Izvarino Pharma manufactures medicinal products for the treatment of oncological diseases such as breast cancer, chronic myelogenous leukemia, metastatic castration-resistant prostate cancer

Imatinib Izvarino Pharma

Imatinib

Composition

1 capsule 50 mg contains:
imatinib mesylate - 59.75 mg; equivalent to imatinib - 50.00 mg.
1 capsule 100 mg contains:
imatinib mesylate - 119.50 mg; equivalent to imatinib - 100.00 mg.

 

Presentation

Capsules 50 mg, 100 mg. 10 capsules in a blister of PVC film and aluminum printed glazed foil or 24, 36, 48, 96, 120 and 180 capsules in a high-pressure polyethylene bottle or jar sealed with a cap with a tamper-evident closure or without it.
1 bottle or jar or 2, 3, 4, 8, 10, 12 or 15 blisters with patient leaflets are placed in a carton pack.

 

Therapeutic indications

•    Treatment of adult and pediatric patients with
newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML);
•    Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or in blast crisis;
•    Newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adult and pediatric patients in combination with chemotherapy;
•   Relapsed or refractory Ph+ ALL as monotherapy in adult patients;
•    Myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements in adult patients;
•    Systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status in adult patients;
•    Hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adult patients with positive or negative abnormal FIP1L1-PDGFR alpha tyrosine kinase;
•    Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors in adult patients;
•    Adjuvant treatment of c-Kit (CD 117) positive gastrointestinal stromal tumors
in adult patients;
•    Unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans in adult patients.

 

