DOCETAXEL HOSPIRA 10 MGML

Israel - English - Ministry of Health

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Active ingredient:
DOCETAXEL
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
L01CD02
Pharmaceutical form:
SOLUTION FOR INFUSION
Composition:
DOCETAXEL 10 MG / 1 ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
HOSPIRA UK LTD, UK
Therapeutic group:
DOCETAXEL
Therapeutic area:
DOCETAXEL
Therapeutic indications:
Breast cancer: Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node- positive breast cancer. Docetaxel in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. Docetaxel monotherapy is indicated for the treatment of patients with metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent. Docetaxel in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who previously have not received chemotherapy for metastatic disease. Docetaxel in combination with capecitabine is indicated for the treatment of patients with metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracy
Authorization number:
148 24 33345 00
Authorization date:
2017-05-31

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ךיראת

21.4.2013

םש

רישכת

תילגנאב

DOCETAXEL HOSPIRA 10 MG/ML

רפסמ

םושיר

148.24.33345.00

םש

לעב

םושירה

המראפהבונ

מ"עב

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Special

warnings and

special

precautions

for use

Current text:

In the case of severe

neutropenia (<500 cells/mm

for 7 days or more) during a

course of docetaxel therapy, a

reduction in dose for

subsequent courses of therapy

or the use of appropriate

symptomatic measures are

recommended (see section

Posology and method of

administration”).

In patients treated with

docetaxel in combination with

cisplatin and 5-fluorouracil

(TCF), febrile neutropenia and

neutropenic infection occurred

at lower rates when patients

received prophylactic G-CSF.

Patients treated with TCF

should receive prophylactic

G-CSF to mitigate the risk of

complicated neutropenia

(febrile neutropenia,

prolonged neutropenia or

neutropenic infection).

Patients receiving TCF should

be closely monitored (see

section “Posology and

method of administration

and “Undesirable effects“).

Congestive heart failure:

Patients should be monitored

for symptoms of congestive

Change to the following text:

In the case of severe neutropenia

(<500 cells/mm

for 7 days or

more) during a course of

docetaxel therapy, a reduction in

dose for subsequent courses of

therapy or the use of appropriate

symptomatic measures are

recommended (see section

Posology and method of

administration”).

In patients treated with

docetaxel in combination with

cisplatin and 5-fluorouracil

(TCF), and docetaxel in

combination with doxorubicin

and cyclophosphamide (TAC),

febrile neutropenia and

neutropenic infection occurred

at lower rates when patients

received prophylactic G-CSF.

Patients treated with TCF and

TAC (for breast cancer) should

receive prophylactic G-CSF to

mitigate the risk of complicated

neutropenia (febrile neutropenia,

prolonged neutropenia or

neutropenic infection). Patients

receiving TCF and TAC should

be closely monitored (see

section “Posology and method

of administration” and

Undesirable effects“).

Congestive heart failure:

Patients should be monitored for

symptoms of congestive heart

failure during therapy and

heart failure during therapy

and during the follow-up

period.

during the follow-up period. In

patients treated with the TAC

regimen for node positive breast

cancer, the risk of congestive

heart failure has been shown to

be higher during the first year of

treatment.

Interaction

with other

medicinal

products and

other forms

of interaction

Current text:

Docetaxel should be

administered with caution in

patients concomitantly

receiving potent CYP3A4

inhibitors (e.g., protease

inhibitors like ritonavir, azole

antifungals like ketoconazole

or itraconazole). A drug

interaction study performed in

patients receiving

ketoconazole and docetaxel

showed that the clearance of

docetaxel was reduced by half

by ketoconazole, probably

because the metabolism of

docetaxel involves CYP3A4

as a major (single) metabolic

pathway. Reduced tolerance

of docetaxel may occur, even

at lower doses.

Change to the following text:

Docetaxel should be

administered with caution in

patients concomitantly receiving

potent CYP3A4 inhibitors (e.g.,

protease inhibitors like ritonavir,

azole antifungals like

ketoconazole or itraconazole

and some macrolides like

clarithromycin or

telithromycin). A drug

interaction study performed in

patients receiving ketoconazole

and docetaxel showed that the

clearance of docetaxel was

reduced by half by

ketoconazole, probably because

the metabolism of docetaxel

involves CYP3A4 as a major

(single) metabolic pathway.

Reduced tolerance of docetaxel

may occur, even at lower doses.

Pregnancy

and lactation

Current text:

Pregnancy: There is no information on

the use of docetaxel in pregnant

women. In vivo studies have shown

docetaxel to be both embryotoxic and

foetotoxic in rabbits and rats (see

section “Preclinical safety data”). As

with other cytotoxic drugs, docetaxel

may cause foetal harm when

administered to pregnant women.

Therefore, docetaxel should not be

used during pregnancy unless the

clinical condition of the woman

requires treatment with docetaxel.

Women of childbearing potential

/contraception: Women of

childbearing age receiving docetaxel

should be advised to avoid becoming

pregnant, and to inform the treating

physician immediately should this

occur. An effective method of

contraception should be used during

and up to 3 months after treatment.

Docetaxel can have genotoxic effects.

Therefore, men being treated with

docetaxel are advised not to father a

child during and up to 6 months after

treatment and to seek advice on

Change to the following text:

Pregnancy: There is no information on

the use of docetaxel in pregnant women.

In vivo studies have shown docetaxel to

be both embryotoxic and foetotoxic in

rabbits and rats, and to reduced fertility in

rats (see section “Preclinical safety

data”). As with other cytotoxic drugs,

docetaxel may cause foetal harm when

administered to pregnant women.

Therefore, docetaxel should not be used

during pregnancy unless the clinical

condition of the woman requires

treatment with docetaxel.

Women of childbearing potential

/contraception: Women of childbearing

age receiving docetaxel should be

advised to avoid becoming pregnant, and

to inform the treating physician

immediately should this occur. An

effective method of contraception should

be used during and up to 3 months after

treatment.

Docetaxel can have genotoxic effects.

Therefore, men being treated with

docetaxel are advised not to father a child

during and up to 6 months after treatment

and to seek advice on conservation of

conservation of sperm prior to

treatment because of the possibility of

irreversible infertility due to therapy

with docetaxel.

Fertility: Adverse effects on the testis

observed in rodent toxicity studies

suggest that docetaxel may impair male

fertility.

sperm prior to treatment because of the

possibility of irreversible infertility due

to therapy with docetaxel.

[This crossed-out paragraph is moved

below to “Fertility”]

Fertility: Adverse effects on the testis

observed in rodent toxicity studies

suggest that docetaxel may impair male

fertility.

Docetaxel can have genotoxic effects.

Therefore, men being treated with

docetaxel are advised not to father a child

during and up to 6 months after treatment

and to seek advice on conservation of

sperm prior to treatment because of the

possibility of irreversible infertility due

to therapy with docetaxel.

Undesirable

effects

Current text:

Respiratory, thoracic and mediastinal

disorders: Acute respiratory distress

syndrome, interstitial pneumonia and

pulmonary fibrosis have rarely been

reported. Rare cases of radiation

pneumonitis have been reported in

patients receiving concomitant

radiotherapy.

Skin and subcutaneous tissue

disorders: Very rare cases of cutaneous

lupus erythematous and bullous

eruptions such as erythema multiforme,

Stevens-Johnson syndrome, toxic

epidermal necrolysis, have been

reported with docetaxel. In some cases

concomitant factors may have

contributed to the development of these

effects. Sclerodermal-like change

usually preceded by peripheral

lymphedema have been reported with

docetaxel.

Neoplasms benign and malignant

(including cysts and polyps): Very rare

Cases of acute myeloid leukaemia and

myelodysplastic syndrome have been

reported in association with docetaxel

when used in combination with other

chemotherapy agents and/or

radiotherapy.

General disorders and administration

site conditions: Radiation recall

phenomena have rarely been reported.

Fluid retention has not been

accompanied by acute episodes of

oliguria or hypotension. Dehydration

and pulmonary oedema have rarely

Change to the following text:

Respiratory, thoracic and mediastinal

disorders: Acute respiratory distress

syndrome, interstitial pneumonia and

pulmonary fibrosis (sometimes fatal) and

pulmonary oedema have rarely been

reported. Rare cases of radiation

pneumonitis have been reported in

patients receiving concomitant

radiotherapy.

Skin and subcutaneous tissue disorders:

Very rare cases of cutaneous lupus

erythematous and bullous eruptions such

as erythema multiforme, Stevens-Johnson

syndrome, toxic epidermal necrolysis,

have been reported with docetaxel. In

some cases concomitant factors may have

contributed to the development of these

effects. Sclerodermal-like change usually

preceded by peripheral lymphedema have

been reported with docetaxel. Cases of

persisting alopecia have been reported.

Neoplasms benign and malignant

(including cysts and polyps): Very rare

Cases of acute myeloid leukaemia and

myelodysplastic syndrome have been

reported in association with docetaxel

when used in combination with other

chemotherapy agents and/or

radiotherapy.

General disorders and administration

site conditions: Radiation recall

phenomena have rarely been reported.

Fluid retention has not been accompanied

by acute episodes of oliguria or

hypotension. Dehydration and pulmonary

oedema have rarely been reported.

been reported.

Renal and urinary disorders:

Renal insufficiency and renal

failure have been reported (in

about 20% of these cases there

were no risk factors for acute

renal failure such as

concomitant nephrotoxic

medicinal products and

gastrointestinal disorders).

Metabolism and nutrition

disorders: Dehydration has

rarely been reported.

Injury, poisoning and

procedural complications:

Radiation recall, phenomena and

radiation pneumonitis have been

reported rarely in patients

receiving concomitant

radiotherapy.

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DOCETAXEL HOSPIRA

®

10 MG/ML

1.

NAME OF THE MEDICINAL PRODUCT

DOCETAXEL HOSPIRA

10 MG/ML.

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA,

HYPERSENSITIVITY REACTIONS and FLUID RETENTION

The incidence of treatment-related mortality associated with DOCETAXEL therapy is

increased in patients with abnormal liver function, in patients receiving higher doses,

and in patients with non-small cell lung carcinoma and a history of prior treatment with

platinum-based chemotherapy who receive DOCETAXEL as a single agent at a dose of

100 mg/m2.

DOCETAXEL should not be given to patients with bilirubin > upper limit of normal

(ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline

phosphatase >2.5 × ULN. Patients with elevations of bilirubin or abnormalities of

transaminase concurrent with alkaline phosphatase are at increased risk for the

development of grade 4 neutropenia, febrile neutropenia, infections , severe

thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with

isolated elevations of transaminase >1.5 × ULN also had a higher rate of febrile

neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin,

AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of

DOCETAXEL therapy.

DOCETAXEL therapy should not be given to patients with neutrophil counts of <1500

cells /mm. In order to monitor the occurrence of neutropenia, which may be severe and

result in infection, frequent blood cell counts should be performed on all patients

receiving DOCETAXEL.

Severe hypersensitivity reactions characterized by generalized rash/erythema,

hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported

in patients who received a 3-day dexamethasone premedication. Hypersensitivity

reactions require immediate discontinuation of the DOCETAXEL infusion and

administration of appropriate therapy. DOCETAXEL must not be given to patients who

have a history of severe hypersensitivity reactions to DOCETAXEL or to other drugs

formulated with polysorbate 80 [see Contraindications].

Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day

dexamethasone premedication regimen. It was characterized by one or more of the

following events : poorly tolerated peripheral edema, generalized edema, pleural

effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced

abdominal distention (due to ascites).

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml concentrate for solution for infusion contains 10 mg docetaxel.

One vial of 2 ml contains 20 mg docetaxel; One vial of 8 ml contains 80 mg docetaxel; One

vial of 16 ml contains 160 mg docetaxel.

