Jext 150 micrograms Solution for Injection in pre-filled pen

1. Name Of The Medicinal Product

Jext 150 micrograms solution for injection in pre-filled pen

2. Qualitative And Quantitative Composition

Jext 150 micrograms: One pre-filled pen delivers one dose of 0.15ml solution for injection containing 150 micrograms of adrenaline (as tartrate).

1 ml solution contains 1mg adrenaline (as tartrate).

Excipients: Sodium metabisulphite (E223) and sodium chloride.

Jext contains less than 1 mmol sodium (23 mg) per dose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection in pre-filled pen.

Clear and colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Jext is indicated in the emergency treatment of severe acute allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis.

4.2 Posology And Method Of Administration

Posology:

Paediatric population

Patients between 15 kg and 30 kg in weight:

The usual dose is 150 micrograms.

A dosage below 150 micrograms cannot be administered in sufficient accuracy in children weighing less than 15 kg and use is therefore not recommended unless life-threatening situation and under medical advice. Children and adolescents over 30 kg in weight should be prescribed a Jext 300 micrograms.

An initial dose should be administered as soon as symptoms of anaphylaxis are recognised.

The effective dose is typically in the range of 0.005-0.01 mg/kg but higher doses may be necessary in some cases.

In the absence of clinical improvement or if deterioration occurs, a second injection with an additional Jext may be administered 5 – 15 minutes after the first injection.

Method of administation:

For intramuscular use.

For single use.

Jext is for intramuscular administration into the anterolateral thigh.

It is designed to inject through clothing or directly through the skin.

Massage around the injection area is advised to accelerate absorption.

Please refer to section 6.6 for detailed instructions for use

4.3 Contraindications

There are no absolute contraindications to the use of Jext during an allergic emergency.

4.4 Special Warnings And Precautions For Use

Do not remove yellow cap until ready for use.

Jext should be administered into the anterolateral thigh. The injection is delivered immediately after the black needle shield of the auto-injector is pressed firmly against the skin or other surface. Patients should be advised not to inject Jext into the gluteus maximus due to the risk of accidental injection into a vein.

The patient should be instructed to seek emergency medical assistance immediately after administering the first dose in order to have close monitoring of the anaphylactic episode and further treatment as required.

Jext contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma. Patients with these conditions must be carefully instructed in regard to the circumstances under which Jext should be used.

Due to an increased risk of adverse reactions following administration of adrenaline special caution should be taken in patients with cardiovascular diseases including angina pectoris, obstructive cardiomyopathy, cardiac arrhythmia, cor pulmonale, atherosclerosis and hypertension.

Special caution should also be taken in patients with hyperthyroidism, phaeochromocytoma, narrow angle glaucoma, severe renal impairment, prostatic adenoma leading to residual urine, hypercalcaemia, hypokalaemia and diabetes.

Caution should also be taken in elderly and pregnant patients.

Peripheral ischaemia following accidental injection into hands or feet may cause loss of blood flow to adjacent areas due to vasoconstriction.

All patients who are prescribed Jext should be thoroughly instructed to understand the indications for use and the correct method of administration.

There is often a prolonged period between supply of Jext and an allergic reaction requiring adrenaline. Patients should be advised to regularly check Jext and ensure it is replaced within the expiry period.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium free.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution is indicated in patients receiving drugs that may sensitise the heart to arrhythmias, including digitalis and quinidine. The effects of adrenaline may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors (MAO-inhibitors) and catechol-O-methyl transferase inhibitors (COMT inhibitors).

Adrenaline inhibits the secretion of insulin, thus increasing the blood glucose level. It may be necessary for diabetic patients receiving adrenaline to increase their dosage of insulin or oral hypoglycaemic drugs.

The alpha- and beta-stimulating effect can be inhibited by concomitant use of alpha- and beta-blocking drugs as well as parasympathomimetic drugs.

4.6 Pregnancy And Lactation

Clinical experience in the treatment of anaphylaxis during pregnancy is limited. Adrenaline should only be used during pregnancy if the potential benefit justifies the potential risk for the foetus.

Adrenaline is not orally bioavailable; any adrenaline excreted in breast milk would not be expected to have any effect on the nursing infant.

4.7 Effects On Ability To Drive And Use Machines

Jext has no or negligible influence on the ability to drive and use machines, however,patients are not recommended to drive or use machines following administration of adrenaline, since they will be affected by the anaphylactic reaction.

4.8 Undesirable Effects

Side effects associated with adrenaline's alpha and beta receptor activity may include cardiovascular effects as well as undesirable effects on the central nervous system.

The following table is based upon post marketing experience with the use of adrenaline. The frequency cannot be estimated from the available data.

