Xeloda - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Capecitabine

Xeloda 150 mg film-coated tablets

Xeloda package inserts are available for pack sizes:
  • Xeloda 150 mg film-coated tablets
  • Xeloda 500 mg film-coated tablets

Why is Xeloda used? What is it for?

Xeloda belongs to a group of medicines called 'cytostatic medicines', which stop the growth of cancer cells. Xeloda contains 150 mg of capecitabine, which itself is not a cytostatic medicine. Only once absorbed by the body is it transformed into an active anticancer medicine (to a greater extent in tumor tissues than in normal tissues).

Xeloda is prescribed by doctors to treat colon, rectal, stomach or breast cancers. Also, Xeloda is prescribed to prevent new colon cancer from appearing following complete surgical removal of the tumor.

Xeloda can be used alone or in combination with other medicines.

Contraindications When Xeloda should not be used

Do not take Xeloda:

  • if you are allergic to capecitabine or any of the other ingredients of this medicine (listed in section 6). You should tell your doctor if you know you are allergic or have an overreaction to this medicine,
  • if you have had a previous serious reaction to fluoropyrimidine therapy (a group of anticancer medicines such as fluorouracil),
  • if you are pregnant or breastfeeding,
  • if you have excessively low levels of white blood cells and platelets in the blood (leukopenia, neutropenia or thrombocytopenia),
  • if you have severe liver or kidney problems,
  • if you have a known deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) involved in the metabolism of uracil and thymine or
  • if you are currently being treated or have been treated within the past 4 weeks with brivudine, sorivudine or substances of similar classes as part of therapy for herpes zoster (chicken pox or St. Anthony's fire).

Precautions for use What you need to know before taking Xeloda

Talk to your doctor or pharmacist before taking Xeloda:

  • if you have kidney or liver disease,
  • if you have had or have heart problems (for example, irregular heart rate or pains radiating from the chest to the jaw and vice versa caused by physical exertion and due to problems with the blood flow to the heart),
  • if you have brain disease (for example a tumor that has spread to the brain) or nerve damage (neuropathy),
  • if you have imbalances in calcium levels (which can be seen in blood tests),
  • if you have diabetes,
  • if you cannot keep food or water in your body due to severe nausea and vomiting,
  • if you suffer from diarrhea,
  • if you are or can become dehydrated,
  • if you have ion imbalances in your blood (electrolyte imbalances, which can be found in blood tests),
  • if you have suffered from eye problems as you may need additional eye monitoring.
  • if you have a severe skin reaction.

Dihydropyrimidine dehydrogenase (DPD) deficiency: DPD deficiency is a rare disease present at birth that is not generally associated with health problems unless certain medications are taken. If you have an unknown DPD deficiency and are taking Xeloda, the side effects listed in section 4 "Possible side effects" may occur in severe form. Tell your doctor if any of the side effects worry you or if you notice any side effects not listed in this leaflet (see section 4 "Possible side effects").

Children and adolescents

Xeloda is not indicated for the treatment of children and adolescents. Do not give Xeloda to children and adolescents.

Interactions Which drugs or foods may change the effect of Xeloda

Other medicines and Xeloda

Before starting treatment, tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is of fundamental importance, since the concomitant intake of several medicines can strengthen or reduce their effect. Particular attention should be paid in case of concomitant intake of:

  • gout medicines (allopurinol),
  • medicines that thin the blood (coumarin, warfarin),
  • certain antiviral medicines (sorivudine and brivudine),
  • medicines to treat seizures or tremor (phenytoin),
  • interferon alpha,
  • radiotherapy and some medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, cisplatin, irinotecan),
  • medicines used to treat folic acid deficiencies.

Xeloda with food and drink

You must take Xeloda within 30 minutes of the end of a meal.

Warnings It is important to know that:

Pregnancy and breastfeeding

Before starting treatment, tell your doctor if you are pregnant, suspect or plan to become pregnant. You should not take Xeloda if you are pregnant or suspected of being pregnant. You must not breast-feed while taking Xeloda. Ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Xeloda can make you feel dizzy, sick or tired. It is therefore possible that Xeloda may affect the ability to drive or use machines.

Xeloda contains anhydrous lactose

If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Xeloda: Posology

Always take this medicine always exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Xeloda should only be prescribed by a doctor who specializes in the use of antineoplastic medicines.

Xeloda tablets should be swallowed whole with water within 30 minutes of the end of a meal.

Your doctor will prescribe the dosage and treatment regimen that is right for you. The dosage of Xeloda is based on the body surface area. This is calculated from height and weight. The usual dose for adults is 1250 mg / m2 of body surface area twice a day (morning and evening). Two examples are proposed: a person whose weight is 64 kg and with height 1.64 m has a body surface area of ​​1.7 m2 and must take 4 tablets of 500 mg and 1 tablet of 150 mg twice a day. A person whose weight is 80 kg and height of 1.80 m has a body surface area of ​​2.00 m2 and must take 5 tablets of 500 mg twice a day.

Xeloda tablets are usually taken for 14 days, followed by a 7 day rest period (during which no tablets are taken). These 21 days correspond to a cycle of therapy.

In combination with other medicines, the usual adult dose may be less than 1250 mg / m2 of body surface area and the tablets may need to be taken for a different length of time (e.g. every day, without any rest period).

Your doctor will tell you what dose you need to take, when to take it and how long you need to take it for.

Your doctor may prescribe a combination of 150 mg and 500 mg tablets for each strength.

  • Take the tablets in the morning and evening as prescribed by your doctor.
  • Take the tablets within 30 minutes of finishing a meal (breakfast and dinner).
  • It is important to take all medications as prescribed by your doctor.

Overdose What to do if you have taken too much Xeloda

If you take more Xeloda than you should

If you take more Xeloda than you should, contact your doctor as soon as possible before taking your next dose.

If you take more Xeloda than you should, you may experience the following side effects: nausea or vomiting, diarrhea, inflammation or ulceration of the gut or mouth, pain or bleeding from the gut or stomach, or bone marrow depression (reduction of a certain type of blood cells). If you get any of these symptoms, contact your doctor immediately.

If you forget to take Xeloda:

Do not take the missed dose and do not double the next one. Instead, continue with your normal dosage and contact your doctor.

If you stop taking Xeloda:

Stopping capecitabine treatment does not cause side effects. Stopping capecitabine, if you are taking coumarin anticoagulants (containing eg phenprocoumon), may require your doctor to change the dose of the anticoagulant.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Side Effects What are the side effects of Xeloda

Like all medicines, this medicine can cause side effects, although not everybody gets them.

STOP taking Xeloda immediately and contact your doctor if any of the following symptoms develop:

  • Diarrhea: if you have an increase of 4 or more bowel movements per day compared to your normal bowel movements or nocturnal diarrhea.
  • Vomiting: if you vomit more than once in a 24 hour period.
  • Nausea: if you lose your appetite and the amount of food ingested in a day is much less than normal.
  • Stomatitis: if you have pain, redness, swelling or ulcers in the mouth or throat.
  • Hand-foot skin reaction: if you have pain, swelling and redness or tingling in your hands and / or feet.
  • Fever: if you have a body temperature of 38 ° C or higher.
  • Infection: if you have any signs of infection with bacteria or viruses, or other organisms.
  • Chest pain: if you experience pain localized to the center of the chest, especially if it occurs during exercise.
  • Steven-Johnson syndrome: if you experience a painful red or purplish rash that spreads and blisters and / or other lesions that begin to appear in the mucous membrane (e.g. mouth and lips), particularly if you previously had sensitivity in the light, infections of the respiratory system (eg bronchitis) and / or fever.

If caught early, these side effects usually improve within 2-3 days of stopping the medicine. If symptoms persist, contact your doctor immediately. Your doctor may advise you to resume taking the medicine at a lower dose.

In addition to those listed above, other very common side effects reported with the use of Xeloda alone, which may affect more than 1 in 10 people, are:

  • abdominal pain
  • rash, dry or itchy skin
  • tiredness
  • loss of appetite (anorexia).

These side effects can become serious. Therefore, always contact your doctor immediately when you notice a side effect. Your doctor will tell you to decrease the dose and / or temporarily stop Xeloda treatment. This will help reduce the likelihood of the side effect persisting or turning it into a serious side effect.

Other side effects are:

Common side effects (may affect up to 1 in 10 people) include:

  • decrease in the number of white or red blood cells in the blood (seen in tests),
  • dehydration, weight loss,
  • lack of sleep (insomnia), depression,
  • headache, sleepiness, dizziness, abnormal skin sensation (numbness or tingling), change in taste,
  • eye irritation, increased tearing, red eye (conjunctivitis),
  • inflammation of the veins (thrombophlebitis),
  • shortness of breath, nosebleed, cough, runny nose,
  • cold sores or other herpes infections,
  • infections of the lungs or respiratory system (e.g. pneumonia or bronchitis),
  • bowel bleeding, constipation, upper abdominal pain, indigestion, excess air, dry mouth,
  • skin rash, hair loss (alopecia), redness of the skin, dry skin, itching, skin discoloration, skin loss, skin inflammation, nail changes,
  • pain in the joints or limbs (extremities), chest or back,
  • fever, swelling of the limbs, feeling unwell,
  • problems with liver function (seen in blood tests) and increased bilirubin in the blood (excreted through the liver).