Each single-dose vial contains ethanol anhydrous 182 mg/ml (23% v/v). For a full list of

excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion. A clear colourless to pale yellow solution.

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4. CLINICAL PARTICULARS

4.1

Therapeutic indications

Breast Cancer

Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the

adjuvant treatment of patients with operable node-positive breast cancer.

Docetaxel in combination with doxorubicin is indicated for the treatment of patients with

locally advanced or metastatic breast cancer who have not previously received cytotoxic

therapy for this condition.

Docetaxel monotherapy is indicated for the treatment of patients with metastatic breast

cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an

anthracycline or an alkylating agent.

Docetaxel in combination with trastuzumab is indicated for the treatment of patients with

metastatic breast cancer whose tumors over-express HER2 and who previously have not

received chemotherapy for metastatic disease.

Docetaxel in combination with capecitabine is indicated for the treatment of patients with

metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should

have included an anthracycline.

Doxorubicin and cyclophosphamide followed by docetaxel in combination with

trastuzumab (AC-TH) is indicated for the adjuvant treatment of patients with HER2 over-

expressing, node-positive or high risk node-negative, breast cancer.

Docetaxel in combination with trastuzumab, and carboplatin (TCH) is indicated for the

adjuvant treatment of patients with HER2 over-expressing, node-positive or high risk

node-negative, breast cancer.

Non-small cell lung cancer: Docetaxel is indicated for the treatment of patients with

advanced non-small cell lung carcinoma.

Ovarian cancer: Docetaxel is indicated for treatment of metastatic carcinoma of the ovary

after failure of first line or subsequent chemotherapy.

Prostate cancer: Docetaxel in combination with prednisone or prednisolone is indicated for

the treatment of patients with hormone refractory metastatic prostate cancer.

Esophageal cancer: Docetaxel for the treatment of esophageal cancer.

Gastric cancer: Docetaxel for the treatment of advanced gastric cancer.

Head and neck (SCCHN):

Docetaxel as monotherapy in the treatment of patients with recurrent and/or metastatic

squamous cell carcinoma of the head and neck after failure of a previous chemotherapy

regimen.

Docetaxel in combination with cisplatin and 5-fluorouracil is indicated for the induction

treatment of patients with locally advanced squamous cell carcinoma of the head and

neck.

4.2

Posology and method of administration

Docetaxel is for intravenous use only. The use of docetaxel should be confined to units

specialised in the administration of cytotoxic chemotherapy and it should be administered

under the supervision of a physician qualified in the use of anticancer chemotherapy (see

section 6.6).

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Recommended dosage

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting

of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days

starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see

section 4.4). Prophylactic G-CSF may be used to mitigate the risk of haematological

toxicities.

For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended

premedication regimen is oral dexamethasone 8mg 12 hours, 3 hours and 1 hour before the

docetaxel infusion (see section 4.4).Docetaxel is administered as a one-hour infusion every

three weeks.

Breast cancer

In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of

docetaxel is 75 mg/m

administered 1-hour after doxorubicin 50 mg/m

cyclophosphamide 500 mg/m

every 3 weeks for 6 cycles (see also ‘

Dosage adjustments

during treatment

’).

For the treatment of patients with locally advanced or metastatic breast cancer, the

recommended dosage of docetaxel is 100 mg/m

in monotherapy. In first-line treatment,

docetaxel 75 mg/m

is given in combination therapy with doxorubicin (50 mg/m

). In

combination with trastuzumab the recommended dose of docetaxel is 100 mg/m

every three

weeks, with trastuzumab administered weekly. In a pivotal trial the initial docetaxel infusion

was started the day following the first dose of trastuzumab. The subsequent docetaxel doses

were administered immediately after completion of the trastuzumab infusion, if the preceding

dose of trastuzumab was well tolerated. For trastuzumab dosage and administration, see the

trastuzumab summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m

every

three weeks, combined with capecitabine at 1250 mg/m

twice daily (within 30 minutes after

a meal) for 2 weeks followed by 1-week rest period. For capecitabine dose calculation

according to body surface area, see capecitabine summary of product characteristics.

In the adjuvant treatment of patients with operable breast cancer whose tumours overexpress

HER2 the recommended docetaxel dose is as follows:

- AC-TH:

AC (cycles 1 - 4): doxorubicin (A) 60 mg/m

followed by cyclophosphamide (C)

600 mg/m

administered every three weeks for 4 cycles.

TH (cycles 5 - 8): docetaxel (T) 100 mg/m

administered every three weeks for 4 cycles, and

trastuzumab (H) administered weekly according the following schedule:

- Cycle 5 (starting three weeks after the last cycle of AC):

Day 1: trastuzumab 4 mg/kg (loading dose)

Day 2: docetaxel 100 mg/m

Days 8 and 15: trastuzumab 2 mg/kg

- Cycles 6 - 8:

Day 1: docetaxel 100 mg/m

and trastuzumab 2 mg/kg

Days 8 and 15: trastuzumab 2 mg/kg

Three weeks after day 1 of cycle 8: trastuzumab 6 mg/kg is given every three weeks.

Trastuzumab is administered for a total duration of 1 year.

- TCH:

TCH (cycles 1 - 6): docetaxel (T) 75 mg/m

and carboplatin (C) at AUC of 6

mg/mL/min administered every three weeks and trastuzumab (H) administered weekly

according the following schedule:

- Cycle 1:

Day 1: trastuzumab 4 mg/kg (loading dose)

Day 2: docetaxel 75 mg/m

and carboplatin at AUC of 6 mg/mL/min

Days 8 and 15: trastuzumab 2 mg/kg

- Cycles 2 - 6:

Day 1: docetaxel 75 mg/m

followed by carboplatin at AUC of 6 mg/mL/min and

trastuzumab 2 mg/kg

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Days 8 and 15: trastuzumab 2 mg/kg

Three weeks after day 1 of cycle 6: trastuzumab 6 mg/kg is given every three weeks.

Trastuzumab is administered for a total duration of 1 year.

Non-small cell lung cancer: In chemotherapy naïve patients treated for non-small cell lung

cancer, the recommended dose regimen is docetaxel 75 mg/m

immediately followed by

cisplatin 75 mg/m

over 30-60 minutes. For treatment after failure of prior platinum based

chemotherapy, the recommended dosage is 75 mg/m

as a single agent.

Prostate cancer: The recommended dose of docetaxel is 75 mg/m

. Prednisone or

prednisolone 5 mg orally twice daily is administered continuously (see section 5.1).

Gastric adenocarcinoma: The recommended dose of docetaxel is 75 mg/m

as a 1-hour

infusion, followed by cisplatin 75 mg/m

, as a 1-to 3-hour infusion (both on day 1 only),

followed by 5-fluorouracil 750 mg/m

per day given as a 24-hour continuous infusion for 5

days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks.

Patients must receive premedication with antiemetics and appropriate hydration for cisplatin

administration. Prophylactic G-CSF should be used to mitigate the risk of haematological

toxicities (see also ‘dosage adjustments during treatment’).

Esophageal cancer: The usual adult dosage is 70 mg/m

(body surface area) as docetaxel,

intraveneously drip infused over 1hour once a day at the intervals of 3 - 4 weeks. The dosage

may be reduced depending on the patient's symptoms.

Head and neck cancer:

Docetaxel as monotherapy in the treatment of patients with recurrent and/or metastatic

squamous cell carcinoma of the head and neck after failure of a previous chemotherapy

regimen.

In patients treated for recurrent and/or metastatic squamous cell carcinoma of the head and

neck after failure of a previous chemotherapy regimen the recommended dosage of

docetaxel is 100 mg/m

administered as a one-hour infusion every three weeks as a single

agent.

Docetaxel plus Cisplatin plus 5-FU as neoadjuvant in patients with locally advanced

unresectable squamous cell carcinoma of the head and neck (SCCHN).

Patients must receive premedication with antiemetics and appropriate hydration (prior to and

after cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of

hematological toxicities. All patients on the docetaxel-containing arm of the TAX 323 and

TAX 324 studies, received prophylactic antibiotics.

Induction chemotherapy followed by radiotherapy (TAX 323): For the induction treatment

of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN),

the recommended dose of docetaxel is 75 mg/m2 as a 1-hour infusion followed by cisplatin

75 mg/m

over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at

750 mg/m

per day for five days. This regimen is administered every 3 weeks for 4 cycles.

Following chemotherapy, patients should receive radiotherapy.

Induction chemotherapy followed by chemoradiotherapy (TAX 324): For the induction

treatment of patients with locally advanced (technically unresectable, low probability of

surgical cure, and aiming at organ preservation) squamous cell carcinoma of the head and

neck (SCCHN), the recommended dose of docetaxel is 75 mg/ m

as a 1-hour intravenous

infusion on day 1, followed by cisplatin 100 mg/m

administered as a 30-minute to 3-hour

infusion, followed by 5-fluorouracil 1,000 mg/m

/day as a continuous infusion from day 1

to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy,

patients should receive chemoradiotherapy.

For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of

product characteristics.

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Dosage adjustments during treatment

General

Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm3. In patients

who experienced either febrile neutropenia, neutrophil <500 cells/mm3 for more than one

week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during

docetaxel therapy, the dose of docetaxel should be reduced from 100 mg/m

to 75 mg/m

and/or 75 mg/m

to 60 mg/m

. If the patient continues to experience these reactions at 60

mg/m

, the treatment should be discontinued.

Adjuvant therapy for breast cancer

In a pivotal trial in patients who received adjuvant therapy for breast cancer and who

experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia or

infection), it was recommended to use G-CSF to provide prophylactic coverage (e.g., day 4 to

11) in all subsequent cycles. Patients who continued to experience this reaction should remain

on G-CSF and have their docetaxel dose reduced to 60 mg/m

However, in clinical practice neutropenia could occur earlier. Thus the use of G-CSF should

be considered a function of the neutropenic risk of the patient and current recommendations.

Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60

mg/m

In combination with cisplatin:

For patients who are dosed initially at docetaxel 75 mg/m

in combination with cisplatin and

whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm

, or

in patients who experience febrile neutropenia, or in patients with serious non-hematologic

toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65 mg/m

. For

cisplatin dosage adjustments, see manufacturer's summary of product characteristics.

In combination with capecitabine

For capecitabine dose modifications, see capecitabine summary of product characteristics.

For patients developing the first appearance of a Grade 2 toxicity, which persists at the

time of the next docetaxel / capecitabine treatment, delay treatment until resolved to Grade

0- 1, and resume at 100% of the original dose.

For patients developing the second appearance of a Grade 2 toxicity, or the first

appearance of a Grade 3 toxicity, at any time during the treatment cycle, delay treatment

until resolved to Grade 0- 1, then resume treatment with docetaxel 55 mg/m².

For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the

docetaxel dose.

For trastuzumab dose modifications, see trastuzumab summary of product characteristics.In

combination with cisplatin and 5-fluorouracil

If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs

despite G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m

. If subsequent

episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to

45 mg/m

. In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from

75 to 60 mg/m

. Patients should not be retreated with subsequent cycles of docetaxel until

neutrophils recover to a level > 1,500 cells/mm3 and platelets recover to a level > 100,000

cells/mm

. Discontinue treatment if these toxicities persist. (see section4.4).

Recommended dose modifications for gastrointestinal toxicities in patients treated with

docetaxel in combination with cisplatin and 5-fluorouracil (5-FU):

Toxicity

Dosage adjustment

Diarrhoea grade 3

First episode: reduce 5-FU dose by 20%.

Second episode: then reduce docetaxel dose by 20%.

Diarrhoea grade 4

First episode: reduce docetaxel and 5-FU doses by 20%.

Second episode: discontinue treatment.