System Organ Class	Adverse Drug Reaction
Metabolism and nutrition disorders	Hyperglycaemia, hypokalaemia, metabolic acidosis
Psychiatric disorders	Anxiety, hallucination
Nervous system disorders	Headache, dizziness, tremor, syncope
Cardiac disorders	Tachycardia, arrhythmia, palpitations, angina pectoris, stress cardiomyopathy
Vascular disorders	Hypertension, vasoconstriction, peripheral ischaemia
Respiratory, thoracic and mediastinal disorders	Bronchospasm
Gastrointestinal disorders	Nausea, vomiting
General disorders and administration site conditions	Hyperhidrosis, asthenia

Peripheral ischaemia following accidental injection of adrenaline in the hands or feet has been reported.

Jext contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions including anaphylactic symptoms and bronchospasm (see section 4.4. Special warning and precautions for use).

4.9 Overdose

Overdose or inadvertent intravascular injection of adrenaline may cause cerebral haemorrhage and ventricular arrhythmias resulting from a sharp rise in blood pressure. Myocardial ischaemias and necroses as well as renal impairment may occur. Fatalities may also result from pulmonary oedema because of peripheral vascular constriction together with cardiac stimulation.

Pulmonary oedema may be treated with alpha-blocking agents such as phentolamine. In case of arrhythmias these may be treated with beta-blocking agents.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cardiac stimulants excl. cardiac glycosides, adrenergic and dopaminergic agents.

ATC code: C01CA24.

Adrenaline is a catecholamine which stimulates the sympathetic nervous system (both alpha and beta receptors) by which cardiac rate, cardiac output and coronary circulation is raised. Adrenaline through its action on beta receptors on bronchial smooth muscles causes bronchial smooth muscle relaxation which alleviates wheezing and dyspnoea.

5.2 Pharmacokinetic Properties

Adrenaline is a naturally occurring substance produced by the adrenal medulla and secreted in response to exertion or stress. It is rapidly inactivated in the body mostly by the enzymes COMT and MAO. The liver is rich in these enzymes and is an important, although not essential, tissue in the degradation process. Much of the dose of adrenaline is accounted for by excretion of metabolites in the urine.

The plasma half-life of adrenaline is about 2.5 min. However local vasoconstriction may retard absorption, so that the effects can last longer than the half-life would predict. Massage around the injection area is advised to accelerate absorption.

5.3 Preclinical Safety Data

Adrenaline has been utilised in the treatment of allergic emergencies for many years. There is no preclinical data of relevance available.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Sodium Metabisulphite (E223)

Hydrochloric Acid (for pH adjustment)

Water for Injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not freeze.

6.5 Nature And Contents Of Container

Pre-filled pen (single dose pen) comprising an auto-injector with a cartridge. The cartridge is made of glass (type 1), sealed with a latex free grey rubber plunger and a latex free bromobutyl rubber seal within an anodised aluminium cap. The auto-injector is made of plastic.

Pack-size: 1 pre-filled pen

6.6 Special Precautions For Disposal And Other Handling

Jext is a single-use pre-filled pen designed for easy use.

The pre-filled pen is operated by simply pressing the black injector tip against the outer thigh. This will activate a plunger, which pushes a concealed needle through the membrane on the black injector tip into the muscle and injects a dose of adrenaline. This can be done through clothing.

Jext 150 micrograms contains 1.4 ml of adrenaline injection 1 mg/ml which is designed to deliver a single dose (0.15 ml) of 150 micrograms adrenaline when activated. After activation of the auto-injector 1.25 ml remains in the pre-filled pen. Discard any unused solution.

A small air bubble may occur in Jext. It has no influence on either the use or the efficacy of the product.

The prescriber may use a “Jext Simulator” during patient instruction. This is a pen without needle or adrenaline, which is also available for patients or carers who may wish to practise at home.

Note: the yellow cap prevents the device from activating, and should not be removed before injection is required. The black injector tip should be kept away from the hand.

	1. Grasp the Jext injector in your dominant hand (the one you use to write with) with your thumb closest to the yellow cap.
	2. Pull off the yellow cap with your other hand.
	3. Place the black injector tip against your outer thigh, holding the injector at a right angle (approx 90°) to the thigh.
	4. Push the black tip firmly into your outer thigh until you hear a 'click' confirming the injection has started, then keep it pushed in. Hold the injector firmly in place against the thigh for 10 seconds (a slow count to 10) then remove. The black tip will extend automatically and hide the needle.
	5. Massage the injection area for 10 seconds. Seek immediate medical help.

Any expired products should be disposed of in accordance with local requirements.

Check the solution periodically through the viewing window of the unit to make sure the solution is clear and colourless.

The solution darkens in colour upon exposure to air or light.