Uncommon side effects (may affect less than 1 in 100 people) include:

  • blood infection, urinary tract infection, skin infection, nose and throat infection, fungal infections (including those of the mouth), flu, gastroenteritis, abscess,
  • soft swellings under the skin (lipoma),
  • decrease in blood cells including platelets, thinning of the blood (seen in tests),
  • allergy,
  • diabetes, decreased blood potassium, malnutrition, increased blood triglycerides,
  • confusional state, panic attacks, mood depression, decreased libido,
  • difficulty speaking, memory impairment, loss of movement coordination, balance disturbance, fainting, nerve damage (neuropathy) and problems with the senses,
  • blurred or double vision,
  • dizziness, ear pain,
  • irregular heartbeat and palpitations (arrhythmia), chest pain and heart attack (heart attack),
  • blood clots in deep veins, high or low blood pressure, flushing, cold in the limbs (extremities), purple spots on the skin,
  • blood clots in the veins of the lung (pulmonary embolism), lung collapse, blood loss with coughing, asthma, shortness of breath with exertion,
  • bowel obstruction, collection of fluid in the abdomen, inflammation of the small or large intestine, stomach or esophagus, pain in the lower abdomen, abdominal discomfort, heartburn (reflux of food from the stomach), blood in the stool,
  • jaundice (yellowing of the skin and eyes),
  • skin ulcer and blistering, skin reactions to sunlight, redness of the palms, swelling or pain of the face,
  • joint swelling or stiffness, bone pain, muscle weakness or stiffness,
  • fluid collection in the kidneys, increased urinary frequency at night, incontinence, blood in the urine, increased blood creatinine (sign of kidney dysfunction),
  • unusual bleeding from the vagina,
  • swelling (edema), chills and stiffness.

Some of these side effects are common when capecitabine is used with other medicines to treat cancer. Other side effects observed in this context are:

Common side effects (may affect up to 1 in 10 people) include:

  • decrease in sodium, magnesium and calcium in the blood, increase in blood sugar,
  • nerve pain,
  • ringing in the ears (tinnitus), hearing loss,
  • inflammation of the veins,
  • hiccups, altered voice,
  • pain or altered / abnormal sensation in the mouth, pain in the jaw,
  • sweating, night sweats,
  • muscle spasm,
  • difficulty urinating, blood or protein in the urine,
  • bruising or injection site reactions (caused by medicines given by injection at the same time).

Rare side effects (may affect up to 1 in 1,000 people) include:

  • narrowing or blockage of the tear duct (tear duct stenosis),
  • liver failure,
  • inflammation leading to dysfunction or blockage of bile secretion (cholestatic hepatitis),
  • specific changes in the electrocardiogram (QT prolongation),
  • certain types of arrhythmias (including ventricular fibrillation, torsades de pointes, and bradycardia),
  • eye inflammation causing pain and potential vision problems,
  • inflammation of the skin leading to red patches and peeling due to a disease of the immune system.

Very rare side effects (may affect up to 1 in 10,000 people) include:

  • severe skin reactions, such as rash, ulceration and blistering, which may involve ulcers of the mouth, nose, genitals, hands, feet and eyes (red and swollen eyes).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep out of the sight and reach of children.

Do not store at temperatures above 30 ° C.

Do not use this medicine after the expiry date which is stated on the outer carton and label after "EXP". The expiry date refers to the last day of the month.

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

Composition and pharmaceutical form

What Xeloda contains

The active substance is capecitabine (150 mg for each film-coated tablet).

The other excipients are:

  • Tablet core: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose, magnesium stearate.
  • Tablet coating: hypromellose, titanium dioxide (E171), yellow and red iron oxide (E172), talc.

What Xeloda looks like and contents of the pack

Light peach, biconvex, oblong shaped film-coated tablet, debossed with "150" on one side and "Xeloda" on the other side.

The pack of Xeloda 150 mg film-coated tablet contains 60 film-coated tablets (6 blisters of 10 tablets).

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Xeloda can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER O 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

XELODA 150 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg of capecitabine.

Excipient (s) with known effect:

each film-coated tablet contains 15.6 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Xeloda 150 mg film-coated tablets are light peach, biconvex, oblong shaped tablets, debossed with "150" on one side and "Xeloda" on the other side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Xeloda is indicated for adjuvant therapy in patients undergoing surgery for stage III (Dukes 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 the 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 must have included an "anthracycline. In addition, Xeloda is indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of a taxane and an anthracycline containing chemotherapy regimen or for whom an anthracycline is not indicated. "further anthracycline therapy.

04.2 Posology and method of administration

Xeloda should only be prescribed by a doctor who specializes in the use of antineoplastic medicines. Close monitoring is recommended for all patients during the first course of treatment.

Treatment should be discontinued if severe toxicity or disease progression occurs. Standard and reduced dose calculations based on body surface area for starting Xeloda dosages of 1250 mg / m2 and 1000 mg / m2 are detailed in Tables 1 and 2, respectively.

Dosage

Recommended posology (see section 5.1):

Monotherapy

Colon, colorectal and breast cancer

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

Association therapy

Colon, colorectal and gastric cancer

In combination treatment, the recommended starting dose of capecitabine 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). In combination with irinotecan, the recommended starting dose is 800 mg / m2 when administered twice daily for 14 days, followed by a 7-day rest period in combination with irinotecan 200 mg / m2 on day 1. The introduction of bevacizumab in the combination regimen has no effect on the starting dose of capecitabine. In patients treated with the combination capecitabine plus cisplatin, premedication to maintain adequate hydration and antiemetic treatment should be initiated prior to cisplatin administration, according to the Summary. of Product Characteristics of cisplatin. Premedication with antiemetics is recommended in patients treated with the combination capecitabine plus oxaliplatin, in accordance with the Summary of Product Characteristics of oxaliplatin. A 6-month duration of adjuvant treatment is recommended in patients with stage III colon cancer.

Breast cancer

In combination with docetaxel, the recommended starting dose of capecitabine in the treatment of metastatic breast cancer is 1250 mg / m2 twice daily for 14 days, followed by a 7-day rest period, in combination with docetaxel 75 mg / m2 in combination with docetaxel. 1 hour intravenous infusion every 3 weeks. In patients receiving the combination capecitabine and docetaxel, premedication with an oral corticosteroid, such as dexamethasone, should be initiated prior to docetaxel administration according to the docetaxel Summary of Product Characteristics.

Calculation of the dose of Xeloda

Table 1 Standard and reduced dose calculations of capecitabine based on body surface area, starting dose of 1250 mg / m2


Dose of 1250 mg / m2 (twice daily) Full dose 1250 mg / m2 Number of 150 mg and / or 500 mg tablets for each administration (to be taken in the morning and in the evening) Reduced dose (75%) 950 mg / m2 Reduced dose (50%) 625 mg / m2 Body surface (m2) Single dose (mg) 150 mg 500 mg Single dose (mg) Single dose (mg) ≤1,26 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 ≥2,19 2800 2 5 2150 1450

Table 2 Standard and reduced dose calculations of capecitabine based on body surface area, starting dose of 1000 mg / m2


Dosage of 1000 mg / m2 (twice daily) Full dose 1000 mg / m2 Number of 150 mg and / or 500 mg tablets for each administration (to be taken in the morning and in the evening) Reduced dose (75%) 750 mg / m2 Reduced dose (50%) 500 mg / m2 Body surface (m2) Single dose (mg) 150 mg 500 mg Single dose (mg) Single dose (mg) ≤1,26 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 ≥2,19 2300 2 4 1750 1100

Dosage adjustments during treatment:

General

Toxicity caused by capecitabine administration can be managed with symptomatic treatment and / or dose modification (treatment interruption or dose reduction). Once the dose has been reduced, it should not be increased thereafter. In case of toxicities which in the opinion of the treating physician are unlikely to become serious or fatal, such as alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. Patients taking capecitabine should be advised of the need to discontinue treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine excluded due to toxicity cannot be substituted. The following are recommended dose modifications in case of toxicity:

Table 3 Capecitabine dose reduction schedule (3-week cycle or continuous treatment)


Degrees of toxicity * Dosage changes during a course of therapy Dose adjustment for next cycle / dose (% of starting dose) • Grade 1 Maintain the dose level Maintain the dose level • Grade 2 - First appearance Discontinue treatment until Grade 0-1 is reached 100% - Second appearance 75% - Third appearance 50% - Fourth appearance Permanent discontinuation of treatment Not applicable • Grade 3 - First appearance Discontinue treatment until Grade 0-1 is reached 75% - Second appearance 50% - Third appearance Permanent discontinuation of treatment Not applicable • Grade 4 - First appearance Permanent interruption or If continuation of treatment is of real benefit to the patient, discontinue treatment until Grade 0-1 is achieved 50% - Second appearance Permanent interruption Not applicable

* According to the Common Toxicity Criteria (version 1) of the National Cancer Institute of Canada Clinical Trial Group (NCIC CGT) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation Program, US National Cancer Institute, version 4.0. For hand-foot syndrome and hyperbilirubinaemia, see section 4.4.

Hematology

Patients with baseline neutrophil counts

Dose modifications for toxicity when capecitabine is used as a 3-week cycle in combination with other medicinal products

When capecitabine is used in 3-week cycles in combination with other medicinal products, dose modifications for toxicity should be performed according to table 3 above for capecitabine and according to the relevant Summary of Product Characteristics for the other medicinal product (s). /the.

At the start of the course of treatment, if a postponement of treatment is indicated for either capecitabine or the other medicinal product (s), the administration of all medicinal products should be postponed until the requirements for resuming administration of all medicines.

During the course of treatment, for those toxicities considered by the treating physician to be unrelated to capecitabine, treatment with capecitabine should be continued and the dose of the other medicinal product adjusted according to the relevant prescribing information.

If the other medicinal product (s) are to be permanently discontinued, treatment with capecitabine can be resumed once the requirements for re-introduction of capecitabine are met.

This approach applies to all indications and all special patient populations.