Stomatitis/mucositis grade 3

First episode: reduce 5-FU dose by 20%.

Second episode: stop 5-FU only, at all subsequent cycles.

Third episode: reduce docetaxel dose by 20%.

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Stomatitis/mucositis grade 4

First episode: stop 5-FU only, at all subsequent cycles.

Second episode: reduce docetaxel dose by 20%.

For cisplatin and 5-fluorouracil dosage adjustments, see manufacturers' summary of product

characteristics.

Patients Treated with Docetaxel in AC-TH or TCH

Patients who received AC-TH or TCH adjuvant therapy for operable breast cancer whose

tumours overexpress HER2 and who experience an episode of febrile neutropenia or infection

should receiveprophylactic G-CSF in all subsequent cycles. For a second episode of febrile

neutropenia or infection, patients should continue prophylactic G-CSF, and docetaxel will be

reduced from 100 mg/m

to 75 mg/m

(in the AC-TH regimen); docetaxel will be reduced

from 75 mg/m

to 60 mg/m

(in the TCH regimen).

However, in clinical practice neutropenia could occur in cycle 1. Thus, G-CSF should be used

inconsideration of the neutropenic risk of the patient and current recommendations.

Depending on thetreatment regimen, patients who experience Grade 3 or 4 stomatitis should

have their dose decreased from100 mg/m

to 75 mg/m

(in the AC-TH regimen) or from 75

mg/m

to 60 mg/m

(in the TCH regimen).

In the pivotal SCCHN studies patients who experienced complicated neutropenia (including

prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF

to provide prophylactic coverage (e.g., day 6-15) in all subsequent cycles.

Special populations

Patients with hepatic impairment

Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who

have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit

of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the

recommended dose of docetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients

with serum bilirubin >ULN and/or ALT and AST >3.5 times the ULN associated with

alkaline phosphatase >6 times the ULN, no dose-reduction can be recommended and

docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric

adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST > 1.5 ×

ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 ×

UNL; for these

patients, no dose-reductions can be recommended and docetaxel should not be used unless

strictly indicated. No data are available in patients with hepatic impairment treated by

docetaxel in combination in the other indications. Pediatric population

The safety and efficacy of Docetaxel in nasopharyngeal carcinoma in children aged 1 month

to less than 18 years have not yet been established.

There is no relevant use of Docetaxel in the paediatric population in the indications breast

cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck

cancer, not including type II and III less differentiated nasopharyngeal carcinoma.

Elderly

Based on a population pharmacokinetic analysis, there are no special instructions for use in

the elderly. In combination with capecitabine, for patients 60 years of age or more, a starting

dose reduction of capecitabine to 75% is recommended (see capecitabine summary of product

characteristics).

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or

to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis,

have occurred.

Patients with baseline neutrophil count of <1,500 cells/mm

Patients with severe liver impairment since there is no data available (see sections 4.4

and 4.2).

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Contraindications for other medicinal products also apply, when combined with

docetaxel.

4.4

Special warnings and special precautions for use

Ethanol:

This product contains ethanol. Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups

such as patients with liver disease, or epilepsy.

The amount of alcohol in this medicinal product may alter the effects of other medicinal

products.

The amount of alcohol in this medicinal product may impair the patient's ability to drive or

use machines.

For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid,

such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting 1 day prior to

docetaxel administration, unless contraindicated, can reduce the incidence and severity of

fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, the

premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel

infusion (see section 4.2).

Haematology:

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil

nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated

patients. Frequent monitoring of complete blood counts should be conducted on all patients

receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a

level of ≥1,500 cells/mm3 (see section 4.2).

In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of

docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of

appropriate symptomatic measures are recommended (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF) and

in patients treated with docetaxel in combination with doxorubicin and cyclophosphamide

(TAC), febrile neutropenia and neutropenic infection occurred at lower rates when patients

received prophylactic G-CSF. Patients treated with TCF and TAC (for breast cancer) should

receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile

neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF and

TAC should be closely monitored, (see sections 4.2 and 4.8).

In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide

(TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients

received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in

patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of

complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic

infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).

Hypersensitivity reactions:

Patients should be observed closely for hypersensitivity reactions

especially during the first and second infusions. Severe hypersensitivity reactions

characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely

fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids.

Hypersensitivity reactions may occur within a few minutes following the initiation of the

infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm

should be available.

If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous

reactions do not require interruption of therapy. However, severe reactions, such as severe

hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation

of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity

reactions should not be rechallenged with docetaxel.

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Cutaneous reactions:

Localised skin erythema of the extremities (palms of the hands and

soles of the feet) with oedema followed by desquamation has been observed. Severe

symptoms such as eruptions followed by desquamation which lead to interruption or

discontinuation of docetaxel treatment have been reported (see section 4.2).

Fluid retention:

Patients with severe fluid retention such as pleural effusion, pericardial

effusion and ascites should be monitored closely.

Severe fluid retention has been reported following docetaxel therapy. Patients should be

premedicated with oral corticosteroids prior to each docetaxel administration to reduce the

incidence and severity of fluid retention. Patients with pre-existing effusions should be

closely monitored from the first dose for the possible exacerbation of the effusions. When

fluid retention occurs, peripheral edema usually starts in the lower extremities and may

become generalized with a median weight gain of 2 kg.

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid

retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose

to onset of moderate or severe fluid retention was 819 mg/m

. Nine of 92 patients (9.8%) of

patients discontinued treatment due to fluid retention: 4 patients discontinued with severe

fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative

dose to treatment discontinuation due to fluid retention was 1021 mg/m

. Fluid retention was

completely, but sometimes slowly, reversible with a median of 16 weeks from the last

infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral

edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

Respiratory disorders:

Acute respiratory distress syndrome, interstitial

pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure

have been reported and may be associated with fatal outcome. Cases of radiation pneumonitis

have been reported in patients receiving concomitant radiotherapy.

If new or worsening

pulmonary symptoms develop, patients should be closely monitored, promptly

investigated,

and appropriately treated. Interruption of docetaxel therapy is recommended until diagnosis is

available. Early use of supportive care measures may help improve the condition. The benefit

of resuming docetaxel treatment must be carefully evaluated.

Patients with liver impairment:

In patients treated with docetaxel at 100 mg/m

as single

agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN

concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a

higher risk of developing severe adverse reactions such as toxic death

including sepsis and

gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections,

thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in

those patients with elevated liver function test (LFTs) is 75 mg/m

and LFTs should be

measured at baseline and before each cycle (see section 4.2).

For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 x the ULN

concurrent with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can

be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric

adenocarcinoma, a pivotal clinical trial excluded patients with ALT and/or AST > 1.5 x ULN

associated with alkaline phosphatase > 2.5 x ULN, and bilirubin > 1 x ULN; for these

patients, no dose-reductions can be recommended and docetaxel should not be used unless

strictly indicated.

No data are available in patients with hepatic impairment treated by docetaxel in combination

in the other indications.

The amount of ethanol in Docetaxel Hospira

should be taken into account when given to

patients with hepatic impairment (see below “Excipients”).

Patients with renal impairment:

There are no data available in patients with severely impaired

renal function treated with docetaxel. Docetaxel Hospira

10 mg/ml solution for infusion

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contains PEG300 which may increase the risk of nephrotoxicity in patients with renal

impairment.

Nervous system:

The development of severe peripheral neurotoxicity requires a reduction of

dose (see section 4.2).

Cardiac toxicity:

Heart failure has been observed in patients receiving docetaxel in

combination with trastuzumab, particularly following anthracycline (doxorubicin or

epirubicin)-containing chemotherapy. This may be moderate to severe and has been

associated with death (see section 4.8).

When patients are candidates for treatment with docetaxel in combination with trastuzumab,

they should undergo baseline cardiac assessment. Cardiac function should be further

monitored during treatment (e.g., every three months) to help identify patients who may

develop cardiac dysfunction. For more details refer to the Summary of Product Characteristics

of trastuzumab.

Eye disorders:

Cystoid macular oedema (CMO) has been reported in patients treated with

docetaxel, Patients with impaired vision should undergo a prompt and complete

ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be

discontinued and appropriate treatment initiated (see section 4.8).

Others:

Contraceptive measures must be taken by both men and women during treatment and

for men at least

6 months after cessation of therapy (see section 4.6).

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia: For patients who experience complicated neutropenia (prolonged

neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be

considered (see section 4.2).

Gastrointestinal reactions:

Symptoms such as early abdominal pain and tenderness, fever,

diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal

toxicity and should be evaluated and treated promptly.

Congestive heart failure:

Patients should be monitored for symptoms of congestive heart

failure during therapy and during the follow up period. In patients treated with the TAC

regimen for node-positive breast cancer, the risk of

congestive heart failure has been shown to

be higher during the first year after treatment (see sections 4.8 and 5.1).

Leukaemia:

In docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk

of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up.

Patients with 4+ nodes:

As the benefit observed in patient with 4+ nodes was not statistically

significant on disease-free

survival (DFS) and overall survival (OS), the positive benefit/risk

ratio for TAC in patients with 4+

nodes was not fully demonstrated at the final analysis (see

section 5.1).

Interactions:

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g.,

ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir,

saquinavir, telithromycin and voriconazole) should be avoided (see section 4.5).

Elderly:

There are limited data available in patients>70 years of age on docetaxel use in

combination with doxorubicin and cyclophosphamide.Of the 333 patients treated with

docetaxel every three weeks in a prostate cancer study, 209 patients were 65 years of age or

greater and 68 patients were older than 75 years. In patients treated with docetaxel every three

weeks, the incidence of related nail changes occurred at a rate of ≥ 10% higher in patients

Docetaxel Hospira 10mg/ml LPD CC technical change 040219

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who were 65 years of age or greater compared to younger patients. The incidence of related

fever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients

who were 75 years of age or greater versus less than 65 years.

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II

part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the

gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or

older. The incidence of serious adverse events was higher in the elderly patients compared to

younger patients. The incidence of the following adverse events (all grades): lethargy,

stomatitis, neutropenic infection occurred at rates ≥10 % higher in patients who were 65 years

of age or older compared to younger patients.

Elderly patients treated with TCF should be closely monitored.

The proportion of older people was 5.5% and 6.6% in the AC-TH and TCH regimens,

respectively, and is too limited to allow for conclusions regarding the adverse events

occurring by age (< 65 years vs. ≥ 65 years).

Excipients: This medicinal product contains 23 vol % ethanol (alcohol).

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, in children and in high-risk

groups such as patients with liver disease, or epilepsy.

Consideration should be given to possible effects on the central nervous system.

The amount of alcohol in this medicinal product may alter the effects of other medicinal

products.

The amount of alcohol in this medicinal product may impair the patient's ability to drive or

use machines.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro

studies have shown that the metabolism of docetaxel may be modified by the

concomitant administration of compounds which induce, inhibit or are metabolised by (and

thus may inhibit the enzyme competitively) cytochrome P450-3A such as ciclosporin,

terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be

exercised when treating patients with these drugs as concomitant therapy since there is a

potential for a significant interaction.

In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse

reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong

CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone,

nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close

clinical surveillance is warranted and a dose-adjustment of docetaxel may be suitable during

the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a pharmacokinetic study

with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor

ketoconazole leads to a significant decrease in docetaxel clearance by 49%.

Docetaxel is highly protein bound (>95%). Although the possible in vivo interaction of

docetaxel with concomitantly administered medication has not been investigated formally, in

vitro interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine,

propanolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did

not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein

binding of docetaxel. Docetaxel did not influence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced

by their coadministration. Limited data from a single uncontrolled study were suggestive of

an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance

of carboplatin was about 50% higher than values previously reported for carboplatin

monotherapy.