Replace and discard the pre-filled pen if the solution is discoloured or contains a precipitate, or at the latest before the expiry date.

The expiry date is indicated on the label and Jext should not be used after this date.

7. Marketing Authorisation Holder

ALK-Abelló A/S

Bøge Allé 6-8

DK-2970 Hørsholm

8. Marketing Authorisation Number(S)

PL 10085/0052

9. Date Of First Authorisation/Renewal Of The Authorisation

12-11-2010

10. Date Of Revision Of The Text

12-11-2010

Xamiol gel

1. Name Of The Medicinal Product

Xamiol 50 micrograms/g + 0.5 mg/g gel

2. Qualitative And Quantitative Composition

One gram of gel contains 50 micrograms of calcipotriol (as monohydrate) and 0.5 mg of betamethasone (as dipropionate).

Excipient: 160 micrograms butylated hydroxytoluene/g gel.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gel.

An almost clear, colourless to slightly off-white gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Topical treatment of scalp psoriasis in adults.

4.2 Posology And Method Of Administration

Posology

Xamiol gel should be applied to affected areas once daily. The recommended treatment period is 4 weeks. If it is necessary to continue or restart treatment after this period, treatment should be continued after medical review and under regular medical supervision.

When using calcipotriol containing medicinal products, the maximum daily dose should not exceed 15 g. The body surface area treated with calcipotriol containing medicinal products should not exceed 30% (see section 4.4).

All the affected scalp areas may be treated with Xamiol gel. Usually an amount between 1 g and 4 g per day is sufficient for treatment of the scalp (4g corresponds to one teaspoon).

Special populations

Renal and hepatic impairment

The safety and efficacy of Xamiol gel in patients with severe renal insufficiency or severe hepatic disorders have not been evaluated.

Paediatric population

The safety and efficacy of Xamiol gel in children below 18 years have not been established. No data are available.

Method of administration

The bottle should be shaken before use and Xamiol gel applied to the affected area. Xamiol gel should not be applied directly to the face or eyes. The hands should be washed after use. In order to achieve optimal effect, it is not recommended to wash the hair immediately after application of Xamiol gel. Xamiol gel should remain on the scalp during the night or during the day.

4.3 Contraindications

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

Xamiol gel is contraindicated in erythrodermic, exfoliative and pustular psoriasis.

Due to the content of calcipotriol, Xamiol gel is contraindicated in patients with known disorders of calcium metabolism.

Due to the content of corticosteroid, Xamiol gel is contraindicated in the following conditions: Viral (e.g. herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis or syphilis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds, perianal and genital pruritus.

4.4 Special Warnings And Precautions For Use

Effects on endocrine system

Xamiol gel contains a potent group III steroid and concurrent treatment with other steroids on the scalp must be avoided. Adverse reactions found in connection with systemic corticosteroid treatment, such as adrenocortical suppression or impact on the metabolic control of diabetes mellitus, may occur also during topical corticosteroid treatment due to systemic absorption. Application under occlusive dressings should be avoided since it increases the systemic absorption of corticosteroids. Application on large areas of damaged skin or on mucous membranes or in skin folds should be avoided since it increases the systemic absorption of corticosteroids (see section 4.8).

In a study in patients with both extensive scalp and extensive body psoriasis using a combination of high doses of Xamiol gel (scalp application) and high doses of Dovobet ointment (body application), 5 of 32 patients showed a borderline decrease in cortisol response to adrenocorticotropic hormone (ACTH) challenge after 4 weeks of treatment (see section 5.1).

Effects on calcium metabolism

Due to the content of calcipotriol, hypercalcaemia may occur if the maximum daily dose (15 g) is exceeded. Serum calcium is, however, quickly normalised when treatment is discontinued. The risk of hypercalcaemia is minimal when the recommendations relevant to calcipotriol are followed.

Treatment of more than 30% of the body surface should be avoided (see section 4.2).

Local adverse reactions

Skin of the face and genitals are very sensitive to corticosteroids. The medicinal product should not be used in these areas. Uncommon local adverse reactions (such as eye irritation or irritation of facial skin) were observed, when the medicinal product was accidentally administered in the area of face, or accidentally to the eyes or conjunctives (see sections 4.8 and 5.1). The patient must be instructed in correct use of the medicinal product to avoid application and accidental transfer to the face, mouth and eyes. Hands must be washed after each application to avoid accidental transfer to these areas.

Concomitant skin infections

When lesions become secondarily infected, they should be treated with antimicrobiological therapy. However, if infection worsens, treatment with corticosteroids should be stopped.

Discontinuation of treatment

When treating psoriasis with topical corticosteroids, there may be a risk of generalised pustular psoriasis or of rebound effects when discontinuing treatment. Medical supervision should therefore continue in the post-treatment period.