Route of administration

Oral. Treatment should be given during a meal and with a large glass of water to minimize the risk of gastrointestinal disturbances.
Doses of 400 mg and 600 mg should be administered once daily; the daily dose of 800 mg should be administered as 400 mg twice a day in the morning and in the evening.
For patients unable to swallow the capsule whole (for example, children), the treatment can be given in diluted form: the capsule content is dispersed in a glass of water or apple juice.
Treatment should be continued as long as the clinical effect is maintained.
 In chronic myeloid leukemia the recommended dose of Imatinib depends on the phase of disease. In chronic phase CML, the daily dose is 400 mg; in accelerated phase or blast crisis  the daily dose is 600 mg. The treatment should be taken once daily. In the absence of pronounced adverse reactions and non-leukemia related neutropenia or thrombocytopenia, the daily dose may be increased from 400 mg to
600 mg to 800 mg for patients in chronic phase and from 600mg to 800 mg for patients in accelerated phase or blast crisis. Such dose increase can be needed in case of CML progression (any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 12 months of treatment or loss of a previously achieved hematologic and/or cytogenetic response.
Dose adjustment for pediatric patients above 2 years old should be based on body surface area. The daily dose of 340 mg/m2 is recommended to pediatric patients with chromic phase CML or accelerated phase. The total daily dose for children should not exceed 600 mg. The treatment can be given as a once daily dose or it may be split into 2 equal administrations – in the morning and in the evening.
In Ph+ Acute Lymphoblastic Leukemia the recommended daily dose of Imatinib is 600 mg.
Dose adjustment for pediatric patients above 1 year old should be based on body surface area. The recommended daily dose is 340 mg/m2. The total daily dose for children should not exceed 600 mg. The treatment should be taken as a once daily dose.
In Myelodysplastic/Myeloproliferative Diseases the recommended daily dose of Imatinib is 400 mg.
In Systemic Mastocytosis without the D816V c-Kit mutation the recommended daily dose of Imatinib is 400mg. For patients with unknown mutation status or not responding satisfactory to other therapies, the recommended daily dose is
400 mg. For patients with abnormal FIP1L1-PDGFR alpha tyrosine kinase generated by the fusion of the FIP 1 like1 and PDGFR genes, a starting dose of 100mg/day is recommended. In the absence of adverse drug reactions and if response to therapy is insufficient the daily dose can be increased to 400mg.
In Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia (HES/CEL) the recommended daily dose for adult patients is 400mg. For patients with HES/CEL associated with abnormal FIP1L1-PDGFR alpha tyrosine kinase, the recommended starting dose is 100 mg/day. In the absence of adverse drug reactions and if response to therapy is insufficient the daily dose can be increased to 400mg. Treatment should be continued as long as the clinical effect is maintained.
In Unresectable and/or Metastatic Malignant Gastrointestinal Stromal Tumors the recommended daily dose of Imatinib is 400 mg. In the absence of adverse drug reactions and if response to therapy is insufficient the daily dose of Imatinib can be increased from 400 mg to 600 mg or to 800 mg.
Treatment with Imatinib should be discontinued in case disease progression is evident.
In administration as adjuvant therapy in patients with gastrointestinal stromal tumors the recommended daily dose is 400 mg. The minimum treatment period is 3 years. The optimal duration of adjuvant treatment is not known.
In Unresectable, Recurrent and/or Metastatic Dermatofibrosarcoma Protuberans  the recommended daily dose of Imatinib is 800 mg.
Patients with Hepatic Impairment
Because imatinib is mainly metabolized in the liver, in patients with mild, moderate and severe hepatic dysfunction the minimum daily dose of Imatinib should be 400 mg. In undesirable toxic effects appear, the dose of the drug must be reduced. Precautions should be taken in administration to patients with severe hepatic insufficiency.
Patients with Renal Impairment
Kidneys do not play any significant role in imatinib and its metabolites excretion. For patients with renal dysfunction or patients needing regular hemodialysis, therapy with Imatinib should started from a minimum single daily dose of 400 mg with precautions.
The dose should be reduced if not tolerable, for lack of efficacy the dose can be increased.
Elderly Patients
Dosage regiment adjustment of the product for elderly patients is not required.
Dose Adjustment for Non-Hematologic Adverse Drug Reactions
If a severe non-hematologic adverse drug reaction develops, the treatment should be withheld until the event has resolved. Thereafter, treatment can be resumed at a dose depending on the severity of the event.
If elevations in bilirubin >3 x upper limit of normal (ULN) or in liver transaminases >5 x ULN occur, the treatment should be withheld until bilirubin levels have returned to a <1.5 x ULN and liver transaminase levels to <2.5 x ULN.
Treatment with Imatinib may be resumed at a reduced daily dose: in adults - from 400mg to 300 mg or from 600 mg to 400 mg, or from 800 mg to 600 mg; in pediatric patients - from 340 mg/m2 to 260 mg/m2.
Dose Adjustment for Serious Hematologic Adverse Drug Reactions (severe thrombocytopenia, neutropenia)
Dose reduction or treatment interruptions for neutropenia and thrombocytopenia are recommended depending on the severity of these adverse reactions. For Systemic Mastocytosis (SM) and Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia (HES/CEL) associated with abnormal FIP1L1-PDGFR alpha tyrosine kinase (the initial dose of Imatinib is
100 mg), where absolute neutrophil count < 1000/µl and/or platelets < 50000/µl the following is recommended:
1.    Stop Imatinib until absolute neutrophil count ≥ 1500/µl and platelets ≥ 75000/µl;
2.    Resume treatment with Imatinib at the dose used before treatment interruption.
In chronic phase CML in children and adults (starting dose for adults - 400 mg, for children - 340 mg/m2), malignant gastrointestinal stromal tumors, myelodysplastic/myeloproliferative diseases, SM and HES/CEL in adult patients (starting dose for adults - 400 mg), where absolute neutrophil count < 1000/µl and/or platelets < 50000/µl the following is recommended:
1.    Stop Imatinib until absolute neutrophil count > 1500/µl and platelets > 75000/µl;
2.    Resume treatment with Imatinib at the dose used before treatment interruption;
3.    If recurrence of absolute neutrophil count < 1000/µl and/or platelets < 50000/µl, step 1 should be repeated, and Imatinib resumed at a dose reduced to 300 mg (for children - 260 mg/m2).
In accelerated phase and blast crisis CML in children and in Ph+ALL in adult patients (starting dose for adults - 600 mg, for children - 340 mg/m2), if absolute neutrophil count < 500/µl and/or platelets
< 10000/µl in a month or longer period of treatment, the following is recommended:
1.    Check if cytopenia is related to leukemia (marrow study);
2.    If cytopenia is unrelated to leukemia, reduce dose of Imatinib to
400 mg (in children - 260 mg/m2);
3.    If cytopenia persists for 2 weeks, reduce the dose to 300 mg.
(in children - 200 mg/m2);
4.   If cytopenia persists for 4 weeks and is still unrelated to leukemia, stop Imatinib until absolute neutrophil count >1000/µl and platelets > 20000/µl; resume treatment with Imatinib at 300mg (in children - 200 mg/m2).
In unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (Imatinib starting dose 800 mg), if absolute neutrophil count < 1000/µl and/or platelets < 50000/µl the following is recommended:
1.    Stop Imatinib until absolute neutrophil count > 1500/µl and platelets > 75000/µl;
2.    Resume Imatinib at 600 mg;
3.    If recurrence of absolute neutrophil count < 1000/µl and/or platelets < 50000/µl, step 1 should be repeated, and Imatinib resumed at a dose reduced to 400 mg.