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Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with

metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to

induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of

docetaxel was observed.

4.6

Fertility, pregnancy and lactation

Pregnancy: There is no information on the use of docetaxel in pregnant women. Docetaxel

has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce

fertility in rats. As with other cytotoxic medicinal products, docetaxel may cause foetal harm

when administered to pregnant women. Therefore, docetaxel must not be used during

pregnancy unless clearly indicated.

Women of childbearing age receiving docetaxel should be advised to avoid becoming

pregnant, and to inform the treating physician immediately should this occur.

Breast-feeding: Docetaxel is a lipophilic substance but it is not known whether it is excreted

in human milk. Consequently, because of the potential for adverse reactions in nursing

infants, breast feeding must be discontinued for the duration of docetaxel therapy.

Contraception in males and females:

An effective method of contraception should be used

during treatment.

Fertility:

In non-clinical studies, docetaxel has genotoxic effects and may alter male fertility

(see section 5.3). Therefore, men being treated with docetaxel are advised not to father a child

during and up

to 6 months after treatment and to seek advice on conservation of sperm prior

to treatment.

4.7 Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed.

amount of ethanol in Docetaxel Hospira

may impair the ability to drive or use machines (see

section 4.4).

4.8 Undesirable effects

Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the administration of

docetaxel have been obtained in:

1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single

agent respectively.

258 patients who received docetaxel in combination with doxorubicin.

406 patients who received docetaxel in combination with cisplatin.

92 patients treated with docetaxel in combination with trastuzumab.

255 patients who received docetaxel in combination with capecitabine.

332 patients who received docetaxel in combination with prednisone or prednisolone

(clinically important treatment related adverse events are presented).

1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received

docetaxel in combination with doxorubicin and cyclophosphamide (clinically important

treatment related adverse events are presented).

300 gastric adenocarcinoma patients (221 patients in phase III part of the study and 79

patients in the phase II part) who received docetaxel in combination with cisplatin and 5-

fluorouracil (clinically important treatment related adverse events are presented).

174 and 251 head and neck cancer patients who received docetaxel in combination with

cisplatin and 5-fluorouracil (clinically important treatment related adverse events are

presented).

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3;

grade 3-4 = G3/4; grade 4 = G4) and the COSTART and the MedDRA terms. Frequencies are

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defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to <

1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated

from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing

seriousness.

The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which is

reversible and not cumulative; the median day nadir was 7 days and the median duration of

severe neutropenia (<500 cells/mm

) is 7 days), anaemia, alopecia, nausea, vomiting,

stomatitis, diarrhoea and asthenia. The severity of adverse events of docetaxel may be

increased when docetaxel is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are

displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34%

vs. 23%) in the trastuzumab combination arm compared to docetaxel monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects (

≥5%) reported in a phase III trial in breast cancer patients failing anthracycline treatment are

presented (see capecitabine Summary of Product Characteristics).

The following adverse reactions are frequently observed with docetaxel:

Nervous System Disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections

4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia,

dysesthesia or pain including burning. Neuro-motor events are mainly characterised by

weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to

moderate.

Reactions were characterised by a rash including localised eruptions mainly on the feet and

hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and

frequently associated with pruritus. Eruptions generally occurred within one week after the

docetaxel infusion. Less frequently, severe symptoms such as eruptions followed by

desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were

reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or

hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyperpigmentation,

inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the

vein.

Fluid retention includes events such as peripheral oedema and less frequently pleural effusion,

pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the

lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid

retention is cumulative in incidence and severity (see section 4.4).

Immune system disorders

Hypersensitivity reactions have generally occurred within a few minutes following the start of

the infusion of docetaxel and were usually mild to moderate. The most frequently reported

symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea

and drug fever or chills. Severe reactions were characterised by hypotension and/or

bronchospasm or generalised rash/erythema (see section 4.4).

Tabulated list of adverse reactions in breast cancer for Docetaxel 100 mg/m² single agent

MedDRA System

Organ classes

Very common adverse

reactions

Common adverse reactions

≥ 1 to < 10 % of patients

Uncommon adverse

reactions

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≥ 10 % of patients

≥ 0.1 to < 1% of

patients

Investigations

G3/4 Blood bilirubin increased

(<5%)

G3/4 Blood alkaline

phosphatase increased (<4%)

G3/4 AST increased (<3%)

G3/4 ALT increased (<2%)

Cardiac disorders

Arrhythmia (G3/4: 0.7%)

Cardiac failure (0.5%)

Blood and the

lymphatic system

disorders

Neutropenia (G4: 76.4%)

Anaemia (G3/4: 8.9%)

Febrile neutropenia

Thrombocytopenia (G4: 0.2%)

Nervous system

disorders

Peripheral sensory

neuropathy (G3: 4.1%)

Peripheral motor neuropathy

(G3/4: 4%)

Dysgeusia (severe 0.07%)

Respiratory, thoracic

and mediastinal

disorders

Dyspnoea (severe 2.7%)

Gastrointestinal

disorders

Stomatitis (G3/4: 5.3%)

Diarrhoea (G3/4: 4%)

Nausea (G3/4: 4%)

Vomiting (G3/4: 3%)

Constipation (severe 0.2%)

Abdominal pain (severe 1%)

Gastrointestinal haemorrhage

(severe 0.3%)

Oesophagitis (severe

0.4%)

Skin and

subcutaneous tissue

disorders

Alopecia

Skin reaction (G3/4: 5.9%)

Nail disorders (severe 2.6%)

Musculoskeletal,

connective tissue

and bone disorders

Myalgia (severe 1.4%)

Arthralgia

Metabolism and

nutrition disorders

Anorexia

Infections and

infestations

Infections (G3/4: 5.7%;

including sepsis and

pneumonia, fatal in 1.7%)

Infection associated with G4

neutropenia (G3/4: 4.6%)

Vascular disorders

Hypotension

Hypertension

Haemorrhage

General disorders

and administration

site conditions

Fluid retention (severe:

6.5%)

Asthenia (severe 11.2%)

Pain

Infusion site reaction

Non-cardiac chest pain (severe

0.4%)

Immune system

disorders

Hypersensitivity (G3/4:

5.3%)

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m

single

agent

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Blood and Lymphatic system disorders:

Rare: Bleeding episodes associated with grade 3/4 thrombocytopenia.

Nervous system disorders:

Reversibility data are available among 35.3% of patients who developed neurotoxicity

following docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously

reversible within 3 months.

Skin and subcutaneous tissue disorders:

Very rare: One case of alopecia non-reversible at the end of the study. 73% of the cutaneous

reactions were reversible within 21 days.

General disorders and administration site conditions:

The median cumulative dose to treatment discontinuation was more than 1,000 mg/m

and the

median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset

of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m

) in

patients with premedication compared with patients without premedication (median

cumulative dose: 489.7 mg/m

); however, it has been reported in some patients during the

early courses of therapy.

Tabulated list of adverse reactions in non-small cell lung cancer for Docetaxel 75 mg/m²

single agent

MedDRA System

Organ classes

Very common adverse reactions

≥ 10 % of patients

Common adverse reactions

≥ 1 to < 10 % of patients

Investigations

G3/4 Blood bilirubin increased (<2%)

Cardiac disorders

Arrhythmia (not severe)

Blood and the

lymphatic system

disorders

Neutropenia (G4: 54.2%)

Anaemia (G3/4: 10.8%)

Thrombocytopenia (G4: 1.7%)

Febrile neutropenia

Nervous system

disorders

Peripheral sensory neuropathy (G3/4:

0.8%)

Peripheral motor neuropathy (G3/4:

2.5%)

Gastrointestinal

disorders

Nausea (G3/4: 3.3%)

Stomatitis (G3/4: 1.7%)

Vomiting (G3/4: 0.8%)

Diarrhoea (G3/4: 1.7%)

Constipation

Skin and

subcutaneous tissue

disorders

Alopecia

Skin reaction (G3/4: 0.8%)

Nail disorders (severe 0.8%)

Musculoskeletal,

connective tissue

and bone disorders

Myalgia

Metabolism and

nutrition disorders

Anorexia

Infections and

infestations

Infections (G3/4: 5%)

Vascular disorders

Hypotension

General disorders

and administration

site conditions

Asthenia (severe 12.4%)

Fluid retention (severe 0.8%)

Pain

Immune system

disorders

Hypersensitivity (not severe)

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Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in combination

with doxorubicin

MedDRA System

Organ classes

Very common adverse

reactions

≥ 10 % of patients

Common adverse

reactions

≥ 1 to < 10 % of patients

Uncommon adverse

reactions

≥ 0.1 to < 1% of

patients

Investigations

G3/4 Blood bilirubin

increased (<2.5%)

G3/4 Blood alkaline

phosphatase increased

(<2.5%)

G3/4 AST increased

(<1%)

G3/4 ALT increased

(<1%)

Cardiac disorders

Cardiac failure

Arrhythmia (not severe)

Blood and the

lymphatic system

disorders

Neutropenia (G4: 91.7%)

Anaemia (G3/4: 9.4%)

Febrile neutropenia

Thrombocytopenia (G4:

0.8%)

Nervous system

disorders

Peripheral sensory

neuropathy (G3: 0.4%)

Peripheral motor

neuropathy (G3/4: 0.4%)

Gastrointestinal

disorders

Nausea (G3/4: 5%)

Stomatitis (G3/4: 7.8%)

Diarrhoea (G3/4: 6.2%)

Vomiting (G3/4: 5%)

Constipation

Skin and

subcutaneous tissue

disorders

Alopecia

Nail disorders (severe

0.4%)

Skin reaction (not severe)

Musculoskeletal,

connective tissue

and bone disorders

Myalgia

Metabolism and

nutrition disorders

Anorexia

Infections and

infestations

Infection (G3/4: 7.8%)

Vascular disorders

Hypotension

General disorders

and administration

site conditions

Asthenia (severe 8.1%)

Fluid retention (severe

1.2%)

Pain

Infusion site reaction

Immune system

disorders

Hypersensitivity (G3/4:

1.2%)

Tabulated list of adverse reactions in non-small cell lung cancer for Docetaxel 75 mg/m² in

combination with cisplatin

Docetaxel Hospira 10mg/ml LPD CC technical change 040219

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MedDRA System

Organ classes

Very common adverse

reactions

≥ 10 % of patients

Common adverse

reactions

≥ 1 to < 10 % of patients

Uncommon adverse

reactions

≥ 0.1 to < 1% of

patients

Investigations

G3/4 Blood bilirubin

increased (2.1%)

G3/4 ALT increased

(1.3%)

G3/4 AST increased

(0.5%)

G3/4 Blood alkaline

phosphatase increased

(0.3%)

Cardiac disorders

Arrhythmia (G3/4: 0.7%)

Cardiac failure

Blood and the

lymphatic system

disorders

Neutropenia (G4: 51.5%)

Anaemia (G3/4: 6.9%)

Thrombocytopenia

(G4:0.5%)

Febrile neutropenia

Nervous system

disorders

Peripheral sensory

neuropathy (G3: 3.7%)

Peripheral motor

neuropathy (G3/4: 2%)

Gastrointestinal

disorders

Nausea (G3/4: 9.6%)

Vomiting (G3/4: 7.6%)

Diarrhoea (G3/4: 6.4%)

Stomatitis (G3/4: 2%)

Constipation

Skin and

subcutaneous

tissue disorders

Alopecia

Nail disorders (severe

0.7%)

Skin reaction (G3/4: 0.2%)

Musculoskeletal,

connective tissue

and bone disorders

Myalgia (severe 0.5%)

Metabolism and

nutrition disorders

Anorexia

Infections and

infestations

Infection (G3/4: 5.7%)

Vascular disorders

Hypotension (G3/4: 0.7%)