Long-term use

With long-term use there is an increased risk of local and systemic corticosteroid adverse reactions. The treatment should be discontinued in case of adverse reactions related to long-term use of corticosteroid (see section 4.8).

Unevaluated uses

There is no experience for the use of Xamiol gel in guttate psoriasis.

Concurrent treatment and UV exposure

Dovobet ointment for body psoriasis lesions has been used in combination with Xamiol gel for scalp psoriasis lesions, but there is no experience of combination of Xamiol with other topical anti-psoriatic products at the same treatment area, other anti-psoriatic medicinal products administered systemically or with phototherapy.

During Xamiol gel treatment, physicians are recommended to advise patients to limit or avoid excessive exposure to either natural or artificial sunlight. Topical calcipotriol should be used with UVR only if the physician and patient consider that the potential benefits outweigh the potential risks (see section 5.3).

Adverse reactions to excipients

Xamiol gel contains butylated hydroxytoluene (E321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Xamiol gel in pregnant women. Studies in animals with glucocorticoids have shown reproductive toxicity (see section 5.3), but a number of epidemiological studies have not revealed congenital anomalies among infants born to women treated with corticosteroids during pregnancy. The potential risk for humans is uncertain. Therefore, during pregnancy, Xamiol gel should only be used when the potential benefit justifies the potential risk.

Breastfeeding

Betamethasone passes into breast milk, but risk of an adverse effect on the infant seems unlikely with therapeutic doses. There are no data on the excretion of calcipotriol in breast milk. Caution should be exercised when prescribing Xamiol gel to women who breast-feed.

Fertility

Studies in rats with oral doses of calcipotriol or betamethasone dipropionate demonstrated no impairment of male and female fertility

4.7 Effects On Ability To Drive And Use Machines

Xamiol gel has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

The clinical trial programme for Xamiol gel has so far included more than 4,400 patients of whom more than 1,900 were treated with Xamiol gel. Approximately 8% of patients treated with Xamiol gel experienced a non-serious adverse reaction.

These reactions are usually mild and cover mainly various skin reactions with pruritus being the most common.

Based on data from clinical trials and postmarket use the following adverse reactions are listed for Xamiol gel.

The adverse reactions are listed by MedDRA System Organ Class, and the individual adverse reactions are listed starting with the most frequently reported. Within each frequency grouping, the adverse reactions are listed in order of decreasing seriousness.

The following terminologies have been used in order to classify the frequencies of adverse reactions:

Very common	1/10
Common	1/100 to <1/10
Uncommon	1/1,000 to <1/100
Rare	1/10,000 to <1/1,000
Very rare	<1/10,000

Not known (cannot be estimated from the available data)

Eye disorders
Uncommon	Eye irritation
Skin and subcutaneous tissue disorders
Common	Pruritus
Uncommon	Exacerbation of psoriasis Burning sensation of skin Skin pain or irritation Folliculitis Dermatitis Erythema Acne Dry skin Rash Pustular rash

The following adverse reactions are considered to be related to the pharmacological classes of calcipotriol and betamethasone, respectively:

Calcipotriol

Adverse reactions include application site reactions, pruritus, skin irritation, burning and stinging sensation, dry skin, erythema, rash, dermatitis, eczema, psoriasis aggravated, photosensitivity and hypersensitivity reactions including very rare cases of angioedema and facial oedema. Systemic effects after topical use may appear very rarely causing hypercalcaemia or hypercalciuria (see section 4.4).

Betamethasone (as dipropionate)

Local reactions can occur after topical use, especially during prolonged application, including skin atrophy, telangiectasia, striae, folliculitis, hypertrichosis, perioral dermatitis, allergic contact dermatitis, depigmentation and colloid milia. When treating psoriasis, there may be a risk of generalised pustular psoriasis.

Systemic reactions due to topical use of corticosteroids are rare in adults, however they can be severe. Adrenocortical suppression, cataract, infections, impact on the metabolic control of diabetes mellitus and increase of intra-ocular pressure can occur, especially after long-term treatment. Systemic reactions occur more frequently when applied under occlusion (plastic, skin folds), when applied on large areas and during long-term treatment (see section 4.4).

4.9 Overdose

Use above the recommended dose may cause elevated serum calcium which should rapidly subside when treatment is discontinued.

Excessive prolonged use of topical corticosteroids may suppress the pituitary-adrenal functions, resulting in secondary adrenal insufficiency which is usually reversible. In such cases, symptomatic treatment is indicated.

In case of chronic toxicity, the corticosteroid treatment must be discontinued gradually.