 

Abiraterone Izvarino Pharma

Abiraterone

Composition

1 tablet 250 mg contains:
Abiraterone acetate - 250 mg.

 

Presentation

Tablets 250 mg. 10 tablets in a blister of PVC/PVDC and aluminum printed glazed foil or 30, 60 or 120 tablets in a bottle of high density polyethylene sealed with a cap of high density polyethylene with a tamper-evident closure (polymer and cardboard based liner) or without it.
1 bottle or 3, 6 or 12 blisters with patient leaflets are placed in a carton pack.

 

Therapeutic indications

Abiraterone is indicated in combination with prednisone for the treatment of metastatic prostate
castration-resistant prostate cancer.

 

Route of administration

The recommended daily dose of abiraterone is 1 g (4 tablets 250mg) as a single daily dose that must be taken 1 hour before or 2 hours after the meal. The tablets should be swallowed whole without chewing with water. Abiraterone is administered with low doses of prednisone. The recommended daily dose of prednisone is 10 mg. Abiraterone must not be taken with food.
No food should be consumed for 1 hour after dose of abiraterone.
Prior to starting treatment with abiraterone, serum transaminases and bilirubin should be measured every 2 weeks for the first 3 months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly. In the event of a missed daily dose of either abiraterone or prednisone, treatment should be
taken the following day with the usual dose.
Dose Adjustment in Patients with Hepatic Impairment
No dosage adjustment is necessary for patients with mild hepatic impairment. Efficacy and safety of abiraterone acetate has not been studied in multiple administrations in patients with moderate or severe hepatic impairment (Child-Pugh B or C), that is why the necessary dose adjustment cannot be predicted. Abiraterone should not be used in patients with moderate or severe hepatic impairment.
For patients who develop hepatotoxicity during treatment (serum alanine aminotransferase or aspartate aminotransferase rise above 5 times the upper limit of normal or bilirubin rises above 3 times the upper limit of normal) treatment should be withheld immediately until liver function tests
normalize.
Re-treatment following return of liver function tests to the norm may be given at a
reduced dose of 500 mg (two tablets) once daily. In this case, serum transaminases and bilirubin should be monitored at a minimum of every 2
weeks for 3 months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment with abiraterone should be discontinued.
If patients develop severe hepatotoxicity (alanine aminotransferase or aspartate aminotransferase 20 times the upper limit of normal) anytime while on therapy, abiraterone should be discontinued and patients should not be re-treated.
Special Populations
Patients with Hepatic Impairment
For patients with pre-existing mild renal impairment (Child-Pugh class A) dose adjustment is not required. Abiraterone should not be used in patients with moderate and severe hepatic impairment (Child-Pugh classes B and С).
Patients with Renal Impairment
For patients with renal impairment dose adjustment is not required.
However, abiraterone must not be prescribed to prostate cancer patients with severe renal impairment because there is no clinical data on usage of abiraterone in such patients.
Pediatric patients
Usage of abiraterone is not relevant for pediatric patients because prostate cancer does not occur in this population.

 

Capecitabine Izvarino Pharma

Capecitabine

Composition

1 film-coated tablet 150 mg contains:
capecitabine – 150.0 mg.


1 film-coated tablet 500 mg contains:
capecitabine – 500.0 mg.

 

Presentation

Film-coated tablets, 150 mg, 500 mg.
10 tablets in a blister of PVC film and aluminum foil or 60 tablets in a bottle of high density polyethylene sealed with a cap of high density polyethylene with a tamper-evident closure (polymer and cardboard based liner) or without it.
3, 6, 9 or 12 blisters or 1 bottle with patient leaflets are placed in a carton pack.

 

Therapeutic indications

Breast Cancer
•    Combination therapy with docetaxel for the treatment of patients with advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.
•    Monotherapy for the treatment of advanced or metastatic breast cancer resistant to taxanes or anthracycline containing chemotherapy or if these agents are contraindicated.
Colorectal Cancer
•    Adjuvant treatment of patients with stage III colon cancer after surgery.
•    Therapy of metastatic colorectal cancer.
Gastric cancer
•    First-line therapy of advanced gastric cancer.