General disorders

and administration

site conditions

Asthenia (severe 9.9%)

Fluid retention (severe

0.7%)

Pyrexia (G3/4: 1.2%)

Infusion site reaction

Pain

Immune system

disorders

Hypersensitivity (G3/4:

2.5%)

Tabulated list of adverse reactions in breast cancer for Docetaxel 100mg/m² in combination

with trastuzumab

MedDRA System

Organ classes

Very common adverse reactions

≥ 10 % of patients

Common adverse reactions

≥ 1 to < 10% of patients

Investigations

Weight increased

Cardiac disorders

Cardiac failure

Blood and the

lymphatic system

disorders

Neutropenia (G3/4: 32%)

Febrile neutropenia (includes

neutropenia associated with fever and

antibiotic use) or neutropenic sepsis

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Nervous system

disorders

Paraesthesia

Headache

Dysgeusia

Hypoaesthesia

Eye disorders

Lacrimation increased

Conjunctivitis

Respiratory, thoracic

and mediastinal

disorders

Epistaxis

Pharyngolaryngeal pain

Nasopharyngitis

Dyspnoea

Cough

Rhinorrhoea

Gastrointestinal

disorders

Nausea

Diarrhoea

Vomiting

Constipation

Stomatitis

Dyspepsia

Abdominal pain

Skin and

subcutaneous tissue

disorders

Alopecia

Erythema

Rash

Nail disorders

Musculoskeletal,

connective tissue

and bone disorders

Myalgia

Arthralgia

Pain in extremity

Bone pain

Back pain

Metabolism and

nutrition disorders

Anorexia

Vascular disorders

Lymphoedema

General disorders

and administration

site conditions

Asthenia

Oedema peripheral

Pyrexia

Fatigue

Mucosal inflammation

Pain

Influenza-like illness

Chest pain

Chills

Lethargy

Psychiatric disorders Insomnia

Description of selected adverse reactions for docetaxel 100mg/m² in combination with

trastuzumab

Cardiac disorders:

Symptomatic cardiac failure was reported in 2.2% of the patients who

received docetaxel plus trastuzumab compared to 0% of patients given docetaxel alone. In the

docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy

compared with 55% in the docetaxel arm alone.

Blood and lymphatic system disorders:

Very common: Haematological toxicity was increased in patients receiving trastuzumab and

docetaxel,

compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using

NCI-CTC criteria). Note that this is likely to be an underestimate since docetaxel alone at a

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2019-0047589

dose of 100 mg/m

is known to result in neutropenia in 97% of patients, 76% grade 4, based

on nadir blood counts. The incidence of febrile neutropenia/neutropenic sepsis was also

increased in patients treated with trastuzumab plus docetaxel (23% versus 17% for patients

treated with docetaxel alone).

Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in combination

with capecitabine

MedDRA System

Organ classes

Very common adverse reactions

≥ 10 % of patients

Common adverse reactions

≥ 1 to < 10 % of patients

Investigations

Weight decreased

G3/4 Blood bilirubin increased (9%)

Blood and the

lymphatic system

disorders

Neutropenia (G3/4: 63%)

Anaemia (G3/4: 10%)

Thrombocytopenia (G3/4: 3%)

Nervous system

disorders

Dysgeusia (G3/4: <1%)

Paraesthesia (G3/4: <1%)

Dizziness

Headache (G3/4: <1%)

Neuropathy peripheral

Eye disorders

Lacrimation increased

Respiratory,

thoracic and

mediastinal

disorders

Pharyngolaryngeal pain (G3/4: 2%)

Dyspnoea (G3/4: 1%)

Cough (G3/4: <1%)

Epistaxis (G3/4: <1%)

Gastrointestinal

disorders

Stomatitis (G3/4: 18%) Diarrhoea

(G3/4: 14%) Nausea (G3/4: 6%)

Vomiting (G3/4: 4%) Constipation

(G3/4: 1%) Abdominal pain (G3/4:

Dyspepsia

Abdominal pain upper

Dry mouth

Skin and

subcutaneous

tissue disorders

Hand-foot syndrome (G3/4: 24%)

Alopecia (G3/4: 6%)

Nail disorders (G3/4: 2%)

Dermatitis

Rash erythematous (G3/4: <1%)

Nail discolouration

Onycholysis (G3/4: 1%)

Musculoskeletal,

connective tissue

and bone disorders

Myalgia (G3/4: 2%) Arthralgia

(G3/4: 1%)

Pain in extremity (G3/4: <1%)

Back pain (G3/4: 1%)

Metabolism and

nutrition disorders

Anorexia (G3/4: 1%)

Decreased appetite

Dehydration (G3/4: 2%)

Infections and

infestations

Oral candidiasis (G3/4: <1%)

General disorders

and administration

site conditions

Asthenia (G3/4: 3%)

Pyrexia (G3/4: 1%)

Fatigue/ weakness (G3/4: 5%)

Oedema peripheral (G3/4: 1%)

Lethargy

Pain

Tabulated list of adverse reactions in prostate cancer for Docetaxel 75 mg/m² in combination

with prednisone or prednisolone

MedDRA System

Organ classes

Very common adverse reactions

≥ 10 % of patients

Common adverse reactions

≥ 1 to < 10 % of patients

Cardiac disorders

Cardiac left ventricular function

decrease (G3/4: 0.3%)

Blood and the

lymphatic system

disorders

Neutropenia (G3/4: 32%)

Anaemia (G3/4: 4.9%)

Thrombocytopenia; (G3/4: 0.6%)

Febrile neutropenia

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Nervous system

disorders

Peripheral sensory neuropathy

(G3/4: 1.2%)

Dysgeusia (G3/4: 0%)

Peripheral motor neuropathy (G3/4:

Eye disorders

Lacrimation increased (G3/4: 0.6%)

Respiratory,

thoracic and

mediastinal

disorders

Epistaxis (G3/4: 0%)

Dyspnoea (G3/4: 0.6%)

Cough (G3/4: 0%)

Gastrointestinal

disorders

Nausea (G3/4: 2.4%)

Diarrhoea (G3/4: 1.2%)

Stomatitis/Pharyngitis (G3/4: 0.9%)

Vomiting (G3/4: 1.2%)

Skin and

subcutaneous

tissue

disorders

Alopecia

Nail disorders (not severe)

Exfoliative rash (G3/4: 0.3%)

Musculoskeletal,

connective tissue

and bone disorders

Arthralgia (G3/4: 0.3%)

Myalgia (G3/4: 0.3%)

Metabolism and

nutrition disorders

Anorexia (G3/4: 0.6%)

Infections and

infestations

Infection (G3/4: 3.3%)

General disorders

and administration

site conditions

Fatigue (G3/4: 3.9%)

Fluid retention (severe 0.6%)

Immune system

disorders

Hypersensitivity (G3/4: 0.6%)

Tabulated list of adverse reactions in breast cancer for adjuvant therapy with Docetaxel

mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive

(TAX 316) and node-negative (GEICAM 9805) breast cancer - pooled data

MedDRA System

Organ classes

Very common adverse

reactions ≥ 10 % of patients

Common

adverse

reactions

≥1 to <10% of

patients

Uncommon

adverse

reactions

≥0.1 to <1% of

patients

Investigations

Weight

increased (G3/4:

0%);

Weight

decreased

(G3/4: 0.2%)

Cardiac disorders

Arrhythmia

(G3/4: 0.2%);

Blood and lymphatic

system disorders

Anaemia (G3/4: 3%);

Neutropenia (G3/4: 59.2 %);

Thrombocytopenia

(G3/4:1.6%);

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Febrile neutropenia (G3/4:

Nervous system

disorders

Dysgeusia (G3/4: 0.6%);

Peripheral sensory

neuropathy (G3/4: <0.1%)

Peripheral motor

neuropathy

(G3/4: 0%);

Syncope (G3/4:

Neurotoxicity

(G3/4:

0%);

Somnolence

(G3/4: 0%)

Eye disorders

Conjunctivitis (G3/4:

<0.1%)

Lacrimation

increased

(G3/4: < 0.1%);

Respiratory, thoracic

and mediastinal

disorders

Cough (G3/4:

Gastrointestinal

disorders

Nausea (G3/4: 5.0%);

Stomatitis (G3/4: 6.0 %);

Vomiting (G3/4: 4.2%);

Diarrhoea (G3/4: 3.4%);

Constipation (G3/4: 0.5%)

Abdominal pain

(G3/4: 0.4%)

Skin and subcutaneous

tissue disorders

Alopecia

(persisting: <3%)

Skin disorder (G3/4: 0.6%);

Nail disorders (G3/4: 0.4%)

Musculoskeletal and

connective tissue

disorders

Myalgia (G3/4: 0.7%);

Arthralgia (G3/4: 0.2%)

Metabolism and

nutrition disorders

Anorexia (G3/4: 1.5 %)

Infections and

infestations

Infection (G3/4: 2.4 %);

Neutropenic infection (G3/4:

2.6%)

Vascular disorders

Hot flush (G3/4: 0.5%)

Hypotension

(G3/4: 0%)

Phlebitis (G3/4:

0%);

Lymphoedema

(G3/4: 0%)

General disorders and

administration site

conditions

Asthenia (G3/4: 10%);

Pyrexia (G3/4:NA);

Oedema peripheral (G3/4:

0.2%)

Immune system

disorders

Hypersensitivity

(G3/4: 0.6%)

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Reproductive system

and breast disorders

Amenorrhoea (G3/4: NA)

Description of selected adverse reactions for adjuvant therapy with Docetaxel 75 mg/m² in

combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX

316) and node-negative (GEICAM 9805) breast cancer

Cardiac disorders:

In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients

(2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each

arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in

the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm

developed congestive heart failure during the follow-up period. One patient in TAC arm died

because of dilated cardiomyopathy.

Nervous system disorders:

Peripheral sensory neuropathy was observed to be ongoing

during

follow-up in 10 patients out of the 84 patients with peripheral sensory neuropathy at the end

of the chemotherapy in study TAX316.

Skin and subcutaneous tissue disorders:

In study TAX316, alopecia persisting into the

follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients and

645 of 736 FAC patients. At the end of the follow-up period (actual median follow-up time of

96 months), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC

patients (2.2%).

In GEICAM 9805 study, alopecia persisted into the follow-up period (median follow-up time

of 10 years and 5 months) and was observed to be ongoing in 49 patients (9.2 %) in TAC arm

and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened

during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in

FAC arm.

General disorders and administration site conditions:

In study TAX316, peripheral oedema

was observed to be ongoing in 19 patients out of the 119 patientswith peripheral oedema in

the TAC arm and 4 patients out of the 23 patients with peripheral oedema in the FAC arm.

In study GEICAM 9805, lymphoedema was observed to be ongoing in 4 of the 5 patients in

TAC arm and in 1 of the 2 patients in FAC arm at the end of the chemotherapy, and did not

resolve during the follow-up period (median follow-up time of 10 years and 5 months).

Asthenia persisted into the follow-up period (median follow-up time of 10 years and 5

months) and was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients

(0.8 %) in FAC arm.

Reproductive system and breast disorders:

Amenorrhoea was observed to be ongoing during

follow-up in 121 patients out of the 202 patients with amenorrhoea at the end of the

chemotherapy in study TAX316.

In GEICAM 9805 study, amenorrhoea persisted into the follow-up period (median follow-up

time of 10 years and 5 months) and was observed to be ongoing in 18 patients (3.4 %) in TAC

arm and 5 patients (1.0 %) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome:

After 10 years of follow up in study TAX316,

acute leukaemia was reported in 4 of 744 TAC patients

and in 1 of 736 FAC patients.

Myelodysplastic syndrome was reported in 2 of 744 TAC patients and

in 1 of 736 FAC

patients.