It has been reported that due to misuse one patient with extensive erythrodermic psoriasis treated with 240 g of Dovobet ointment weekly (corresponding to a daily dose of approximately 34g) for 5 months (maximum recommended dose 15g daily) developed Cushing's syndrome and pustular psoriasis after abruptly stopping treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations.

ATC Code: D05AX52

Calcipotriol is a vitamin D analogue. In vitro data suggest that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.

Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties, however, without curing the underlying condition. Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. In general, the mechanism of the anti-inflammatory activity of the topical steroids is unclear.

Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Xamiol gel and Dovobet ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients. With regard to HPA suppression, therefore, this study shows some evidence that very high doses of Xamiol gel and Dovobet ointment may have a weak effect on the HPA axis.

The efficacy of once daily use of Xamiol gel was investigated in two randomised, double-blind, 8-week clinical studies including a total of more than 2,900 patients with scalp psoriasis of at least mild severity according to the Investigator's Global Assessment of disease severity (IGA). Comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and (in one of the studies) the gel vehicle alone, all used once daily. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than the comparators. Results for speed of onset based on similar data at week 2 also showed Xamiol gel to be statistically significantly more effective than the comparators.

% of patients with absent or very mild disease	Xamiol gel (n=1,108)	Betamethasone dipropionate (n=1,118)	Calcipotriol (n=558)	Gel vehicle (n=136)
week 2	53.2 %	42.8 %1	17.2 %1	11.8 %1
week 8	69.8 %	62.5 %1	40.1 %1	22.8 %1

¹ Statistically significantly less effective than Xamiol gel (P<0.001)

Another randomised, investigator-blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA investigated use of Xamiol gel once daily compared with Dovonex Scalp solution twice daily for up to 8 weeks. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that Xamiol gel was statistically significantly more effective than Dovonex Scalp solution.

% of patients with absent or very mild disease	Xamiol gel (n=207)	Dovonex Scalp solution (n=105)
week 8	68.6 %	31.4 %1

¹ Statistically significantly less effective than Xamiol gel (P<0.001)

A randomised, double-blind long-term clinical study including 873 patients with scalp psoriasis of at least moderate severity (according to the IGA) investigated the use of Xamiol gel compared with calcipotriol in the gel vehicle. Both treatments were applied once daily, intermittently as required, for up to 52 weeks. Adverse events possibly related to long-term use of corticosteroids on the scalp, were identified by an independent, blinded panel of dermatologists. There was no difference in the percentages of patients experiencing such adverse events between the treatment groups (2.6% in the Xamiol gel group and 3.0% in the calcipotriol group; P=0.73). No cases of skin atrophy were reported.

5.2 Pharmacokinetic Properties

The systemic exposure to calcipotriol and betamethasone dipropionate from topically applied Xamiol gel is comparable to Dovobet ointment in rats and minipigs. Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Dovobet ointment formulation is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm²) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Absorption through damaged skin is approx. 24 %.

Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised. Protein binding is approx. 64 %. Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation of a depot in the skin elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in the kidneys to glucuronide and sulphate esters. The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate, respectively, showed that the kidney and liver had the highest level of radioactivity.

Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Xamiol gel and Dovobet ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.

5.3 Preclinical Safety Data

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.

A dermal carcinogenicity study with calcipotriol in mice revealed no special hazard to humans.

Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce skin tumours.

No carcinogenicity or photocarcinogenicity studies have been performed with betamethasone dipropionate.

In local tolerability studies in rabbits, Xamiol gel caused mild to moderate skin irritation and a slight transient irritation of the eye.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Paraffin, liquid

Polyoxypropylene-15 stearyl ether

Castor oil, hydrogenated

Butylhydroxytoluene (E321)

All-rac-α-tocopherol

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

After first opening: 3 months.

6.4 Special Precautions For Storage

Do not refrigerate. Keep the bottle in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

High-density polyethylene bottles with low-density polyethylene nozzle and a high-density polyethylene screw cap. The bottles are placed in cartons.

Pack sizes: 15, 30, 60 and 2 x 60 g.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

LEO Pharmaceutical Products Ltd. A/S

Industriparken 55

DK-2750 Ballerup

Denmark

8. Marketing Authorisation Number(S)

PL 05293/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

25/09/2008

10. Date Of Revision Of The Text

11/03/2011

Xeloda

1. Name Of The Medicinal Product

Xeloda 150 mg and 500 mg film-coated tablets.

2. Qualitative And Quantitative Composition

150 mg or 500 mg capecitabine.

Excipient: 15.6 mg anhydrous lactose (150 mg tablet).

Excipient: 52 mg anhydrous lactose (500 mg tablet).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Light peach film-coated tablet of biconvex, oblong shape with the marking '150' on the one side and 'Xeloda' on the other side.