Dose modifications for toxicity when capecitabine is used as continuous treatment in combination with other medicinal products

Dose modifications for toxicity when capecitabine is used as continuous treatment in combination with other medicinal products should be performed according to Table 3 above for capecitabine and in accordance with the relevant Summary of Product Characteristics for the other medicinal product (s).

Dosage adjustments in particular patient populations:

Impaired liver function

There are insufficient safety and efficacy data to provide guidance on dose adjustments for patients with impaired hepatic function. There are no data on liver failure due to cirrhosis or hepatitis.

Impaired renal function

Capecitabine is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 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 higher than in the total population. A 75% reduction is recommended for a starting dose of 1250 mg / m2 in patients with moderate renal impairment at baseline. No dose reduction is required for a starting dose of 1000 mg / m2 in patients with moderate renal impairment at baseline. starting dose in patients with mild renal impairment (creatinine clearance 51-80 ml / min at baseline). If the patient develops a grade 2, 3 or 4 adverse event during treatment, close monitoring and "Immediate discontinuation of treatment, and the next dose should be adjusted as indicated in Table 3 above. If the calculated creatinine clearance falls during treatment nde below 30 ml / min, Xeloda should be discontinued. These recommendations on dose adjustments in renal impairment apply to both monotherapy and combination use (see also section "Elderly" below).

Senior citizens

No starting dose adjustment is required when using capecitabine alone. However, patients ≥ 60 years of age compared to younger subjects more frequently reported Grade 3 or 4 treatment-related adverse reactions.

When capecitabine was used in combination with other agents, elderly patients (≥ 65 years) experienced more grade 3 and 4 adverse drug reactions, including those leading to treatment discontinuation, than younger patients. Close monitoring of patients ≥ 60 years of age is advisable.

- In combination with docetaxel: An increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions was observed in patients 60 years of age and older (see section 5.1). An initial dosage of capecitabine reduced to 75% (950 mg / m2 twice daily) in patients 60 years of age and older. If no toxicity occurs in patients ≥ 60 years of age treated with a reduced starting dose of capecitabine in combination with docetaxel , the capecitabine dose can be cautiously increased to 1250 mg / m2 twice daily.

Pediatric population

There is no relevant use of capecitabine in the pediatric population in the indications of colon, colorectal, gastric and breast cancer.

Method of administration

Xeloda tablets should be swallowed with water within 30 minutes of the end of a meal.

04.3 Contraindications

• History of severe or unexpected reactions to fluoropyrimidine therapy.

• Hypersensitivity to capecitabine or to any of the excipients listed in section 6.1 or to fluorouracil.

• In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see section 4.4).

• During pregnancy and breastfeeding.

• In patients with severe forms of leukopenia, neutropenia or thrombocytopenia.

• In patients with severe hepatic impairment.

• In patients with severe renal impairment (creatinine clearance less than 30 ml / min).

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

• If there are contraindications to any of the medicines in the combination regimen, that medicine should not be used.

04.4 Special warnings and appropriate precautions for use

The dose limiting toxicities include diarrhea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysaesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although dose interruption or reduction may be necessary.

Diarrhea. Patients with severe diarrhea should be closely monitored and, in the event of dehydration, given fluids and electrolytes. Standard antidiarrheal treatments (e.g. loperamide) may be given. Grade 2 diarrhea according to the Common Toxicity Criteria of the NCIC means an increase from 4 to 6 discharges per day or nocturnal discharges, for grade 3 diarrhea an increase of 7 to 9 discharges per day or incontinence and malabsorption, and for diarrhea Grade 4 an increase of ≥10 discharges per day or heavily bleeding diarrhea or need for parenteral support. If necessary, a dose reduction should be made (see section 4.2).

Dehydration. Dehydration must be prevented or corrected when it occurs. Patients with anorexia, asthenia, nausea, vomiting or diarrhea can rapidly become dehydrated. Dehydration can cause acute renal failure, especially in patients with pre-existing renal impairment or when capecitabine is administered in combination with known nephrotoxic drugs. Acute renal failure secondary to dehydration could be potentially fatal. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be stopped immediately and dehydration corrected. Treatment should not be resumed until the patient has been rehydrated and any precipitating cause corrected or controlled. Dose modifications should be made for the precipitating adverse event as needed (see section 4.2).

Hand-foot syndrome (also known as hand-foot skin reaction or palmar-plantar erythrodysaesthesia or chemotherapy-induced erythema of the extremities). Grade 1 hand-foot syndrome is defined as numbness, dysesthesia / paraesthesia, tingling, painless edema or erythema of the hands and / or feet, and / or discomfort that does not prevent the patient from functioning normally.

Grade 2 hand-foot syndrome is defined as painful erythema and edema in the hands and / or feet and / or discomfort that affects the patient's daily activities.

Grade 3 hand-foot syndrome is defined as wet scaling, ulceration, blistering and severe pain in the hands and / or feet and / or severe discomfort that makes it impossible for the patient to work or perform daily activities. If Grade 2 or 3 hand-foot syndrome occurs, withhold capecitabine administration until symptom intensity is resolved or reduced to Grade 1. Following onset of Grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) for symptomatic or secondary prophylaxis treatment of hand-foot syndrome is not recommended, as published cases have shown that it may reduce the efficacy of cisplatin. There is some evidence that dexpanthenol is effective for the prophylaxis of hand-foot syndrome in patients treated with Xeloda.

Cardiotoxicity. Fluoropyrimidine therapy has been associated with cardiotoxicity, including myocardial infarction, angina, arrhythmia, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT interval prolongation). These adverse reactions may occur more commonly in patients with previous history of coronary artery disease. Cardiac arrhythmia (including ventricular fibrillation, torsades de pointes and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients taking capecitabine. significant angina pectoris special caution should be exercised (see section 4.8).

Hypo- or hypercalcemia. Cases of hypo- or hypercalcaemia have been reported during treatment with capecitabine. Particular caution should be exercised in patients with a pre-existing history of hypo- or hypercalcaemia (see section 4.8).

Diseases of the central or peripheral nervous system. Patients with central or peripheral nervous system diseases, e.g. brain metastases or neuropathy, should be viewed with caution (see section 4.8).

Diabetes mellitus or electrolyte disturbances. Patients with diabetes mellitus or electrolyte disturbances, given the possibility of aggravation during treatment with capecitabine, should be considered with caution.

Coumarin-derived anticoagulants. In an interaction study with the administration of a single dose of warfarin, there was a significant increase in the mean AUC (+ 57%) of S-warfarin. These data suggest an "interaction, probably due to" inhibition of the cytochrome P450 isoenzyme 2C9 by capecitabine. Patients taking coumarin-derived oral anticoagulants together with capecitabine should be monitored regularly for the possible occurrence of alterations in the parameters of coagulation (INR or prothrombin time) and the dose of anticoagulants should be adjusted accordingly (see section 4.5).

Impaired liver function. In the absence of data on safety and efficacy in patients with impaired hepatic function, the use of capecitabine should be closely monitored in patients with mild to moderate hepatic dysfunction, regardless of the presence or absence of liver metastases. Administration of capecitabine should be discontinued if treatment-related elevations in bilirubin greater than 3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) greater than 2.5 x ULN occur. monotherapy can be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases decrease to ≤2.5 x ULN.

Impaired renal function. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance 30-50 ml / min) is higher than in the overall population (see sections 4.2 and 4.3).

Dihydropyrimidine dehydrogenase (DPD) deficiency: Rare, unexpected and severe toxicity (eg stomatitis, diarrhea, mucositis, neutropenia and neurotoxicity) associated with 5-FU has been related to a deficit in DPD activity.

Patients with low or no activity of DPD, an enzyme involved in the breakdown of fluorouracil, are at increased risk of severe, life-threatening or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely identified, it is known that patients with certain homozygous or compound heterozygous mutations of the gene locus DPYD, which cause complete or almost complete absence of DPD enzymatic activity (as determined by laboratory analysis), have the greatest risk of life-threatening or fatal toxicity and should not be treated with Xeloda (see section 4.3). No dose was found to be safe for patients with a total absence of DPD activity.

Patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD) and for which the benefit of Xeloda is considered to outweigh its risks (taking into account the appropriateness of an alternative non-fluopyrimidine chemotherapy regimen) should be treated with extreme caution and frequently monitored with dose adjustment according to toxicity. There are insufficient data to recommend a specific dose in patients with partial DPD activity as measured by a specific test.

Life-threatening toxicities such as acute overdose episodes may occur in patients with unidentified DPD deficiency who are treated with capecitabine (see section 4.9). In case of acute grade 2-4 toxicity, treatment should be stopped immediately. Permanent discontinuation of treatment should be considered based on the clinical assessment of the onset, duration and severity of the observed toxicities.

Ophthalmological complications: Patients should be closely monitored for ophthalmological complications such as keratitis and corneal disorders, especially if they have a previous history of eye disorders. Treatment of eye disorders should be initiated in a clinically appropriate manner.

Severe skin reactions: Xeloda can induce severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. In patients who experience a severe skin reaction during treatment with Xeloda, this medicine should be permanently discontinued.

As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary forms of galactose intolerance, the Lapp lactase enzyme deficiency and glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Interactions with other medicines:

Substrates of cytochrome P-450 2C9: In addition to the warfarin studies, no formal drug-drug interaction studies have been conducted between capecitabine and other CYP2C9 substrates. Caution should be exercised when administering capecitabine together with 2C9 substrates (e.g. phenytoin). See also interaction with other coumarin-derived anticoagulants and section 4.4.