After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532

(0.2%) patients in TAC arm . No cases were reported in patients in FAC arm. No patient was

diagnosed with myelodysplastic syndrome in either treatment groups.

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Neutropenic complications:

The table below shows that the incidence of Grade 4

neutropenia, febrile neutropenia and neutropenic

infection was decreased in patients who

received primary G-CSF prophylaxis after it was made

mandatory in the TAC arm –

GEICAM study.

Neutropenic complications in patients receiving TAC with or without primary G-CSF

prophylaxis (GEICAM 9805)

Without primary

G-CSF prophylaxis

(n = 111)

n (%)

With primary

G-CSF prophylaxis

(n = 421)

n (%)

Neutropenia (Grade 4)

104 (93.7)

135 (32.1)

Febrile neutropenia

28 (25.2)

23 (5.5)

Neutropenic infection

14 (12.6)

21 (5.0)

Neutropenic infection (Grade 3-4)

2 (1.8)

5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for Docetaxel 75 mg/m²

in combination with cisplatin and 5-fluorouracil

MedDRA

System Organ

classes

Very common adverse reactions

≥ 10 % of patients

Common adverse reactions

≥ 1 to < 10 % of patients

Cardiac

disorders

Arrhythmia (G3/4: 1.0%)

Blood and the

lymphatic

system disorders

Anaemia (G3/4: 20.9%)

Neutropenia (G3/4: 83.2%)

Thrombocytopenia (G3/4: 8.8%)

Febrile neutropenia

Nervous system

disorders

Peripheral sensory neuropathy (G3/4:

8.7%)

Dizziness (G3/4: 2.3%)

Peripheral motor neuropathy (G3/4:

1.3%)

Eye disorders

Lacrimation increased (G3/4: 0%)

Ear and labyrinth

disorders

Hearing impaired (G3/4: 0%)

Gastrointestinal

disorders

Diarrhoea (G3/4: 19.7%)

Nausea (G3/4: 16%)

Stomatitis (G3/4: 23.7%)

Vomiting (G3/4: 14.3%)

Constipation (G3/4: 1.0 %)

Gastrointestinal pain (G3/4: 1.0%)

Oesophagitis/dysphagia/odynophagia

(G3/4: 0.7%)

Skin and

subcutaneous

tissue disorders

Alopecia (G3/4: 4.0%)

Rash pruritus (G3/4: 0.7%)

Nail disorders (G3/4: 0.7%)

Skin exfoliation (G3/4: 0%)

Metabolism and

nutrition

disorders

Anorexia (G3/4: 11.7%)

Infections and

infestations

Neutropenic infection

Infection (G3/4: 11.7%)

General

disorders and

administration

Lethargy (G3/4: 19.0%)

Pyrexia (G3/4: 2.3%)

Fluid retention (severe/life-

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site conditions

threatening: 1%)

Immune system

disorders

Hypersensitivity (G3/4: 1.7)

Description of selected adverse reactions in gastric adenocarcinoma cancer for Docetaxel 75

mg/m

in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders:

Febrile neutropenia and neutropenic infection

occurred in 17.2% and 13.5% of patients respectively,

regardless of G-CSF use. G-CSF was

used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile

neutropenia and neutropenic infection occurred respectively, in 12.1% and 3.4% of patients

when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without

prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for Docetaxel 75 mg/m² in

combination with cisplatin and 5-fluorouracil

Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA

System Organ

classes

Very common adverse

reactions

≥ 10 % of patients

Common adverse

reactions

≥ 1 to < 10 % of patients

Uncommon adverse

reactions

≥ 0.1 to < 1 % of

patients

Investigations

Weight increased

Cardiac disorders

Myocardial ischaemia

(G3/4: 1.7%)

Arrhythmia (G3/4:

0.6%)

Blood and the

lymphatic system

disorders

Neutropenia

(G3/4:76.3%)

Anaemia (G3/4: 9.2)

Thrombocytopenia

(G3/4: 5.2%)

Febrile neutropenia

Nervous system

disorders

Dysgeusia/Parosmia

Peripheral sensory

neuropathy (G3/4: 0.6%)

Dizziness

Eye disorders

Lacrimation increased

Conjunctivitis

Ear and labyrinth

disorders

Hearing impaired

Gastrointestinal

disorders

Nausea (G3/4: 0.6%)

Stomatitis (G3/4: 4.0%)

Diarrhoea (G3/4: 2.9%)

Vomiting (G3/4: 0.6%)

Constipation

Oesophagitis/dysphagia/

odynophagia (G3/4:

0.6%)

Abdominal pain

Dyspepsia

Gastrointestinal

haemorrhage (G3/4:

0.6%)

Skin and

subcutaneous

tissue disorders

Alopecia (G3/4: 10.9%)

Rash pruritic

Dry skin

Skin exfoliative (G3/4:

0.6%)

Musculoskeletal,

connective tissue

and bone

Myalgia (G3/4: 0.6%)

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disorders

Metabolism and

nutrition

disorders

Anorexia (G3/4: 0.6%)

Infections and

infestations

Infection (G3/4: 6.3%)

Neutropenic infection

Neoplasms

benign and

malignant

(including cysts

and polyps)

Cancer pain (G3/4: 0.6%)

Vascular

disorders

Venous disorder (G3/4:

0.6%)

General disorders

administration

site conditions

Lethargy (G3/4: 3.4%)

Pyrexia (G3/4: 0.6%)

Fluid retention

Oedema

Immune system

disorders

Hypersensitivity (not

severe)

Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring i.v.

antibiotics and/or

hospitalization.

Induction chemotherapy followed by radiotherapy (TAX 324)

MedDRA

System Organ

classes

Very common adverse

reactions

≥ 10 % of patients

Common adverse

reactions

≥ 1 to < 10 % of

patients

Uncommon adverse

reactions

≥ 0.1 to < 1 % of

patients

Investigations

Weight decreased

Weight increased

Cardiac

disorders

Arrhythmia (G3/4:

2.0%)

Ischaemia myocardial

Blood and the

lymphatic

system disorders

Neutropenia (G3/4:

83.5%)

Anaemia (G3/4: 12.4%)

Thrombocytopenia

(G3/4: 4.0%)

Febrile neutropenia

Nervous system

disorders

Dysgeusia/Parosmia

(G3/4: 0.4%)

Peripheral sensory

neuropathy (G3/4: 1.2%)

Dizziness (G3/4: 2.0%)

Peripheral motor

neuropathy (G3/4: 0.4%)

Eye disorders

Lacrimation increased

Conjunctivitis

Ear and labyrinth

disorders

Hearing impaired (G3/4:

1.2%)

Gastrointestinal

disorders

Nausea (G3/4: 13.9%)

Stomatitis (G3/4: 20.7%)

Vomiting (G3/4: 8.4%)

Diarrhoea (G3/4: 6.8%)

Oesophagitis/dysphagia/

odynophagia (G3/4:

12.0%)

Constipation (G3/4:

Dyspepsia (G3/4: 0.8%)

Gastrointestinal pain

(G3/4: 1.2%)

Gastrointestinal

haemorrhage (G3/4:

0.4%)

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0.4%)

Skin and

subcutaneous

tissue disorders

Alopecia (G3/4: 4.0%)

Rash pruritic

Dry skin

Desquamation

Musculoskeletal,

connective tissue

and bone

disorders

Myalgia (G3/4: 0.4%)

Metabolism and

nutrition

disorders

Anorexia (G3/4: 12.0%)

Infections and

infestations

Infection (G3/4: 3.6%)

Neutropenic infection

Neoplasms

benign and

malignant

(including cysts

and polyps)

Cancer pain (G3/4:

1.2%)

Vascular

disorders

Venous disorder

General

disorders and

administration

site conditions

Lethargy (G3/4: 4.0%)

Pyrexia (G3/4: 3.6%)

Fluid retention (G3/4:

1.2%)

Oedema (G3/4: 1.2%)

Immune system

disorders

Hypersensitivity

Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring i.v.

antibiotics and/or hospitalization.

Combination therapy with docetaxel for adjuvant treatment of patients with operable breast

cancer whose tumours overexpress HER2 and who received either AC-TH or TCH

Adverse Events (AEs) Related to Study Treatment, Occurring at Any Time During the Study:

Safety population (incidence of ≥ 5% for non-cardiac AEs; incidence of ≥ 1% for cardiac

)

AC-TH

n=1068

TCH

n=1056

Adverse Event

(NCI-CTC term)

Overall

n (%)

Grade 3/4

n (%)

Overall

n (%)

Grade 3/4

n (%)

Alopecia

1047 (98.0)

1012 (95.8)

Haemoglobin

1036 (97.0)

34 (3.2)

1017 (96.3)

61 (5.8)

Nausea

931 (87.2)

57 (5.3)

853 (80.8)

49 (4.6)

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Leucocytes

929 (87.0)

643 (60.2)

877 (83.0)

507 (48.0)

Neutrophils

922 (86.3)

761 (71.3)

859 (81.3)

696 (65.9)

Fatigue

868 (81.3)

71 (6.6)

849 (80.4)

73 (6.9)

Stomatitis/

694 (65.0)

32 (3.0)

547 (51.8)

15 (1.4)

Vomiting

591 (55.3)

68 (6.4)

416 (39.4)

32 (3.0)

SGPT (ALT)

579 (54.2)

19 (1.8)

561 (53.1)

25 (2.4)

Fluid retention

558 (52.2)

16 (1.5)

539 (51.0)

15 (1.4)

Myalgia

544 (50.9)

52 (4.9)

353 (33.4)

15 (1.4)

Diarrhoea

484 (45.3)

55 (5.1)

589 (55.8)

52 (4.9)

Neuropathy-sensory

478 (44.8)

20 (1.9)

316 (29.9)

6 (0.6)

SGOT (AST)

454 (42.5)

9 (0.8)

401 (38.0)

11 (1.0)

Arthralgia

424 (39.7)

32 (3.0)

230 (21.8)

11 (1.0)

Nail changes

423 (39.6)

246 (23.3)

Platelets

350 (32.8)

13 (1.2)

667 (63.2)

57 (5.4)

Irregular menses

311 (29.1)

213 (19.9)

340 (32.2)

226 (21.4)

Taste disturbance

290 (27.2)

312 (29.5)

Constipation

289 (27.1)

10 (0.9)

232 (22.0)

6 (0.6)

Rash/desquamation

277 (25.9)

14 (1.3)

241 (22.8)

4 (0.4)

Hot flashes/flushes

230 (21.5)

192 (18.2)

Tearing

228 (21.3)

3 (0.3)

109 (10.3)

Alkaline phosphatase

206 (19.3)

3 (0.3)

215 (20.4)

3 (0.3)

Anorexia

205 (19.2)

5 (0.5)

222 (21.0)

5 (0.5)

Dyspepsia/heartburn

203 (19.0)

3 (0.3)

211 (20.0)

4 (0.4)

Headache

175 (16.4)

6 (0.6)

160 (15.2)

3 (0.3)

Dyspnea

166 (15.5)

16 (1.5)

157 (14.9)

18 (1.7)

Weight gain

159 (14.9)

3 (0.3)

154 (14.6)

2 (0.2)

Infection without neutropenia

135 (12.6)

20 (1.9)

98 (9.3)

16 (1.5)

Abdominal pain or cramping

132 (12.4)

4 (0.4)

141 (13.4)

5 (0.5)

Insomnia

119 (11.1)

1 (0.1)

93 (8.8)

Febrile neutropenia

116 (10.9)

116 (10.9)

103 (9.8)

103 (9.8)

Fever (without neutropenia)

116 (10.9)

4 (0.4)

70 (6.6)

3 (0.3)

Allergic reaction/hypersensitivity

105 (9.8)