 

Route of administration

Orally whole with water within 30 min after a meal. The tablets should not be broken or crushed.
Standard dosing regimen
Monotherapy
Colorectal cancer, colon cancer, breast cancer
1250 mg/m2 twice daily in the morning and in the evening (total daily dose 2500 mg/m2) for 14 days followed by a 7-day rest period.
Combination Therapy
Breast Cancer
1250 mg/m2 twice daily for 14 days followed by a 7-day rest period in combination with docetaxel dose of 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks.
The premedication prior to docetaxel administration is carried out in accordance with its prescribing information.
Colorectal Cancer, Colon Cancer, Gastric Cancer
In combination (except for therapy in combination with irinotecan) the dose of capecitabine is 800-1000 mg/m2 twice daily during
14 days followed by a 7-day rest period or up to 625 mg/m2 twice daily for continuous regimen.
In Combination with Irinotecan  (XELIRI regimen) the recommended dose of capecitabine is 800 mg/m2 twice daily for 14 days followed by a 7-day rest period. Bevacizumab added to the combination therapy does not affect the starting dose of capecitabine.
Premedication to maintain adequate anti-emesis and hydration should be started prior to cisplatin and oxaliplatin administration according to the cisplatin and oxaliplatin product instructions for use in combination with capecitabine.
In adjuvant therapy of stage III colon cancer capecitabine therapy should be given for 6 months, i.e. 8 cycles.
In Combination with Cisplatin
1000 mg/m2 twice daily for 14 days followed by a 7-day rest period in combination with cisplatin (80 mg/m2 given once 3 weeks as a 2-hour i/v infusion, the first infusion is given on the first day of the cycle). The first dose of capecitabine is given on the evening of day 1 of the cycle and the last dose is given on the morning of day 15.
In Combination with Oxaliplatin or Oxaliplatin and Bevacizumab
1000 mg/m2 twice daily for 14 days followed by a 7-day rest period in combination with oxaliplatin or oxaliplatin and bevacizumab. The first dose of capecitabine is given on the evening of day 1 of the cycle and the last dose is given on the morning of day 15. Bevacizumab is given in the dose of 7.5 mg/kg once 3 weeks as an i/v infusion for
30-90 min, the first infusion is given on the first day of the cycle. After bevacizumab oxaliplatin dose of 130 mg/m2 is given as a 2-hour i/v infusion.
In Combination with Epirubicin and a Platinum-Based Drug
625 mg/m2 twice daily as a continuous regiment in combination with epirubicin
(50 mg/m2 once 3 weeks, bolus i/v starting on day 1 of the cycle) and a platinum-based drug. The platinum-based drug (cisplatin dose of 60 mg/m2 or oxaliplatin dose of 130 mg/m2) should be administered on day 1 of the cycle as a 2-hour i/v infusion followed by a 3-weekly schedule.
In Combination with Irinotecan or Irinotecan and Bevacizumab
The recommended dose of capecitabine is 800 mg/m2 twice daily for 14 days followed by a 7-day rest period in combination with irinotecan or irinotecan and bevacizumab.
Irinotecan dose of 200 mg/m2 is administered once 3 weeks as a 30-minute i/v infusion, the first infusion is given on day 1 of the cycle.
Bevacizumab dose of 7.5 mg/kg is administered once 3 weeks as an i/v infusion for 30-90 min, the first infusion is given on day 1 of the cycle.
Dose Calculation The dose is calculated according to body surface area. Tables below show examples of the standard and reduced dose calculations for a capecitabine starting dose of either 1250 mg/m2 or 1000 mg/m2.


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

 

Dose of 1250 mg/m2 twice daily

Full dose 1250 mg/m2

Number of 150 mg tablets and/or

500 mg tablets per administration (each administration to be given twice daily - in the morning and in the evening)

Reduced dose

(75 % of starting dose) 950 mg/m2

Reduced dose

(50 % of

starting dose)

625 mg/m2

Body Surface Area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per administration (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 according to body surface area for a starting capecitabine dose of 1000 mg/m2.

 

Dose of 1000 mg/m2 twice daily

Full dose 1000 mg/m2

Number of 150 mg tablets and/or

500 mg tablets per administration (each administration to be given twice daily - in the morning and in the evening)

Reduced dose

(75 % of starting dose) 750 mg/m2

Reduced dose

(50 % of

starting dose)

500 mg/m2

Body Surface Area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per administration (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

 

 