Coumarin-derived anticoagulants: in patients treated concomitantly with capecitabine and coumarin-derived anticoagulants, such as warfarin and phenprocoumon, changes in coagulation parameters and / or haemorrhages have been reported. These reactions occurred over a period of a few days to several months after initiation of capecitabine therapy and, in some cases, within one month of discontinuation of capecitabine therapy. In a clinical pharmacokinetic interaction study, following administration of a single 20 mg dose of warfarin, treatment with capecitabine increased S-warfarin AUC by 57% with a 91% increase in INR value. Since the metabolism of R-warfarin was not altered, these data suggest that capecitabine reduces the isoenzyme 2C9 but has no effect on isoenzymes 1A2 and 3A4. Patients taking coumarin-derived anticoagulants concomitantly with capecitabine should be monitored regularly for the possible occurrence of alterations in coagulation parameters (PT or INR) and the dosage of anticoagulants must be adjusted accordingly.

Phenytoin: Increases in plasma phenytoin concentrations have been recorded during concomitant use of capecitabine and phenytoin, resulting in symptoms of phenytoin intoxication in individual cases. Patients taking phenytoin concomitantly with capecitabine should be monitored regularly for possible occurrence of increased plasma concentrations of phenytoin.

Folinic acid / folic acid: A study involving the combination of capecitabine and folinic acid showed that folinic acid has no significant effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid produces effects on the pharmacodynamics of capecitabine whose toxicity may be increased by folinic acid: the maximum tolerated dose (MTD) of capecitabine monotherapy in intermittent regimens is 3000 mg / m2 per day, whereas when capecitabine was associated with folinic acid (30 mg po twice daily) the maximum tolerated dose fell to only 2000 mg / m2 per day. The increase in toxicity may be relevant when switching from 5-FU / LV to a capecitabine-based regimen. Due to the similarity between folinic acid and folic acid the increased toxicity may also be relevant with supplementation of folic acid in the treatment of folate deficiency.

Sorivudine and analogues: A clinically significant drug-drug interaction has been reported between sorivudine and 5-FU resulting from sorivudine inhibition of dihydropyrimidine dehydrogenase. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. For this reason capecitabine should not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine (see section 4.3). A rest period of at least 4 weeks should be observed between the end of treatment with sorivudine or its chemically related analogues, such as brivudine, and the initiation of capecitabine therapy.

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

Allopurinol: Interactions of 5-FU with allopurinol have been observed, with possible decreased efficacy of 5-FU. Concomitant use of allopurinol and capecitabine should be avoided.

Interferon alpha: the maximum tolerated dose (MTD) of capecitabine was 2000 mg / m2 per day when taken in combination with interferon alfa-2a (3 MIU / m2 per day), compared with 3000 mg / m2 per day when capecitabine was administered by alone.

Radiotherapy: The maximum tolerated dose (MTD) of capecitabine monotherapy using the intermittent regimen is 3000 mg / m2 per day while, when combined with radiotherapy for rectal cancer, the maximum tolerated dose (MTD) of capecitabine is 2000 mg / m2 per day, using either a continuous dosing or a daily dosing from Monday to Friday in conjunction with the 6-week radiotherapy treatment cycle.

Oxaliplatin: There was no clinically significant difference in exposure to capecitabine or its metabolites, free platinum or total platinum 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.

Interaction with food

In all clinical trials, patients were advised to take capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based on administration of the medicinal product with food, it is recommended that capecitabine be administered with food. Administration with food decreases the rate of absorption of capecitabine (see section 5.2).

04.6 Pregnancy and breastfeeding

Women of childbearing age / Contraception in men and women

Women of childbearing potential should be advised to avoid the risk of pregnancy during treatment with capecitabine. If pregnancy occurs during treatment with capecitabine, the patient should be informed of the potential risk to the fetus. An effective method of contraception should be used during treatment.

Pregnancy

No studies have been performed with capecitabine in pregnant women; however, it can be assumed that capecitabine, when administered to pregnant women, may cause harm to the fetus. In reproductive toxicity studies in animals, administration of capecitabine resulted in embryonic lethality and teratogenicity. These results are the expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated in pregnancy.

Feeding time

It is unknown whether capecitabine is excreted in human milk. Significant amounts of capecitabine and its metabolites were found in lactating mouse milk. Breastfeeding should be discontinued during the capecitabine treatment period.

Fertility

There is no data on Xeloda and its impact on fertility. The pivotal studies of Xeloda included women of childbearing potential and men only if they were willing to use adequate contraception to avoid pregnancy throughout the study and for a reasonable period thereafter.

Effects on fertility were observed in animal studies (see section 5.3).

04.7 Effects on ability to drive and use machines

Capecitabine has a mild or moderate influence on the ability to drive or use machines. Capecitabine can induce dizziness, fatigue and nausea.

04.8 Undesirable effects

Summary of the safety profile

The overall safety profile of capecitabine is based on data from more than 3000 patients treated with capecitabine alone or with capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy in patient populations with metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer are similar. See section 5.1 for details on main studies, including study designs and key efficacy results.

The most commonly reported and / or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disturbances (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palmar-plantar erythrodysaesthesia), fatigue, asthenia, anorexia, cardiotoxicity, worsening of renal function where function was already previously impaired and thrombosis / embolism.

Summary of adverse reactions in tabular form

The ADRs considered by the investigator to be possibly, probably or remotely related to the administration of capecitabine are listed in Table 4 for taking capecitabine alone and in Table 5 for taking capecitabine in combination with different chemotherapy regimens in multiple indications. The following terms are used to classify ADRs according to their frequency: very common (≥ 1/10), common (≥ 1/100,

Capecitabine as monotherapy:

Table 4 lists the ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of safety data from three main studies including over 1900 patients (studies M66001, SO14695 and SO14796). The ADRs were included in the specific frequency group according to the "overall incidence deriving from the aggregate analysis".

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


Body system Very common All grades common All grades Uncommon Serious and / or life-threatening (grade 3-4) or considered clinically relevant Rare / Very Rare (Post marketing experience) Infections and infestations - Herpetic viral infection, Nasopharyngitis, Lower respiratory tract infection Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Flu, Gastroenteritis, Fungal infection, Infection, Tooth abscess Neoplasms benign, malignant and unspecified - - Lipoma Disorders of the blood and lymphatic system - Neutropenia, Anemia Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leukopenia, Haemolytic anemia, International normalized ratio (INR) increase / Prothrombin time prolongation Disorders of the immune system - - Hypersensitivity Metabolism and nutrition disorders Anorexia Dehydration, Weight Loss Diabetes, Hypokalaemia, Appetite disorders, Malnutrition, Hypertriglyceridemia Psychiatric disorders - Insomnia, Depression Confusional state, Panic attack, Mood depression, Reduced libido Nervous system disorders - Headache, Lethargy, Dizziness, Paresthesia Dysgeusia Aphasia, Memory disturbances, Ataxia, Syncope, Balance disturbances, Sensory disturbances, Peripheral neuropathy Toxic leukoencephalopathy (very rare) Eye disorders - Increased lacrimation, Conjunctivitis, Irritation of the eye Reduced visual acuity, Diplopia Tear duct stenosis (rare), Corneal disorders (rare), Keratitis (rare), Punctate keratitis (rare) Ear and labyrinth disorders - - Vertigo, Pain in the ear Cardiac pathologies - - Unstable angina, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations Ventricular fibrillation (rare), QT prolongation (rare), Torsades de pointes (rare), Bradycardia (rare), Vasospasm (rare) Vascular pathologies - Thrombophlebitis Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Flushing, Cold in extremities Respiratory, thoracic and mediastinal disorders - Dyspnea, Epistaxis, Cough, Rhinorrhea Pulmonary embolism, Pneumothorax, Hemoptysis, Asthma, Dyspnea on exertion Gastrointestinal disorders Diarrhea, Vomiting, Nausea, Stomatitis, Abdominal pain Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Lower abdominal pain, Esophagitis, Abdominal discomfort, Gastroesophageal reflux disease, Colitis, Blood in stool Hepatobiliary disorders - Hyperbilirubinemia, Abnormal liver function tests Jaundice Hepatic failure (rare), Cholestatic hepatitis (rare) Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyperpigmentation, Macular rash, Skin peeling, Dermatitis, Pigmentation disorders, Nail disorders Vesicle, Skin ulceration, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Facial swelling, Purpura, Radiation "recall" syndrome Cutaneous lupus erythematosus (rare), Severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare) (see section 4.4) Musculoskeletal and connective tissue disorders - Pain in extremities, back pain, arthralgia Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscle weakness Renal and urinary disorders - - Hydronephrosis, Urinary incontinence, Hematuria, Nocturia, Increased creatininemia Diseases of the reproductive system and breast - - Vaginal bleeding General disorders and administration site conditions Fatigue, Asthenia Pyrexia, peripheral edema, malaise, chest pain Edema, Chills, Flu-like illness, Stiffness, Increased body temperature

Capecitabine in combination therapy:

Table 5 lists ADRs related to the use of capecitabine in combination with different chemotherapy regimens in multiple indications based on safety data from over 3000 patients. The ADRs have been included in the specific frequency group (Very Common or Common) in based on the highest incidence observed in the pivotal clinical studies and only if additional to those observed with capecitabine monotherapy or if belonging to a higher frequency group than capecitabine monotherapy (see table 4). The uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or for monotherapy with combination medicinal products (in the literature and / or respective SPCs).

Some of the ADRs are reactions frequently observed with the combination medicinal product (eg peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension with bevacizumab); however, worsening induced by capecitabine therapy cannot be excluded.

Table 5 Summary of ADRs reported in patients treated with capecitabine in combination therapy in addition to those observed with capecitabine alone or observed in a higher frequency group compared to capecitabine alone.