15 (1.4)

139 (13.2)

26 (2.5)

Bone pain

104 (9.7)

4 (0.4)

67 (6.3)

1 (0.1)

Infection with Grade 3/4 neutropenia

98 (9.2)

98 (9.2)

81 (7.7)

81 (7.7)

Pain

86 (8.1)

4 (0.4)

57 (5.4)

Conjunctivitis

86 (8.1)

35 (3.3)

Dizziness /lightheadedness

78 (7.3)

7 (0.7)

70 (6.6)

4 (0.4)

Creatinine

72 (6.7)

5 (0.5)

102 (9.7)

6 (0.6)

Hand-foot skin reaction

72 (6.7)

15 (1.4)

29 (2.7)

Epistaxis

72 (6.7)

104 (9.8)

4 (0.4)

Weight loss

71 (6.6)

56 (5.3)

1 (0.1)

Dry skin

69 (6.5)

41 (3.9)

Cough

66 (6.2)

2 (0.2)

36 (3.4)

Rhinitis

64 (6.0)

1 (0.1)

47 (4.5)

Rigors, chills

63 (5.9)

54 (5.1)

Infection with unknown

59 (5.5)

59 (5.5)

38 (3.6)

38 (3.6)

Neuropathy-motor

57 (5.3)

4 (0.4)

38 (3.6)

3 (0.3)

Bilirubin

54 (5.1)

4 (0.4)

61 (5.8)

4 (0.4)

Injection site reaction

50 (4.7)

1 (0.1)

61 (5.8)

2 (0.2)

Mouth dryness

43 (4.0)

29 (2.7)

Cardiac left ventricular function

37 (3.5)

5 (0.5)

15 (1.4)

1 (0.1)

Palpitations

36 (3.4)

47 (4.5)

Sinus tachycardia

19 (1.8)

23 (2.2)

Docetaxel Hospira 10mg/ml LPD CC technical change 040219

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AC-TH = doxorubicin and cyclophosphamide, followed by docetaxel in combination with

trastuzumab.

TCH = Docetaxel in combination with trastuzumab and carboplatin.

Regardless of causality

Fluid retention AEs are defined as "oedema only", or "weight gain only", or "lung oedema

only", or "oedema and weight gain", or "oedema and lung oedema", or "oedema + weight

gain + lung oedema". "Fluid retention" corresponds to the NCI-CTC term "oedema".

COSTART term The 3 year cumulative incidence of all symptomatic cardiac events was

2.36% and 1.16% in the AC-TH and TCH arms, respectively (versus 0.52% in the AC-T

control arm, see CLINICAL TRIALS section). The 3 year cumulative incidence of CHF

events (Grade 3 or 4) was 1.9% and 0.4% in the AC-TH and TCH arms, respectively (versus

0.3% in the AC-T control arm).

Post-Marketing Experience

Cardiac disorders:

Rare cases of myocardial infarction have been reported.

Blood and lymphatic system disorders:

Bone marrow suppression and other haematologic

adverse reactions have been reported. Disseminated

intravascular coagulation (DIC), often in

association with sepsis or multiorgan failure, has been reported.

Nervous system disorders:

Rare cases of convulsion or transient loss of consciousness have

been observed with docetaxel

administration. These reactions sometimes appear during

infusion of the drug.

Eye Disorders:

Very rare cases of transient visual disturbances (flashes, flashing lights,

scotomata) typically occurring during

drug infusion and in association with hypersensitivity

reactions have been reported.

These were reversible upon discontinuation of the infusion. Cases of lacrimation with or

without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing

have been rarely reported.

Cases of Cystoid Macular Oedema (CMO) have been reported in patients treated with

docetaxel.

Ear and labyrinth disorders:

Rare cases of ototoxicity, impaired hearing and/or hearing loss

have been reported.

Respiratory, thoracic and mediastinal disorders:

Acute respiratory distress syndrome

interstitial pneumonia / pneumonitis, interstitial lung

disease, pulmonary fibrosis, pulmonary

edema, respiratory failure, and radiation recall phenomena have rarely been reported, and may

be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in

patients receiving concomitant radiotherapy.

Gastrointestinal disorders:

Rare occurrences of dehydration as a consequence of

gastrointestinal events, gastrointestinal perforation,

colitis ischaemic, colitis and neutropenic

enterocolitis have been reported. Rare cases of ileus and intestinal

obstruction have been

reported.

Skin and subcutaneous tissue disorders:

Very rare cases of cutaneous lupus erythematous and

bullous eruptions such as erythema multiforme,

Stevens-Johnson syndrome, toxic epidermal

necrolysis, have been reported with docetaxel. In some cases

concomitant factors may have

contributed to the development of these effects. Sclerodermal-like change usually preceded

by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia

(frequency not known) have been reported.

Hypotension

10 (0.9)

13 (1.2)

2 (0.2)

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Neoplasms benign and malignant (including cysts and polyps):

Cases of acute myeloid

leukaemia and myelodysplastic syndrome have been reported in association with docetaxel

when used in combination with other chemotherapy agents and/or radiotherapy.

Vascular disorders:

Venous thromboembolic events have rarely been reported.

General disorders and administration site conditions:

Radiation recall phenomena have

rarely been reported.

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension.

Dehydration and pulmonary oedema have rarely been reported.

Immune system disorders:

Some cases of anaphylactic shock, sometimes fatal, have been

reported.

Renal and urinary disorders:

Renal insufficiency and renal failure have been reported. In

about 20% of these cases there were no risk

factors for acute renal failure such as concomitant

nephrotoxic medicinal products and gastro-intestinal

disorders.

Hepatobiliary disorders:

Very rare cases of hepatitis, sometimes fatal primarily in patients

with pre-existing liver disorders, have been reported.

Metabolism and nutrition disorders:

Cases of hyponatraemia have been reported, mostly

associated with dehydration, vomiting and pneumonia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

mType=AdversEffectMedi

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?for

c@moh.gov.il

4.9 Overdose

There were a few reports of overdose. There is no known antidote for docetaxel overdose. In

case of overdose, the patient should be kept in a specialised unit and vital functions closely

monitored. In cases of overdose, exacerbation of adverse events may be expected. The

primary anticipated complications of overdose would consist of bone marrow suppression,

peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as

possible after discovery of overdose. Other appropriate symptomatic measures should be

taken, as needed.

5

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Taxanes, ATC Code: L01CD 02

Preclinical data:

Docetaxel is an antineoplastic agent which acts by promoting the assembly

of tubulin into stable microtubules and inhibits their disassembly which leads to a marked

decrease of free tubulin. The binding of docetaxel to microtubules does not alter the number

of protofilaments.

Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is

essential for vital mitotic and interphase cellular functions.Docetaxel was found to be

cytotoxic in vitro against various murine and human tumour cell lines and against freshly

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excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular

concentrations with a long cell residence time. In addition, docetaxel was found to be active

on some but not all cell lines over expressing the p-glycoprotein which is encoded by the

multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad

spectrum of experimental antitumour activity against advanced murine and human grafted

tumours.

Clinical data:

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy

Patients with operable node-positive breast cancer (TAX 316): Data from a multicenter open

label randomized study support the use of docetaxel or the adjuvant treatment of patients with

operable node-positive breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After

stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were

randomized to receive either docetaxel 75 mg/m

administered 1-hour after doxorubicin 50

mg/m

and cyclophosphamide 500 mg/m

(TAC arm), or doxorubicin 50 mg/m

followed by

fluorouracil 500 mg/m

and cyclophosphamide 500 mg/m

(FAC arm). Both regimens were

administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour

infusion, all other drugs were given as IV bolus on day one. G-CSF was administered as

secondary prophylaxis to patients who experienced complicated neutropenia (febrile

neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received

antibiotic prophylaxis with ciprofloxacin 500 mg orally b.i.d. for 10 days starting on day 5 of

each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with

positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5

years. Adjuvant radiation therapy was prescribed according to guidelines in place at

participating institutions and was given to 69% of patients who received TAC and 72% of

patients who received FAC. Two interim analyses and one final analysis were performed. The

first interim analysis was planned 3 years after the date when half of study enrollment was

done. The second interim analysis was done after 400 DFS events had been recorded overall,

which led to a median follow-up of 55 months. The final analysis was performed when all

patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to

follow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall

survival (OS) was the secondary efficacy endpoint.

A final analysis was performed with an actual median follow up of 96 months. Significantly

longer disease free survival for the TAC arm compared to the FAC arm was demonstrated.

Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those

who received FAC (39% versus 45%, respectively) i.e., an absolute risk reduction by 6%

(p=0.0043). Overall survival at 10 years was also significantly increased with TAC compared

to FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7%

(p=0.002). As the benefit observed in patient with 4+ nodes was not statistically significant on

DFS and OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully

demonstrated at the final analysis. Overall, the study results demonstrate a positive benefit

risk ratio for TAC compared to FAC.

TAC-treated patient subsets according to prospectively defined major prognostic factors were

analyzed:

Disease-Free Survival

Overall Survival

Patient subset

Number

of patients

Hazard

ratio*

95% CI

p=

Hazard

ratio*

95% CI

p=

No. of positive

nodes

Overall

0.80

0.68-0.93 0.0043

0.74

0.61-0.90 0.0020

0.72

0.58-0.91 0.0047

0.62

0.46-0.82 0.0008

0.87

0.70-1.09 0.2290

0.87

0.67-1.12 0.2746

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*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free

survival and overall survival compared to FAC

Patients with operable node-negative breast cancer eligible to receive chemotherapy

(GEICAM 9805): Data from a multicenter open label randomized trial support the use of

docetaxel for the adjuvant treatment of patients with operable node-negative breast cancer

eligible to receive chemotherapy. 1060 patients were randomized to receive either docetaxel

75 mg/m

administered 1-hour after doxorubicin 50 mg/m

and cyclophosphamide 500 mg/m

(539 patients in TAC arm), or doxorubicin

50 mg/m

followed by fluorouracil 500 mg/m

cyclophosphamide 500 mg/m

(521 patients in FAC arm), as adjuvant treatment of operable

node-negative breast cancer patients with high risk of relapse according to 1998 St. Gallen

criteria (tumour size >2 cm and/or negative ER and PR and/or high histological/nuclear grade

(grade 2 to 3) and /or age <35 years). Both regimens were administered once every 3 weeks

for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products

were given intravenously on day 1 every three weeks. Primary prophylactic G-CSF was made

mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4

neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who

received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle of

chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day

for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in

place at participating institutions and was given to 57.3% of patients who received TAC and

51.2% of patients who received FAC.

One primary analysis and one updated analysis were performed. The primary analysis was

done when all patients had a follow-up of greater than 5 years (median follow-up time of 77

months). The updated analysis was performed when all patients had reached their 10-year

(median follow up time of 10 years and 5 months) follow-up visit (unless they had a DFS

event or were lost to follow-up previously). Disease-free survival (DFS) was the primary

efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint.

At the median follow-up time of 77 months, significantly longer DFS for the TAC arm

compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in

the risk of relapse compared to those treated with FAC [hazard ratio = 0.68, 95% CI (0.49-

0.93), p = 0.01]. At the median follow up time of 10 years and 5 months, TAC-treated

patients had a 16.5% reduction in the risk of relapse compared to those treated with FAC

[hazard ratio = 0.84, 95% CI (0.65-1.08), p = 0.1646]. DFS data were not statistically

significant but were still associated with a positive trend in favor of TAC.

At the median follow-up time of 77 months OS was longer in the TAC arm with TAC-treated

patients having a 24% reduction in the risk of death compared to FAC [hazard ratio = 0.76,

95% CI (0.46-1.26), p = 0.29]. However, the distribution of OS was not significantly different

between the 2 groups.

