupus erythematosis, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4 Special warnings and precautions for use).

Eye disorders

- rare: visual disturbances such as blurred vision (see section 4.4 Special warnings and precautions for use)

- not known: optic neuritis

Ear and labyrinth disorders

- rare: tinnitus

Cardiac disorders

- not known: heart failure, oedema

Vascular disorders

- not known: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

- rare: asthma, asthmatic attack

- not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis, non-specific allergic reactions, dyspnoea

Gastrointestinal disorders

- common: dyspepsia, nausea, abdominal pain, vomiting

- uncommon: constipation, diarrhoea, flatulence, gastritis

- rare: stomatitis, peptic ulcer

- very rare: pancreatitis (very rare reports of pancreatitis have been noted with NSAIDs)

- not known: exacerbation of colitis and Crohn's disease, gastrointestinal haemorrhage and perforation, gastralgia, melaena, haematemesis

Gastrointestinal bleeding may sometimes be fatal, particularly in the elderly (see section 4.4 Special warnings and precautions for use).

Hepatobiliary disorders

- rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis disorders

- not known: abnormal liver function, jaundice

Skin and subcutaneous disorders

- uncommon: rash, pruritis

- not known: photosensitivity reactions, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis, exfoliative and bullous dermatoses (including epidermal necrolysis, erythema multiforme), purpura

Renal and urinary disorders

- not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome, renal function tests abnormal

General disorders and administration site conditions

- uncommon: oedema, fatigue

- not known: headache, taste perversion

Investigations

- rare: weight increased

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 Special warnings and precautions for use).

In all cases of major adverse effects Oruvail should be withdrawn at once.

4.9 Overdose

Symptoms

Cases of overdose have been reported with doses up to 2.5g of ketoprofen. In most instances, the symptoms have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. Headache, rarely diarrhoea, disorientation, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions may also occur. Adverse effects seen after overdose with propionic acid derivatives such as hypotension, bronchospasm and gastro-intestinal haemorrhage should be anticipated.

In cases of significant poisoning, acute renal failure and liver damage are possible.

If renal failure is present, haemodialysis may be useful to remove circulating medicinal product.

Therapeutic measures:

There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present.

Owing to the slow release characteristics of Oruvail, it should be expected that ketoprofen will continue to be absorbed for up to 16 hours after ingestion.

Within one hour of ingestion, consideration should be given to administering activated charcoal in an attempt to reduce absorption of slowly-released ketoprofen.

Alternatively, in adults, gastric lavage, aimed at recovering pellets that may still be in the stomach, should be considered if the patient presents within 1 hour of ingesting a potentially toxic amount.

It should be possible to identify the pellets in the gastric contents. Correction of severe electrolyte abnormalities may need to be considered.

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.

The benefit of gastric decontamination is uncertain.

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ketoprofen overall has the properties of a potent non-steroidal anti- inflammatory agent. It has the following pharmacological effects:

Anti-inflammatory

It inhibits the development of carageenan-induced abscesses in rats at 1mg/kg, UV-radiation induced erythema in guinea pigs at 6mg/kg. It is also a potent inhibitor of PGE₂ and PFG_2∝ synthesis in guinea pig and human chopped lung preparations.

Analgesic

Ketoprofen effectively reduced visceral pain in mice caused by phenyl benzoquinone or by bradykinin following p.o. Administration at about 6mg/kg.

Antipyretic

Ketoprofen (2 and 6mg/kg) inhibited hyperthermia caused by s.c injection of brewer's yeast in rats and, at 1mg/kg hyperthermia caused by i.v. administration of anticoagulant vaccine to rabbits.

Ketoprofen at 10mg/kg i.v. did not affect the cardiovascular, respiratory, central nervous system or autonomic nervous systems.

5.2 Pharmacokinetic Properties

Ketoprofen is slowly but completely absorbed from Oruvail capsules. Maximum plasma concentration occurs after 6 - 8 hours. It declines thereafter with a half-life of about 8 hours. There is no accumulation on continued daily dosing. Ketoprofen is very highly bound to plasma protein

5.3 Preclinical Safety Data

No additional data of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Pellets

Sugar spheres

Colloidal anhydrous silica

Shellac

Ethylcellulose

Talc

Capsule shell-body

Gelatin

Erythrosine (E127)

Capsule shell – cap

Gelatin

Titanium dioxide (E171)

6.2 Incompatibilities

None stated

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25°C in a dry place and protect from light.

6.5 Nature And Contents Of Container

UPVC/Aluminium foil blister or UPVC coated with PVDC aluminium foil blister containing either 28 capsules

6.6 Special Precautions For Disposal And Other Handling

None stated

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0599

9. Date Of First Authorisation/Renewal Of The Authorisation

21 September 2006

10. Date Of Revision Of The Text

11 May 2011

LEGAL CLASSIFICATION

POM