Body system Very common All grades common All grades Rare / Very Rare (Post marketing experience) Infections and infestations - Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection, Rhinitis, Influenza, + Infection, Oral herpes Disorders of the blood and lymphatic system + Neutropenia, + Leukopenia, + Anemia, + Neutropenic fever, Thrombocytopenia Bone marrow depression, + Febrile neutropenia Disorders of the immune system - Hypersensitivity Metabolism and nutrition disorders Reduction of appetite Hypokalaemia, Hyponatremia, Hypomagnesaemia, Hypocalcemia, Hyperglycemia Psychiatric disorders - Sleep disturbances, Anxiety Nervous system disorders Paresthesia, Dysesthesia, Peripheral neuropathy, Peripheral sensory neuropathy, Dysgeusia, Headache Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction, Hypoesthesia Eye disorders Increased lacrimation Visual disturbance, Dry eye, Eye pain, Visual impairment, Vision blurred Ear and labyrinth disorders - Tinnitus, Hypoacusis Cardiac pathologies - Atrial fibrillation, Cardiac ischemia / infarction Vascular pathologies Edema of the lower limbs, Hypertension, + Embolism and thrombosis Redness, Hypotension, Hypertensive crisis, Hot flashes, Phlebitis Respiratory, thoracic and mediastinal disorders Sore throat, Dysesthesia of the pharynx Hiccups, Pharyngolaryngeal pain, Dysphonia Gastrointestinal disorders Constipation, Dyspepsia Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Mouth pain, Dysphagia, Rectal haemorrhage, Lower abdominal pain, Oral dysesthesia, Oral paraesthesia, Oral hypoesthesia, Abdominal pain Hepatobiliary disorders - Abnormal liver function Skin and subcutaneous tissue disorders Alopecia, Nail disorders Hyperhidrosis, Erythematous rash, Urticaria, Night sweats Musculoskeletal and connective tissue disorders Myalgia, Arthralgia, Pain in extremities Jaw pain, Muscle spasms, Trismus, Muscle weakness Renal and urinary disorders - Haematuria, Proteinuria, Decreased renal creatinine clearance, Dysuria Acute renal failure secondary to dehydration (rare) General disorders and administration site conditions Pyrexia, Weakness, + Lethargy, Temperature intolerance Mucosal inflammation Pain in limb, Pain, Chills, Chest pain, Flu-like syndrome, + Fever, Infusion related reactions, Injection site related reactions, Infusion site pain, Injection site pain Injury, poisoning and procedural complications - Bruise

+ For each term, the frequency was calculated on the basis of the ADRs of all grades. For terms marked with a "+", the frequency was calculated on the basis of grade 3-4 ADRs. ADRs were included based on the highest incidence observed in the pivotal combination therapy clinical trials.

Description of a selection of adverse reactions

Hand-foot syndrome (see section 4.4):

In studies of capecitabine monotherapy (including adjuvant therapy studies in colon cancer, treatment of metastatic colorectal cancer and treatment of breast cancer), with 1250 mg / m2 capecitabine twice daily in days 1 to 14 every three weeks, hand-foot syndrome of any grade has been observed with a frequency ranging from 53% to 60%; in the capecitabine / docetaxel arm for the treatment of metastatic breast cancer the frequency was 63%. In combination therapy with capecitabine, with capecitabine 1000 mg / m2 twice daily on days 1 to 14 every three weeks, any grade of hand-foot syndrome was observed with a frequency ranging from 22% and 30%.

As part of a meta-analysis on 14 clinical trials, with data from more than 4,700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer ), hand-foot syndrome of any grade occurred in 2066 patients (43%) after a median of 239 days (95% CI: 201, 288) from initiation of capecitabine treatment. In all studies combined there was a "statistically significant association between the following covariates and an increased risk of developing hand-foot syndrome: increase in starting dose of capecitabine (gram), decrease in cumulative dose of capecitabine (0.1 * kg), increased relative dose intensity in the first 6 weeks, increased duration of study treatment (weeks), advancing age (10-year increments), female gender, and good baseline ECOG performance status ( 0 vs ≥1).

Diarrhea (see section 4.4):

Capecitabine can induce the onset of diarrhea, which has been observed in up to 50% of patients.

The results of a meta-analysis of 14 clinical studies with data from more than 4,700 patients treated with capecitabine showed that in all studies combined there was a "statistically significant association between the following covariates and an increased risk of developing diarrhea: increased starting dose of capecitabine (gram), increased duration of study treatment (weeks), advancing age (10-year increments) and female gender. A statistically significant association was observed between the following covariates and a reduction in the risk of developing diarrhea: increase in the cumulative dose of capecitabine (0.1 * kg) and increase in relative dose intensity in the first 6 weeks.

Cardiotoxicity (see section 4.4):

In addition to the ADRs described in Tables 4 and 5, based on a "pooled analysis of clinical safety data from 7 clinical studies including 949 patients (2 phase III and 5 phase II studies in metastatic colorectal cancer) and in metastatic breast cancer), the following ADRs with an incidence of less than 0.1% have been observed in association with the use of capecitabine alone: ​​cardiomyopathy, heart failure, sudden death and ventricular extrasystoles.

Encephalopathy:

In addition to the ADRs described in tables 4 and 5, on the basis of the aforementioned pooled analysis of clinical safety data from 7 clinical studies, the use of capecitabine alone was also associated with encephalopathy, with an incidence of less than 0.1% .

Special populations

Older patients (see section 4.2):

An "analysis of safety data in patients ≥ 60 years of age treated with capecitabine monotherapy and an" analysis of patients treated with the therapeutic combination of capecitabine and docetaxel showed an increased incidence of grade 3 and 4 adverse reactions treatment-related and treatment-related serious adverse reactions compared to patients less than 60 years of age. In addition, patients ≥60 years of age treated with capecitabine and docetaxel discontinued treatment prematurely due to more frequent adverse reactions than patients less than 60 years of age.

The results of a meta-analysis of 14 clinical studies with data from more than 4,700 patients treated with capecitabine showed that in all studies combined there was a "statistically significant association between" advancement in age (10-year increments). and an increased risk of developing hand-foot syndrome and diarrhea, and a reduced risk of developing neutropenia.

Sex

The results of a meta-analysis of 14 clinical trials with data from more than 4,700 patients treated with capecitabine showed that in all studies combined there was a "statistically significant association between female sex and an increased risk of developing the syndrome. hand-foot and diarrhea, and a reduced risk of developing neutropenia.

Patients with renal impairment (see sections 4.2, 4.4 and 5.2):

An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with renal impairment at baseline showed an increased incidence of grade 3 and 4 treatment-related adverse reactions compared to patients with normal renal (36% in patients without renal impairment n = 268 vs 41% in mild impairment n = 257 and 54% in moderate n = 59, respectively) (see section 5.2). An increase in the dose reduction rate (44%) was observed in patients with moderately impaired renal function vs 33% and 32% in patients with mild or no renal impairment and an increase in premature discontinuation of treatment ( 21% interruptions during the first two cycles) vs 5% and 8% in patients with little or no renal impairment.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system www .agenziafarmaco.gov.it / it / responsible.

04.9 Overdose

Manifestations of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, as well as bone marrow depression. Clinical management of overdose should take place through conventional therapy and supportive medical intervention in order to correct the clinical manifestations present and prevent any possible complications thereof.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: cytostatic (antimetabolite).

ATC code: L01BC06.

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate that acts as an orally administrable precursor of the cytotoxic form 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps (see section 5.2). The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase (ThyPase), is found in tumor tissues, but also in normal tissues, although generally at a lower concentration. In human xenograft tumor models, capecitabine has been shown to have a synergistic effect in combination with docetaxel, which may be related to the hyperegulation of thymidine phosphorylase by docetaxel.

The metabolism of 5-FU in the anabolic pathway has been observed to block the methylation reaction of deoxyuridyl acid to thymidyl acid, thus interfering in the synthesis of deoxyribonucleic acid (DNA). Incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, 5-FU can result in thymidine deficiency which causes unbalanced growth and cell death. The effects of DNA and RNA deprivation are particularly marked in cells that grow faster and metabolize 5-FU faster.

Colon and colorectal cancer:

Capecitabine monotherapy in the adjuvant treatment of colon cancer

Data from a multicentre, randomized, controlled phase III clinical trial in patients with stage III (Dukes C) colon cancer support the use of capecitabine for adjuvant therapy in patients with colon cancer (X-ACT Study , M66001). In this study, 1987 patients were randomized to treatment with capecitabine (1250 mg / m2 twice daily for 2 weeks, followed by 1 week off, as 3-week cycles for 24 weeks) or 5-FU and leucovorin (Mayo Clinic schedule: 20 mg / m2 IV leucovorin followed by 425 mg / m2 IV 5-FU bolus, on days 1 to 5, every 28 days for 24 weeks). Capecitabine was at least equivalent to 5-FU / LV IV in disease-free survival in the per protocol population (HR 0.92; 95% CI: 0.80-1.06). disease-free survival and overall survival showed an HR of 0.88 (95% CI: 0.77-1.01; p = 0.068) and 0.86 (95% CI: 0.74-1.01; p = 0.060) respectively. The median follow-up at the time of analysis was 6.9 years. In a previously planned multivariate Cox analysis, superiority of capecitabine over 5-FU / LV bolus was demonstrated. The following factors were predefined in the statistical analysis for inclusion in the model: age, time from surgery to randomization, gender, baseline CEA levels, baseline lymph nodes, and country. Across the randomized population, capecitabine was shown to be superior to 5-FU / LV both in terms of disease-free survival (HR: 0.849; 95% CI: 0.739-0.976; p = 0.0212) and in terms of overall survival (HR: 0.828; 95% CI: 0.705-0.971; p = 0.0203).