Peach film-coated tablet of biconvex, oblong shape with the marking '500' on the one side and 'Xeloda' on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Xeloda is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer (see section 5.1).

Xeloda is indicated for the treatment of metastatic colorectal cancer (see section 5.1).

Xeloda is indicated for first-line treatment of advanced gastric cancer in combination with a platinum-based regimen (see section 5.1).

Xeloda in combination with docetaxel (see section 5.1) is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline. Xeloda is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.

4.2 Posology And Method Of Administration

Xeloda should only be prescribed by a qualified physician experienced in the utilisation of anti-neoplastic agents. Xeloda tablets should be swallowed with water within 30 minutes after a meal. Treatment should be discontinued if progressive disease or intolerable toxicity is observed. Standard and reduced dose calculations according to body surface area for starting doses of Xeloda of 1250 mg/m² and 1000 mg/m² are provided in tables 1 and 2, respectively.

Recommended posology (see section 5.1):

Monotherapy

Colon, colorectal and breast cancer

Given as single agent, the recommended starting dose for Xeloda in the adjuvant treatment of colon cancer, in the treatment of metastatic colorectal cancer or of locally advanced or metastatic breast cancer is 1250 mg/m² administered twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 14 days followed by a 7-day rest period. Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months.

Combination therapy

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of Xeloda should be reduced to 800 – 1000 mg/m² when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m² twice daily when administered continuously (see section 5.1). The inclusion of biological agents in a combination regimen has no effect on the starting dose of Xeloda. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the Xeloda plus cisplatin combination. Premedication with antiemetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the Xeloda plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for a duration of 6 months.

Breast cancer

In combination with docetaxel, the recommended starting dose of Xeloda in the treatment of metastatic breast cancer is 1250 mg/m² twice daily for 14 days followed by a 7-day rest period, combined with docetaxel at 75 mg/m² as a 1 hour intravenous infusion every 3 weeks. Pre-medication with an oral corticosteroid such as dexamethasone according to the docetaxel summary of product characteristics should be started prior to docetaxel administration for patients receiving the Xeloda plus docetaxel combination.

Xeloda Dose Calculations

Table 1 Standard and reduced dose calculations according to body surface area for a starting dose of Xeloda of 1250 mg/m²

	Dose level 1250 mg/m2 (twice daily)
	Full dose   1250 mg/m2	Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)	Reduced dose (75%) 950 mg/m2	Reduced dose (50%) 625 mg/m2
Body Surface Area (m2)	Dose per administration (mg)	150 mg	500 mg	Dose per administration (mg)	Dose per administration (mg)
	1500	-	3	1150	800
1.27 - 1.38	1650	1	3	1300	800
1.39 - 1.52	1800	2	3	1450	950
1.53 - 1.66	2000	-	4	1500	1000
1.67 - 1.78	2150	1	4	1650	1000
1.79 - 1.92	2300	2	4	1800	1150
1.93 - 2.06	2500	-	5	1950	1300
2.07 - 2.18	2650	1	5	2000	1300
	2800	2	5	2150	1450

Table 2 Standard and reduced dose calculations according to body surface area for a starting dose of Xeloda of 1000 mg/m²

	Dose level 1000 mg/m2 (twice daily)
	Full dose   1000 mg/m2	Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)	Reduced dose (75%) 750 mg/m2	Reduced dose (50%) 500 mg/m2
Body Surface Area (m2)	Dose per administration (mg)	150 mg	500 mg	Dose per administration (mg)	Dose per administration (mg)
	1150	1	2	800	600
1.27 - 1.38	1300	2	2	1000	600
1.39 - 1.52	1450	3	2	1100	750
1.53 - 1.66	1600	4	2	1200	800
1.67 - 1.78	1750	5	2	1300	800
1.79 - 1.92	1800	2	3	1400	900
1.93 - 2.06	2000	-	4	1500	1000
2.07 - 2.18	2150	1	4	1600	1050
	2300	2	4	1750	1100

Posology adjustments during treatment:

General

Toxicity due to Xeloda administration may be managed by symptomatic treatment and/or modification of the dose (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased at a later time. For those toxicities considered by the treating physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Patients taking Xeloda should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Doses of Xeloda omitted for toxicity are not replaced. The following are the recommended dose modifications for toxicity:

Table 3 Xeloda Dose Reduction Schedule (3-weekly Cycle or Continuous Treatment)

Toxicity grades*	Dose changes within a treatment cycle	Dose adjustment for next cycle/dose (% of starting dose)
• Grade 1	Maintain dose level	Maintain dose level
• Grade 2
-1st appearance	Interrupt until resolved to grade 0-1	100%
-2nd appearance	75%
-3rd appearance	50%
-4th appearance	Discontinue treatment permanently	Not applicable
• Grade 3
-1st appearance	Interrupt until resolved to grade 0-1	75%
-2nd appearance	50%
-3rd appearance	Discontinue treatment permanently	Not applicable
• Grade 4
-1st appearance	Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1	50%
-2nd appearance	Discontinue permanently	Not applicable

*According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria (version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 3.0. For hand-foot syndrome and hyperbilirubinemia, see section 4.4.

