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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





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