Combination therapy in the adjuvant treatment of colon cancer

Data from a multicentre, randomized, controlled, phase III clinical trial in patients with stage III (Dukes C) colon cancer support the use of capecitabine in combination with oxaliplatin (XELOX) for adjuvant treatment in patients with colon cancer (Study NO16968).In this study, 944 patients were randomized to treatment with capecitabine (1000 mg / m2 twice daily for 2 weeks, followed by 1 week off, as 3-week courses for 24 weeks) in combination with oxaliplatin (130 mg / m2 by intravenous infusion for 2 hours on day 1 every 3 weeks); 942 patients were randomized to bolus 5-FU and leucovorin. In the primary analysis for DFS in the ITT population, XELOX was shown to be significantly superior to 5-FU / LV (HR = 0.80, 95% CI = [0.69; 0.93]; p = 0, 0045). The 3-year DFS rate was 71% in the XELOX arm compared to 67% in the 5-FU / LV arm. The analysis performed for the secondary endpoint of RFS supports these results with a HR of 0.78 (95% CI = [0.67; 0.92]; p = 0.0024) in the XELOX arm compared to the 5-FU / LV arm. XELOX demonstrated a trend of superiority in terms of OS with an HR of 0.87 (95% CI = [0.72; 1.05]; p = 0.1486) which translates into a 13% reduction in the risk of death. 5-year OS was 78% for XELOX versus 74% for 5-FU / LV. Efficacy data are based on a median observation time of 59 months for OS and 57 months for DFS. The study withdrawal rate for adverse events was higher in the XELOX arm (21%) than in the 5-FU / LV monotherapy arm (9%) in the ITT population.

Capecitabine monotherapy in metastatic colorectal cancer

Data from two similarly designed, multicentre, randomized, controlled phase III clinical trials (SO14695: SO14796) support the use of capecitabine for first-line treatment of metastatic colorectal cancer. In these studies, 603 patients were randomized to treatment with capecitabine (1250 mg / m2 twice daily for 2 weeks, followed by a 1-week rest, and administered in 3-week cycles). 604 patients were randomized to treatment with 5-FU and leucovorin (regimen Mayo: 20 mg / m2 iv leucovorin followed by 425 mg / m2 intravenous bolus 5-FU, on days 1 to 5, every 28 days). investigator) were: 25.7% (capecitabine) versus 16.7% (Mayo regimen); p

Combination therapy in the first-line treatment of metastatic colorectal cancer

Data from a multicentre, randomized, controlled phase III clinical trial (NO16966) support the use of capecitabine in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer. study included two parts: an initial two-arm part in which 634 patients were randomized to two different treatment regimens, i.e. XELOX or FOLFOX-4, and a subsequent 2x2 factorial part in which 1401 patients were randomized to four different treatment regimens. treatment, ie XELOX plus placebo, FOLFOX-4 plus placebo, XELOX plus bevacizumab and FOLFOX-4 plus bevacizumab See table 6 for treatment regimens.

Table 6 Treatment regimens in study NO16966 (mCRC)


Treatment Initial dose Schedule FOLFOX-4 or FOLFOX-4 + Bevacizumab Oxaliplatin 85 mg / m2 i.v. 2 hours Oxaliplatin on day 1, every 2 weeks Leucovorin on days 1 and 2, every 2 weeks i.v. 5-fluorouracil. as a bolus / infusion, on days 1 and 2, every two weeks Leucovorin 200 mg / m2 i.v. 2 hours 5-Fluorouracil 400 mg / m2 i.v. as a bolus, followed by 600 mg / m2 i.v. 22 hours Placebo or Bevacizumab 5 mg / kg i.v. 30-90 min Day 1, prior to FOLFOX-4, every 2 weeks XELOX or XELOX + Bevacizumab Oxaliplatin 130 mg / m2 i.v. 2 hours Oxaliplatin on day 1, every 3 weeks Oral capecitabine 2 times daily for 2 weeks (followed by one week off) Capecitabine 1000 mg / m2 oral twice daily Placebo or Bevacizumab 7.5 mg / kg i.v. 30-90 min Day 1, before XELOX, every 3 weeks 5-Fluorouracil: bolus injection i.v. immediately after leucovorin

In the overall comparison, non-inferiority of the XELOX-containing arms compared to those containing FOLFOX-4 was demonstrated in terms of progression-free survival in the eligible patient population and the intent-to-treat population (see table 7). The results indicate that XELOX is equivalent to FOLFOX-4 in terms of overall survival (see Table 7). Comparison of XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab consisted of a "pre-planned exploratory analysis. When comparing these treatment subgroups, XELOX plus bevacizumab was similar to FOLFOX-4 plus bevacizumab in terms of progression-free survival ( hazard ratio 1.01; 97.5% CI: 0.84 - 1.22). Median follow-up at the time of the primary analyzes in the intent-to-treat population was 1.5 years; data derived from performed after a further year of follow-up are also included in table 7. The analysis of PFS during treatment did not however confirm the results of the analysis of general PFS and OS: the hazard ratio of XELOX versus FOLFOX -4 was 1.24 with 97.5% CI: 1.07 - 1.44. Although sensitivity analyzes show that differences in regimen planning and tumor assessment time affect the ongoing PFS analysis of treatment, no definitive explanation for this was found result.

Table 7 Key efficacy results for the non-inferiority analysis of Study NO16966


PRIMARY ANALYSIS XELOX / XELOX + P / XELOX + BV (PPE *: N = 967; ITT **: N = 1017) FOLFOX-4 / FOLFOX-4 + P / FOLFOX-4 + BV (PPE *: N = 937; ITT **: N = 1017) Population Median time to event (days) HR (97.5% CI) Parameter: Progression-free survival EPP 241 259 1,05 (0,94; 1,18) ITT 244 259 1,04 (0,93; 1,16) Parameter: Overall survival EPP 577 549 0,97 (0,84; 1,14) ITT 581 553 0,96 (0,83; 1,12) FURTHER YEAR OF FOLLOW UP Population Median time to event (days) HR (97.5% CI) Parameter: Progression-free survival EPP 242 259 1,02 (0,92; 1,14) ITT 244 259 1,01 (0,91; 1,12) Parameter: Overall survival EPP 600 594 1,00 (0,88; 1,13) ITT 602 596 0,99 (0,88; 1,12)

* PPE = population of eligible patients; ** ITT = intent-to-treat population.

In a phase III, randomized, controlled study (CAIRO), the effect of using capecitabine at a starting dose of 1000 mg / m2 for 2 weeks every 3 weeks in combination with irinotecan for first-line treatment was investigated. of patients with metastatic colorectal cancer. 820 patients were randomized to receive sequential (n = 410) or combination (n = 410) treatment. Sequential treatment consisted of first-line treatment with capecitabine (1250 mg / m2 twice daily for 14 days), a second-line treatment with irinotecan (350 mg / m2 on day 1), and a third-line combination with capecitabine. (1000 mg / m2 twice daily for 14 days) and oxaliplatin (130 mg / m2 on day 1). Combination treatment consisted of first-line capecitabine treatment (1000 mg / m2 twice daily for 14 days ) combined with irinotecan (250 mg / m2 on day 1) (XELIRI) and a second line with capecitabine (1000 mg / m2 twice daily for 14 days) plus oxaliplatin (130 mg / m2 on day 1). were given at 3-week intervals. In first-line treatment, the median progression-free survival in the intent-to-treat population was 5.8 months (95% CI; 5.1 - 6.2 months ) for capecitabine monotherapy and 7.8 months (95% CI: 7.0 - 8.3 months; p = 0.0002) for XELIRI. this was associated with an increased incidence of gastrointestinal toxicity and neutropenia during first-line treatment with XELIRI (26% and 11% for XELIRI and first-line capecitabine, respectively).

In three randomized studies in patients with metastatic colorectal cancer, the XELIRI regimen was compared with 5-FU + irinotecan (FOLFIRI). The XELIRI regimens included capecitabine 1000 mg / m2 twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg / m2 on day 1. In the larger study (BICC-C), patients were randomized to open-label treatment with FOLFIRI (n = 144), bolus 5-FU (mIFL) (n = 145) or XELIRI (n = 141) and further randomized to double-blind celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (p = 0.004 for comparison with FOLFIRI) and 5.8 months for XELIRI (p = 0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p = 0.09) and 18.9 months for XELIRI (p = 0.27). Patients treated with XELIRI experienced excessive gastronintestinal toxicity compared to those treated with FOLFIRI (48% and 14% diarrhea for XELIRI and FOLFIRI, respectively).

In the EORTC study, patients were randomized to open-label treatment with FOLFIRI (n = 41) or XELIRI (n = 44) and further randomized to double-blind celecoxib or placebo. Median PFS and overall survival (OS) were lower for XELIRI compared to FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months); in addition, excessive rates of diarrhea have been reported in patients receiving the XELIRI regimen (41% XELIRI; 5.1% FOLFIRI).

In the study published by Skof et al., patients were randomized to receive either FOLFIRI or XELIRI. The overall response rate was 49% in the XELIRI arm and 48% in the FOLFIRI arm (p = 0.76). At the end of treatment, 37% of patients in the XELIRI arm and 26% of patients in the FOLFIRI arm had no evidence of disease (p = 0.56). Toxicity was similar between treatments, with the exception of neutropenia, which was most commonly reported in patients treated with FOLFIRI.