Haematology: Patients with baseline neutrophil counts of <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L should not be treated with Xeloda. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 x 10⁹/L or that the platelet count drops below 75 x 10⁹/L, treatment with Xeloda should be interrupted.

Dose modifications for toxicity when Xeloda is used as a 3 weekly cycle in combination with other agents:

Dose modifications for toxicity when Xeloda is used as a 3 weekly cycle in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either Xeloda or the other agent(s), then administration of all agents should be delayed until the requirements for restarting all drugs are met.

During a treatment cycle for those toxicities considered by the treating physician not to be related to Xeloda, Xeloda should be continued and the dose of the other agent should be adjusted according to the appropriate Prescribing Information.

If the other agent(s) have to be discontinued permanently, Xeloda treatment can be resumed when the requirements for restarting Xeloda are met.

This advice is applicable to all indications and to all special populations.

Dose modifications for toxicity when Xeloda is used continuously in combination with other agents:

Dose modifications for toxicity when Xeloda is used continuously in combination with other agents should be made according to Table 3 above for Xeloda and according to the appropriate summary of product characteristics for the other agent(s).

Posology adjustments for special populations:

Hepatic impairment: insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal impairment: Xeloda is contraindicated in patients with severe renal impairment (creatinine clearance below 30 ml/min [Cockcroft and Gault] at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min at baseline) is increased compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1250 mg/m² is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1000 mg/m². In patients with mild renal impairment (creatinine clearance 51-80 ml/min at baseline) no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse event during treatment and subsequent dose adjustment as outlined in Table 3 above. If the calculated creatinine clearance decreases during treatment to a value below 30 ml/min, Xeloda should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use (see also section “Elderly” below).

There is no experience in children (under 18 years).

Elderly:

During Xeloda monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients

When Xeloda was used in combination with other agents, elderly patients (

- In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1). For patients 60 years of age or more , a starting dose reduction of Xeloda to 75% (950 mg/m² twice daily) is recommended. If no toxicity is observed in patients ² twice daily.

- In combination with irinotecan: for patients 65 years of age or more, a starting dose reduction of Xeloda to 800 mg/m² twice daily is recommended.

4.3 Contraindications

• History of severe and unexpected reactions to fluoropyrimidine therapy,

• Hypersensitivity to capecitabine or to any of the excipients or fluorouracil,

• In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency,

• During pregnancy and lactation,

• In patients with severe leucopenia, neutropenia, or thrombocytopenia,

• In patients with severe hepatic impairment,

• In patients with severe renal impairment (creatinine clearance below 30 ml/min),

• Treatment with sorivudine or its chemically related analogues, such as brivudine (see section 4.5),

• If contraindications exist to any of the agents in the combination regimen, that agent should not be used.

4.4 Special Warnings And Precautions For Use

Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.

Diarrhoea. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard antidiarrhoeal treatments (e.g. loperamide) may be used. NCIC CTC grade 2 diarrhoea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhoea as an increase of 7 to 9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of

Dehydration. Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occurs, Xeloda treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be applied for the precipitating adverse event as necessary (see section 4.2).

Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysesthesia or chemotherapy induced acral erythema). Grade 1 hand- foot syndrome is defined as numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt the patient's normal activities.

Grade 2 hand- foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living.

Grade 3 hand- foot syndrome is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand- foot syndrome occurs, administration of Xeloda should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand- foot syndrome, subsequent doses of Xeloda should be decreased. When Xeloda and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand–foot syndrome, because of published reports that it may decrease the efficacy of cisplatin.

Cardiotoxicity. Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsade de pointes, and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving Xeloda. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris (See section 4.8).

Hypo- or hypercalcaemia. Hypo- or hypercalcaemia has been reported during Xeloda treatment. Caution must be exercised in patients with pre-existing hypo- or hypercalcaemia (see section 4.8).

Central or peripheral nervous system disease. Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy (see section 4.8).

Diabetes mellitus or electrolyte disturbances. Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during Xeloda treatment.

Coumarin-derivative anticoagulation. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients receiving concomitant Xeloda and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly (see section 4.5).

Hepatic impairment. In the absence of safety and efficacy data in patients with hepatic impairment, Xeloda use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of Xeloda should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with Xeloda monotherapy may be resumed when bilirubin decreases to

Renal impairment. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml/min) is increased compared to the overall population (see section 4.2 and 4.3).