Dose Modification during Treatment
General Guidelines
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or dose adjustment (by interruption or reduction of capecitabine dose). Once the dose has been reduced it should not be increased at a later time.
For those toxicities considered by the treating physician to be unlikely to become serious or life- threatening, treatment can be continued at the same dose without reduction or interruption.
For grade 1 toxicity, the dosage should be not modified. Therapy with capecitabine should be interrupted for grade 2 or 3 toxicity.
Once the adverse event has resolved or decreased in intensity to grade 1, capecitabine therapy may be restarted at full dose or as adjusted according to guidelines given in Table 3.
If a grade 4 event occurs, therapy should be discontinued or interrupted until resolved or decreased to grade 1, and then therapy should be restarted at 50% of the original dose. The patient should immediately inform the physician of the developed adverse events. Capecitabine should be immediately discontinued if moderate or severe toxicity occurs. If several doses of capecitabine are omitted for toxicity, they are not replaced.
Hematologic Toxicity
Patients with baseline neutrophil counts of < 1.5 × 109/L and/or thrombocyte counts of <100 × 109/L should not be treated with capecitabine.
If unscheduled laboratory assessments show neutrophil counts below 1.0 × 109/L and thrombocyte counts below 75 × 109/L (grade 3 or 4 haematologic toxicity), treatment with capecitabine should be interrupted.
The table below shows guidelines for capecitabine dose modifications due to toxicity events associated with the treatment.

 

Table 3. Scheme of Capecitabine Dose Modifications

Toxicity NCIC Grade*

 

Dose Adjustment During a Course of Therapy

Dose Adjustment for Next Cycle

(% of starting dose)

Grade 1

Maintain dose level

Maintain dose level

Grade 2

1st appearance

Interrupt until resolved to grade 0 - 1

100 %

2nd appearance

75 %

3rd appearance

50 %

4th appearance

Discontinue treatment permanently

Not applicable

Grade 3

1st appearance

Interrupt until resolved to grade 0 - 1

75 %

2nd appearance

50 %

3rd appearance

Discontinue treatment permanently

Not applicable

Grade 4

1st appearance

Discontinue permanently OR if physician deems it to be in the patient’s best interest to continue, interrupt until resolved to grade 0 - 1

50 %

2nd appearance

Discontinue treatment permanently

Not applicable

*According to the National Cancer Institute of Canada Clinical Trial Group Common Toxicity Criteria ( (NCIC CTG Version 1) or the Common Terminology Criteria for Adverse Events of the Cancer Therapy Evaluation Program, US National Cancer Institute (CTCAE, version 3). For Hand-and-Foot Syndrome and hyperbilirubinemia see section ‘Warning and Precautions’.

General Guidelines for Combination Therapy
Dose modifications for toxicity when capecitabine is used in combination with other therapies should be made according to recommendations given in Table 3 above and appropriate recommendations of other products instructions.
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other agent(s), then administration of all agents should be delayed until the requirements for restarting all drugs are met.
During a treatment cycle for those toxicities considered by the treating physician not to be related to capecitabine, capecitabine should be continued and the dose of the other agent adjusted according to the appropriate product instructions.
If the other agent(s) have to be discontinued permanently, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.
These recommendations are applicable to all indications and to all special populations.


Dose Adjustment in Special Populations
Hepatic Impairment
In patients with mild to moderate hepatic dysfunction due to liver metastases, no starting dose adjustment is necessary. These patients, however, should be carefully monitored. Usage of capecitabine in patients with severe hepatic dysfunction have not been studied.
Renal Impairment
In patients with moderate renal impairment (CC 30-50 ml/min according to Cockroft and Gault) at baseline a dose reduction to 75% from a starting dose of 1250 mg/m2 is recommended; no dose adjustment is required for the 1000 mg/m2 starting dose.
In patients with mild renal impairment (CC 51-80 ml/min) no adjustment in starting dose is required.
Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3, or 4 adverse event, with subsequent dose adjustment as outlined in Table 3. If the calculated CC decreases during treatment to a value below 30 ml/min, capecitabine should be discontinued. The dose adjustment recommendation for patients with moderate renal impairment applies both to monotherapy and combination use. Dosage calculations are given in Tables 1 and 2.
Pediatric patients
The safety and effectiveness of capecitabine have not been established in children <18 years of age.
Geriatric Patients
No adjustment of the starting dose is needed for capecitabine monotherapy. However severe Grade 3 or 4 treatment-related adverse events were more frequent in patients over 80 years of age compared to younger patients.
When capecitabine was used in combination with other anti-tumor agents, elderly patients (≥ 65 years) experienced more grade 3 and grade 4 adverse reactions and adverse reactions that led to discontinuation, than younger patient. Careful monitoring of elderly patients is recommended.
For treatment in combination with docetaxel, an increased incidence of Grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events was observed in patients 60 years of age or more. For patients 60 years of age or more to be treated with capecitabine in combination with docetaxel, the starting dose of capecitabine should be reduced to 75% (950 mg/m2 twice daily). Dose calculation is given in Table 1. If no toxicity events develop, the dose may by increased to 1250 mg/m2 twice daily.