Montagnani et al. they used the results from the three aforementioned studies to provide a "global analysis of the randomized trials comparing the FOLFIRI and XELIRI therapeutic regimens in the treatment of mCRC." A significant reduction in the risk of disease progression was associated with FOLFIRI treatment (HR 0.76; 95% CI: 0.62-0.95; p

Data from a randomized clinical trial (Souglakos et al., 2012) comparisons between FOLFIRI + bevacizumab and XELIRI + bevacizumab showed no significant differences in terms of PFS and OS between treatments. Patients were randomized to treatment with FOLFIRI plus bevacizumab (Arm A, n = 167) or XELIRI plus bevacizumab (Arm B, n = 166). For Arm B, the XELIRI regimen used capecitabine 1000 mg / m2 twice daily for 14 days + irinotecan 250 mg / m2 on day 1. For treatment with FOLFIRI-Bev and treatment with XELIRI-Bev, respectively, the median progression-free survival (PFS), overall survival, and response rates were as follows: 10.0 months and 8.9 months (p = 0.64); 25.7 months and 27.5 months (p = 0.55); 45.5% and 39.8% (p = 0.32). Patients treated with XELIRI + bevacizumab reported a significantly higher incidence of diarrhea, febrile neutropenia and hand-foot skin reactions compared to patients treated with FOLFIRI + bevacizumab with significantly increased treatment delays, dose reductions and treatment interruptions.

Data from a phase II, multicentre, randomized, controlled study (AIO KRK 0604) support the use of capecitabine at a starting dose of 800 mg / m2 for 2 weeks every 3 weeks in combination with irinotecan and bevacizumab for treatment. first-line of patients with metastatic colorectal cancer.

120 patients were randomized to a modified XELIRI regimen with capecitabine 800 mg / m2 twice daily for two weeks followed by 7 days of rest), irinotecan (200 mg / m2 as a 30-minute infusion on day 1 every 3 weeks), and bevacizumab (7.5 mg / kg infused for 30 to 90 minutes on day 1 every 3 weeks); 127 patients were randomized to treatment with capecitabine (1000 mg / m2 twice daily for two weeks followed by 7 days of rest), oxaliplatin (130 mg / m2 as a 2-hour infusion on day 1 every 3 weeks) and bevacizumab ( 7.5 mg / kg infused for 30 to 90 minutes on day 1 every 3 weeks). Following a mean follow-up duration for the study population of 26.2 months, responses to treatment were as follows:

Table 8 Efficacy results for the AIO KRK study


XELOX + bevacizumab (ITT: n = 127) Modified XELIRI + bevacizumab (ITT: n = 120) Hazard ratio 95% CI P value Progression-free survival after 6 months ITT 76% 84% - 95% CI 69 - 84% 77 - 90% Median progression-free survival ITT 10.4 months 12.1 months 0,93 95% CI 9,0 - 12,0 10,8 - 13,2 0,82 - 1,07 p = 0.30 Median overall survival ITT 24.4 months 25.5 months 0,90 95% CI 19,3 - 30,7 21,0 - 31,0 0,68 - 1,19 p = 0.45

Combination therapy in the second-line treatment of metastatic colorectal cancer

Data from a multicentre, randomized, controlled phase III clinical trial (NO16967) support the use of capecitabine in combination with oxaliplatin for the second-line treatment of metastatic colorectal cancer. In this study 627 patients with metastatic colorectal cancer who had received previous treatment with irinotecan in combination with a fluoropyrimidine-based regimen as first-line treatment were randomized to treatment with XELOX or FOLFOX-4. For the XELOX and FOLFOX-4 dosing regimen (without the addition of placebo or bevacizumab) , see table 6. XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of progression-free survival in the protocol and intent-to-treat population (see table 9). Results indicate that XELOX is equivalent to FOLFOX -4 in terms of overall survival (see table 9). Median follow-up at the time of primary analyzes in the intent-to-treat population was at 2.1 years; data from analyzes performed after a further 6 months of follow-up are also included in table 9.

Table 9 Key efficacy results for the non-inferiority analysis of study NO16967


PRIMARY ANALYSIS XELOX (PPP *: N = 251; ITT **: N = 313) FOLFOX-4 (PPP *: N = 252; ITT **: N = 314) Population Median time to event (days) HR (95% CI) Parameter: Progression-free survival PPP 154 168 1,03 (0,87; 1,24) ITT 144 146 0,97 (0,83; 1,14) Parameter: Overall survival PPP 388 401 1,07 (0,88; 1,31) ITT 363 382 1,03 (0,87; 1,23) ADDITIONAL 6 MONTHS OF FOLLOW UP Population Median time to event (days) HR (95% CI) Parameter: Progression-free survival PPP 154 166 1,04 (0,87; 1,24) ITT 143 146 0,97 (0,83; 1,14) Parameter: Overall survival PPP 393 402 1,05 (0,88; 1,27) ITT 363 382 1,02 (0,86; 1,21)

* PPP = population per protocol; ** ITT = intent-to-treat population.

Advanced gastric cancer:

Data from a multicentre, randomized, controlled phase III clinical trial in patients with advanced gastric cancer support the use of capecitabine in the first-line treatment of advanced gastric cancer (ML17032). In this study, 160 patients were randomized. treatment with capecitabine (1000 mg / m2 twice daily for 2 weeks followed by 7 days of rest) and cisplatin (80 mg / m2 as a 2-hour infusion every 3 weeks). A total of 156 patients were randomized to treatment with 5-FU (800 mg / m2 per day, as a continuous infusion from day 1 to day 5 every 3 weeks) and cisplatin (80 mg / m2 as a 2-hour infusion on day 1 every 3 weeks). Capecitabine in combination with cisplatin has demonstrated non-inferiority to 5-FU in combination with cisplatin in terms of progression-free survival in the per-protocol analysis (HR 0.81; 95% CI: 0.63 - 1.04). Median progression-free survival was 5.6 months (capecitabine + cisplatin) compared with 5.0 months (5-FU + cisplatin). The hazard ratio for duration of survival (overall survival) was similar to the hazard ratio for progression-free survival (HR 0.85; 95% CI: 0.64 - 1.13). Median duration of survival was 10.5 months (capecitabine + cisplatin) compared with 9.3 months (5-FU + cisplatin).

Data from a phase III, multicentre, randomized, clinical trial comparing capecitabine to 5-FU and oxaliplatin and cisplatin in patients with advanced gastric cancer support the use of capecitabine in the first-line treatment of advanced gastric cancer ( REAL-2) In this study, 1002 patients were randomized with a 2x2 factorial design to one of the following 4 arms:

- ECF: epirubicin (50 mg / m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg / m2 as a 2-hour infusion on day 1 every 3 weeks) and 5-FU (200 mg / m2 administered daily as an infusion continues via central catheter).

- ECX: epirubicin (50 mg / m2 as a bolus on day 1 every 3 weeks), cisplatin (60 mg / m2 as a 2-hour infusion on day 1 every 3 weeks) and capecitabine (625 mg / m2 twice daily as treatment continuous).

- EOF: epirubicin (50 mg / m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg / m2 as a 2-hour infusion on day 1 every 3 weeks) and 5-FU (200 mg / m2 administered daily as an infusion continues via central catheter).

- EOX: epirubicin (50 mg / m2 as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg / m2 as a 2-hour infusion on day 1 every 3 weeks) and capecitabine (625 mg / m2 twice daily as treatment continuous).

Primary efficacy analyzes in the per-protocol population demonstrated non-inferiority in overall survival for capecitabine-containing regimens compared to 5-FU-based regimens (HR 0.86; 95% CI: 0.8-0.0, 99) and for oxaliplatin-containing regimens compared to cisplatin-based regimens (HR 0.92; 95% CI: 0.80 - 1.1). Median overall survival was 10.9 months in the capecitabine-based regimens and 9.6 months in those containing 5-FU. Median overall survival was 10.0 months in the cisplatin-based regimens and 10.4 months in the oxaliplatin-based regimens.

Capecitabine has also been used in combination with oxaliplatin in the treatment of advanced gastric cancer. Studies with capecitabine alone indicate that capecitabine exhibits activity in advanced gastric cancer.

Advanced gastric, colon and colorectal cancer: meta-analysis

A meta-analysis of six clinical studies (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) supports the use of capecitabine as a substitute for 5-FU alone and in the combination treatment of gastrointestinal cancer. The pooled analysis includes 3097 patients treated with capecitabine-containing regimens and 3074 patients treated with 5-FU-containing regimens. Median overall survival was 703 days (95% CI: 671; 745) in patients treated with capecitabine-containing regimens and 683 days (95% CI: 646; 715) in those treated with 5-FU-containing regimens. The hazard ratio for overall survival was 0.94 (95% CI: 0.89; 1.00, p = 0.0489), indicating that regimens containing capecitabine are non-inferior to those containing 5- FU.

Breast cancer

Combination therapy with capecitabine and docetaxel in locally advanced or metastatic breast cancer

Data from a phase III, multicentre, randomized, controlled clinical trial support the use of capecitabine in combination with docetaxel for the treatment of patients with progressing locally advanced or metastatic breast cancer following failure of cytotoxic chemotherapy which included a "anthracycline. In this study, 255 patients were randomized to treatment with capecitabine (1250 mg / m2 twice daily for 2 weeks followed by a 1-week rest period and docetaxel 75 mg / m2 as a 1 hour intravenous infusion every 3 weeks). 256 patients were randomized to treatment with docetaxel alone (100 mg / m2 as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the capecitabine + docetaxel combination arm (p = 0.0126). Median survival was 442 days (capecitabine + docetaxel) compared with 352 days (docetaxel alone). The overall objective response rates in the entire randomized population (investigator assessment) were: 41.6% (capecitabine + docetaxel) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progression disease was superior in the capecitabine + docetaxel combination arm (p

Capecitabine monotherapy following failure of taxane and an anthracycline-containing chemotherapy and where anthracycline therapy is not indicated

Data from two multicentre Phase II clinical trials support the use of capecitabine monotherapy for the treatment of patients who are progressing following failure of chemotherapy that included taxanes and an anthracycline or for whom no further therapy is indicated. anthracyclines. In these studies, a total of 236 patients were treated with capecitabine (1250 mg / m2 twice daily for 2 weeks followed by 1 week rest period). Overall objective response rates (investigator assessment) were 20 % (first study) and 25% (second study) Median time to progression was 93 and 98 days Median survival was 384 and 373 days.