As this medicinal product contains anhydrous lactose as an excipient, 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

Interaction studies have only been performed in adults.

Interaction with other medicinal products:

Coumarin-derivative anticoagulants: altered coagulation parameters and/or bleeding have been reported in patients taking Xeloda concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions occurred within several days and up to several months after initiating Xeloda therapy and, in a few cases, within one month after stopping Xeloda. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, Xeloda treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with Xeloda should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anti-coagulant dose adjusted accordingly.

Phenytoin: increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of Xeloda with phenytoin. Patients taking phenytoin concomitantly with Xeloda should be regularly monitored for increased phenytoin plasma concentrations.

Folinic acid: a combination study with Xeloda and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of Xeloda and its metabolites. However, folinic acid has an effect on the pharmacodynamics of Xeloda and its toxicity may be enhanced by folinic acid: the maximum tolerated dose (MTD) of Xeloda alone using the intermittent regimen is 3000 mg/m² per day whereas it is only 2000 mg/m² per day when Xeloda was combined with folinic acid (30 mg orally bid).

Sorivudine and analogues: a clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, Xeloda must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see section 4.3). There must be at least a 4-week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and start of Xeloda therapy.

Antacid: the effect of an aluminum hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).

Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5-FU. Concomitant use of allopurinol with Xeloda should be avoided.

Interaction with cytochrome P-450: For potential interactions with isozymes 1A2, 2C9 and 3A4, see interactions with coumarin-derivative anticoagulation.

Interferon alpha: the MTD of Xeloda was 2000 mg/m² per day when combined with interferon alpha-2a (3 MIU/m² per day) compared to 3000 mg/m² per day when Xeloda was used alone.

Radiotherapy: the MTD of Xeloda alone using the intermittent regimen is 3000 mg/m² per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of Xeloda is 2000 mg/m² per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.

Oxaliplatin: no clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.

Bevacizumab: there was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.

Food interaction: In all clinical trials, patients were instructed to administer Xeloda within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that Xeloda be administered with food. Administration with food decreases the rate of capecitabine absorption (see section 5.2).

4.6 Pregnancy And Lactation

Women of childbearing potential

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Xeloda. If the patient becomes pregnant while receiving Xeloda, the potential hazard to the foetus must be explained.

Pregnancy

There are no studies in pregnant women using Xeloda; however, it should be assumed that Xeloda may cause foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, Xeloda administration caused embryolethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Xeloda is contraindicated during pregnancy.

Breastfeeding

It is not known whether Xeloda is excreted in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. Breast-feeding should be discontinued while receiving treatment with Xeloda.

4.7 Effects On Ability To Drive And Use Machines

Xeloda has minor or moderate influence on the ability to drive and use machines. Xeloda may cause dizziness, fatigue and nausea.

4.8 Undesirable Effects

a. Summary of the safety profile

The overall safety profile of Xeloda is based on data from over 3000 patients treated with Xeloda as monotherapy or Xeloda in combination with different chemotherapy regimens in multiple indications. The safety profiles of Xeloda monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See section 5.1 for details of major studies, including study designs and major efficacy results.

The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

b. Tabulated summary of adverse reactions

ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of Xeloda are listed in Table 4 for Xeloda given as a single agent and in Table 5 for Xeloda given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common (

Xeloda Monotherapy:

Table 4 lists ADRs associated with the use of Xeloda monotherapy based on a pooled analysis of safety data from three major studies including over 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.

Table 4 Summary of related ADRs reported in patients treated with Xeloda monotherapy

Body System	Very Common All grades	Common All grades	Uncommon Severe and/or Life-threatening (grade 3-4) or considered medically relevant
Infections and infestations	-	Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection	Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess
Neoplasm benign, malignant and unspecified	-	-	Lipoma
Blood and lymphatic system disorders	-	Neutropenia, Anaemia	Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leucopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/Prothrombin time prolonged
Immune system disorders	-	-	Hypersensitivity
Metabolism and nutrition disorders	Anorexia	Dehydration, Decreased appetite, Weight decreased	Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia,
Psychiatric disorders	-	Insomnia, Depression	Confusional state, Panic attack, Depressed mood, Libido decreased
Nervous system disorders	-	Headache, Lethargy Dizziness, Parasthesia Dysgeusia	Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral
Eye disorders	-	Lacrimation increased, Conjunctivitis, Eye irritation	Visual acuity reduced, Diplopia
Ear and labyrinth disorders	-	-	Vertigo, Ear pain
Cardiac disorders	-	-	Angina unstable, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations
Vascular disorders	-	Thrombophlebitis