All indications:

A meta-analysis of 14 clinical trials with data from more than 4,700 patients treated with capecitabine alone or in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed overall survival more prolonged in capecitabine-treated patients who developed hand-foot syndrome than in patients who did not: median overall survival 1100 days (95% CI: 1007, 1200) vs 691 days (95% CI: 638; 754) with a hazard ratio of 0.61 (95% CI: 0.56, 0.66).

Pediatric population:

The European Medicines Agency has exempted from the obligation to conduct studies with Xeloda in all subclasses of the pediatric population in colon and rectal adenocarcinoma, gastric adenocarcinoma and breast cancer (see section 4.2 for information on "pediatric use).

05.2 Pharmacokinetic properties

The pharmacokinetics of capecitabine were evaluated over a dose range of 502-3514 mg / m2 / day. The parameters of capecitabine, 5 "-deoxy-5-fluorocytidine (5" -DFCR) and 5 "-deoxy-5-fluorouridine (5" DFUR) measured at days 1 and 14 were similar. The AUC of 5-FU on day 14 was 30-35% higher. Capecitabine dose reduction decreases systemic exposure to 5-FU in a more dose-proportional manner due to non-linear pharmacokinetics of the active metabolite. .

Absorption

After oral administration, capecitabine is completely and rapidly absorbed; subsequently it is completely converted into the 5 "-DFCR and 5" -DFUR metabolites. Administration with food decreases the absorption rate of capecitabine, but only causes a minor effect on the AUC of 5 "-DFUR and the AUC of the subsequent metabolite 5-FU. At a dose of 1250 mg / m2 on day 14 administered after meals , the maximum plasma concentrations (Cmax in mcg / ml) of capecitabine, 5 "-DFCR, 5" -DFUR, 5-FU and FBAL were respectively 4.67 - 3.05 - 12.1 - 0.95 and 5.46. The time to reach maximum plasma concentrations (Tmax in hours) was 1.50 - 2.00 - 2.00 - 2.00 and 3.34. The AUC0- ∞ values ​​in mcg • h / ml were 7.75 - 7.24 - 24.6 - 2.03 and 36.3.

Distribution

Human plasma studies carried out in vitro showed that capecitabine, 5 "DFCR, 5" -DFUR and 5-FU are bound to proteins, mainly albumin, in percentages of 54%, 10%, 62% and 10% respectively.

Biotransformation

Capecitabine is first metabolised by hepatic carboxylesterase to 5 "-DFCR, which is subsequently converted to 5" -DFUR by cytidine deaminase, mainly located in liver and tumor tissues. There is then a "further catalytic activation of 5" -DFUR by the thymidine phosphorylase (ThyPase). The enzymes involved in catalytic activation are present in tumor tissues, but also in healthy tissues, although generally in lower quantities. The sequential enzymatic biotransformation of capecitabine into 5-FU leads to higher concentrations within the neoplastic tissues. In colorectal cancers, 5-FU generation appears to be largely localized in tumor stromal cells. After oral administration of capecitabine to patients with colorectal cancer, the ratio of 5-FU concentration in colorectal cancers to adjacent tissues was 3.2 (ranging from 0.9 to 8.0). The ratio of 5-FU concentration in tumor to plasma was 21.4 (ranging from 3.9 to 59.9, n = 8), while the ratio in healthy tissue to plasma was 8.9 ( with variation from 3.0 to 25.8, n = 8). Thymidine phosphorylase activity was measured and found to be 4 times higher in primary colorectal cancer than reported values ​​in adjacent normal tissue. Based on immunohistochemistry studies, thymidine phosphorylase appears to be largely localized in tumor stromal cells. .

5-FU is subsequently catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) into dihydro-5-fluorouracil (FUH2) which is much less toxic. The dihydropyrimidase acts on the pyrimidine ring to obtain 5-fluoro-ureidopropionic acid (FUPA) Finally, b-ureido-propionase transforms FUPA into a-fluoro-b-alanine (FBAL) which is eliminated in the urine. The activity of dihydropyrimidine dehydrogenase (DPD) is the critical limiting factor. DPD deficiency may induce "increased toxicity of capecitabine (see sections 4.3 and 4.4).

Elimination

The elimination half-life (t½ in hours) of capecitabine, 5 "-DFCR, 5" -DFUR, 5-FU and FBAL was 0.85 - 1.11 - 0.66 - 0.76 and 3, respectively, 23. Capecitabine and its metabolites are eliminated primarily in the urine; 95.5% of the administered dose of capecitabine was recovered in the urine. Faecal excretion is minimal (2.6%). The major metabolite excreted in the urine is FBLA, which accounts for 57% of the administered dose. Approximately 3% of the administered dose is excreted in the urine as unchanged drug.

Association therapy

Phase I studies evaluating the effects of capecitabine on the pharmacokinetics of docetaxel or paclitaxel and vice versa have shown that there is no effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and that there is no effect of docetaxel or paclitaxel on the pharmacokinetics of 5 "-DFUR.

Pharmacokinetics in particular patient populations

A population pharmacokinetic analysis was conducted following treatment with capecitabine administered at a dose of 1250 mg / m2 twice daily in 505 patients with colorectal cancer. Gender, presence or absence of liver metastases at baseline, Karnofsky performance status, total bilirubin, serum albumin, ASAT and ALAT did not statistically significantly affect the pharmacokinetics of 5 "-DFUR, 5-FU and FBAL.

Patients with impaired hepatic function due to liver metastases: A pharmacokinetic study showed that capecitabine bioavailability and exposure to 5-FU may be increased in cancer patients with mild to moderate hepatic impairment due to liver metastases compared to patients without hepatic impairment. availability of pharmacokinetic data in patients with severe hepatic impairment.

Patients with impaired renal functionBased on the results of a pharmacokinetic study conducted in cancer patients with mild to severe renal impairment, there is no evidence that creatinine clearance affects the pharmacokinetics of parent drug and 5-FU. Creatinine clearance was found to influence "systemic exposure to 5" -DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and FBAL (114% increase in AUC when creatinine clearance decreases by 50%). 50%). FBAL is a metabolite with no antiproliferative activity.

Senior citizens: Based on population pharmacokinetic analyzes conducted on patients of various ages (27 to 86 years) and of which 234 (46%) patients were 65 years of age or older, age does not affect the pharmacokinetics of 5 " -DFUR and 5-FU. The AUC of FBAL increased with age (a 20% increase in age leads to a 15% increase in the AUC of FBAL). This increase is probably due to a change in renal function.

Ethnic factors: Following oral administration of capecitabine 825 mg / m2 twice daily for 14 days, Japanese patients (n = 18) had approximately 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients (n = 22). Japanese patients also had approximately 25% lower Cmax and 34% lower AUC for FBAL than Caucasian patients. The clinical relevance of these differences is unknown. There were no significant differences in exposure to other metabolites (5 "DFCR, 5" DFUR and 5-FU).

05.3 Preclinical safety data

In repeat dose toxicity studies, daily administration of oral capecitabine to cynomolgus monkeys and mice produced gastrointestinal, haematopoietic and lymphatic toxic effects typical of fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterized by degenerative / regressive changes, due to capecitabine has been observed. Capecitabine showed no evidence of hepatic and CNS toxicity. Cardiovascular toxicity (e.g. prolongation of the PR interval and QT interval) has been identified in the cynomolgus monkey following intravenous administration (100 mg / kg), but not after repeated dosing (1379 mg / m2 / day). ) orally.

A two-year mouse carcinogenicity study yielded no evidence of carcinogenicity due to capecitabine.

In standard fertility studies, female mice taking capecitabine exhibited fertility disturbances; this effect was however reversible after a period of drug suspension. In addition, atrophic and degenerative changes were found in the reproductive organs of male mice during a 13-week study; however, these effects were reversible after a drug withdrawal period (see section 4.6).

Studies on embryotoxicity and teratogenicity in mice showed a dose-related increase in fetal resorption and teratogenicity. In the monkey, abortions and embryonic lethality were observed at high doses, but there was no evidence of teratogenicity.

Capecitabine was not mutagenic in vitro for bacteria (Ames test) or for mammalian cells (Chinese hamster V79 / HPRT gene mutation test). However, like other nucleoside analogues (i.e. 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and showed a positive trend in the test (in vivo) of micronuclei in the mouse bone marrow.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Core of the tablet:

anhydrous lactose,

croscarmellose sodium,

hypromellose,

microcrystalline cellulose,

magnesium stearate.

Tablet coating:

hypromellose,

titanium dioxide (E171),

yellow and red iron oxide (E172),

talc.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

Do not store above 30 ° C.

06.5 Nature of the immediate packaging and contents of the package

Nature: PVC / PVDC blister.

Contents: 60 film-coated tablets (6 blisters of 10 tablets).

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

UK

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/00/163/001

035219017

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 2 February 2001

Date of last renewal: February 2, 2006

10.0 DATE OF REVISION OF THE TEXT

September 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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