At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9%

reduction in the risk of death compared to FAC-treated patients [hazard ratio = 0.91, 95% CI

(0.63-1.32)]. The survival rate was 93.7% in the TAC arm and 91.4% in the FAC arm, at the

8-year follow-up timepoint, and 91.3% in the TAC arm and 89% in the FAC arm, at the 10-

year follow-up timepoint.

The positive benefit risk ratio for TAC compared to FAC remained unchanged.

TAC-treated patient subsets according to prospectively defined major prognostic factors were

analyzed in the primary analysis (median follow-up time of 77 months) (see table below):

Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study

(primary analysis for Intent-to-Treat population)

Patient subset

Number of

patients

in TAC group

Disease Free Survival

Hazard ratio*

95% CI

Overall

0.68

0.49-0.93

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Age category 1

<50 years

≥50 years

0.67

0.67

0.43-1.05

0.43-1.05

Age category 2

<35 years

≥35 years

0.31

0.73

0.11-0.89

0.52-1.01

Hormonal receptor Status

Negative

Positive

0.62

0.45-1.1

0.4-0.97

Tumour size

≤ 2 cm

>2 cm

0.69

0.68

0.43-1.1

0.45-1.04

Histological grade

Grade1 (includes grade not

assessed)

Grade 2

Grade 3

0.79

0.77

0.59

0.24-2.6

0.46-1.3

0.39-0.9

Menopausal status

Pre-Menopausal

Post-Menopausal

0.64

0.72

0.40-1

0.47-1.12

*a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer

disease free survival compared to FAC.

Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St.

Gallen chemotherapy criteria – (ITT population) were performed and presented here below

TAC

FAC

Hazard ratio

(TAC/FAC)

Subgroups

(n=539)

(n=521)

(95% CI)

p-

value

Meeting relative indication for

chemotherapy

18/214 (8.4%)

26/227 (11.5%)

0.796 (0.434 - 1.459)

0.4593

48/325 (14.8%)

69/294 (23.5%)

0.606 (0.42 - 0.877)

0.0072

TAC = docetaxel, doxorubicin and cyclophosphamide. FAC = 5-fluorouracil, doxorubicin

and cyclophosphamide

CI = confidence interval; ER = estrogen receptor. PR = progesterone receptor.

ER/PR-negative or Grade 3 or tumor size >5 cm

The estimated hazard ratio was using Cox proportional hazard model with treatment group as

the factor.

Docetaxel as single agent:

Two randomised phase III comparative studies, involving a total

of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been

performed with docetaxel at the recommended dose and regimen of 100 mg/m² every 3

weeks.

In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3

weeks). Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14

months, p=0.38) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks,

p=0.54), docetaxel increased response rate (52% vs. 37%, p=0.01) and shortened time to

response (12 weeks vs. 23 weeks, p=0.007). Three docetaxel patients (2%) discontinued the

treatment due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due to

cardiac toxicity (three cases of fatal congestive heart failure). In anthracycline-failure patients,

docetaxel was compared to the combination of Mitomycin C and Vinblastine (12 mg/m²

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every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate (33% vs. 12%,

p<0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p=0.0004) and prolonged

overall survival (11 months vs. 9 months, p=0.01).

During these two phase III studies, the safety profile of docetaxel was consistent with the

safety profile observed in phase II studies (see section 4.8).

An open-label, multicenter, randomized phase III study was conducted to compare docetaxel

monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose

previous therapy should have included an anthracycline. A total of 449 patients were

randomized to receive either docetaxel monotherapy 100 mg/m² as a 1 hour infusion or

paclitaxel 175 mg/m² as a 3 hour infusion. Both regimens were administered every 3 weeks.

Without affecting the primary endpoint, overall response rate (32% vs 25%, p=0.10),

docetaxel prolonged median time to progression (24.6 weeks vs 15.6 weeks; p<0.01) and

median survival (15.3 months vs 12.7 months; p=0.03). More grade 3/4 adverse events were

observed for docetaxel monotherapy (55.4%) compared to paclitaxel(23.0%).

Docetaxel in combination with doxorubicin:

One large randomized phase III study,

involving 429 previously untreated patients with metastatic disease, was performed with

doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²) (AT arm) versus

doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²)

(AC arm). Both

regimens were administered on day 1 every 3 weeks.

Time to progression (TTP) was significantly longer in the AT arm versus AC arm,

p=0.0138. The median TTP was 37.3 weeks (95%CI: 33.4 - 42.1) in AT arm and 31.9

weeks (95%CI: 27.4 - 36.0) in AC arm.

Overall response rate (ORR) was significantly higher in the AT arm versus AC arm,

p=0.009. The ORR was 59.3% (95%CI: 52.8 - 65.9) in AT arm versus 46.5% (95%CI :

39.8 - 53.2) in AC arm.

In this trial, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%),

febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus

1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other

hand, AC arm showed a higher incidence of severe anaemia (15.8% versus 8.5%) than AT

arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure

(3.8% versus 2.8%), absolute LVEF decrease ≥ 20% (13.1 % versus 6.1%), absolute LVEF

decrease ≥ 30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm

(congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to

congestive heart failure). In both arms, quality of life measured by the EORTC questionnaire

was comparable and stable during treatment and follow-up.

Docetaxel in combination with trastuzumab:

Docetaxel in combination with trastuzumab

was studied for the treatment of patients with metastatic breast cancer whose tumours

overexpress HER2, and who previously had not received chemotherapy for metastatic

disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m

with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant

chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they

had received prior adjuvant anthracyclines. The main test method used to determine HER2

positivity in this pivotal trial was immunohistochemistry (IHC). A minority of patients were

tested using fluorescence in-situ hybridization (FISH). In this trial, 87% of patients had

disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or

FISH positive. Efficacy results are summarized in the following table:

Parameter

Docetaxel plus trastuzumab

1

n=92

Docetaxel

1

n=94

Response rate (95% CI)

61% (50-71)

34% (25-45)

Median Duration of response

(months) (95% CI)

11.4 (9.2-15.0)

5.1 (4.4-6.2)

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Median TTP (months) (95%

10.6 (7.6-12.9)

5.7 (5.0-6.5)

Median Survival (months)

(95% CI)

30.5

(26.8-ne)

22.1

(17.6-28.9)

TTP=time to progression; “ne” indicates that it could not be estimated or it was not yet

reached.

Full analysis set (intent-to-treat)

Estimated median survival

Docetaxel in combination with capecitabine:

Data from one multicentre, randomised,

controlled phase III clinical trial supported the use of docetaxel in combination with

capecitabine for treatment of patients with locally advanced or metastatic breast cancer after

failure of cytotoxic chemotherapy, including an anthracycline. In this trial, 255 patients were

randomised to treatment with docetaxel (75 mg/m

as a 1 hour intravenous infusion every 3

weeks) and capecitabine (1250 mg/m

twice daily for 2 weeks followed by 1-week rest

period). 256 patients were randomised to treatment with docetaxel alone (100 mg/ m

as a 1

hour intravenous infusion every 3 weeks).

Survival was superior in the docetaxel

+capecitabine combination arm (p=0.0126). Median survival was 442 days (docetaxel +

capecitabine) vs. 352 days (docetaxel alone). The overall objective response rates in the all-

randomised population (investigator assessment) were 41.6% (docetaxel + capecitabine) vs.

29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was superior in the

docetaxel + capecitabine combination arm (p<0.0001). The median time to progression was

186 days (docetaxel + capecitabine) vs.128 days (docetaxel alone).

Doxorubicin and Cyclophosphamide followed by docetaxel in combination with

Trastuzumab (AC-TH), or docetaxel in combination with Trastuzumab and

Carboplatin (TCH)

The efficacy and safety of docetaxel in combination with trastuzumab was studied for the

adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2

(with node-positive and high risk node-negative). A total of 3,222 women were randomised in

the study, and 3,174 were treated with either: AC-T, AC-TH, or TCH.

AC-T

(control arm): Doxorubicin 60 mg/m

IV in combination with cyclophosphamide 600

mg/m

IV on an every 3 week basis for 4 cycles, followed by docetaxel 100 mg/m

as a 1-

hour IV infusion on an every 3 week basis for 4 cycles;

AC-TH

: Doxorubicin 60 mg/m

IV in combination with cyclophosphamide 600 mg/m

on an every 3 week basis for 4 cycles. Three weeks after the last cycle of AC, trastuzumab 4

mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 5 was administered,

followed by trastuzumab 2 mg/kg by IV infusion over 30-minutes weekly starting day 8 of

cycle 5; and docetaxel 100 mg/m

administered by IV infusion over 1-hour on day 2 of

cycle 5, then on day 1 on an every 3 week basis for all subsequent cycles (total 4 cycles of

docetaxel). Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6

mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of

first administration);

TCH

: Trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle

1 only, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting on

day 8 until three weeks after the last cycle of chemotherapy. Docetaxel 75 mg/m

administered on day 2 of cycle 1, then on day 1 of all subsequent cycles by IV infusion over

1-hour followed by carboplatin (AUC 6 mg/mL/min) as a 30-60 minute IV infusion, for a

total of six cycles of docetaxel and carboplatin. Beginning three weeks after the last cycle of

chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3

weeks (for 1-year from the date of first administration).

The patients and disease characteristics at baseline were well balanced between the 3

treatment arms.

Disease Free Survival (DFS) was the primary endpoint, and Overall Survival (OS) was the

secondary endpoint.

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Results of the second interim analysis, performed with a median follow-up of 36 months,

demonstrated that docetaxel and trastuzumab given concurrently as part of either an

anthracycline-based (AC-TH) or nonanthracycline- based (TCH) adjuvant treatment

regimens, for patients with HER2-positive operable breast cancer, statistically prolonged both

DFS and OS compared with the control arm (AC-T). The relative reduction in the risk of

relapse was 39 % (p < 0.0001) and 33% (p = 0.0003) for the AC-TH and TCH arms,

respectively, compared with the AC-T arm. The relative reduction in the risk of death was

42% (p = 0.0024) and 34% (p = 0.0182) for the AC-TH and TCH arms, respectively,

compared with the AC-T arm. There was no statistically significant difference between the

two trastuzumab-containing arms AC-TH and TCH for DFS and OS. Efficacy results are

summarised in the following table:

Doxorubicin and cyclophosphamide followed by docetaxel in combination with trastuzumab,

or docetaxel in combination with trastuzumab, and carboplatin (Intent-to-Treat Population)

Disease Free Survival (DFS)

Overall Survival (OS)

AC-T

n=1073

AC-TH

n=1074

TCH

n=1075

AC-T

n=1073

AC-TH

n=1074

TCH

n=1075

Stratified analysis

Hazard ratio

95% CI

p-value

Percent event

free at 3 years

(95% CI)

Absolute benefit

80.9%

(78.3-83.5%)

0.61

(0.49-0.77)

< 0.0001

86.7%

(84.4-89.0%)

5.8%

0.67

(0.54-0.83)

0.0003

85.5%

(83.2-87.9%)

4.6%

93.0%

(91.2-94.8%)

0.58

(0.40-0.83)

0.0024

95.5%

(94.0-96.9%)

2.5%

0.66

(0.47-0.93)

0.0182

95.2%

(93.7-96.6%)

2.2%

AC-T=doxorubicin plus cyclophosphamide, followed by docetaxel; AC-TH=doxorubicin plus

cyclophosphamide, followed by docetaxel in combination with trastuzumab; TCH= docetaxel

in combination with trastuzumab and carboplatin.

CI=confidence interval; NA=not applicable.

=Relative to AC-T. Estimated using Cox regression stratified by number of nodes and

hormonal receptor status.

=Stratified log-rank p-value.

=Absolute benefit in percent event free compared with AC-T.

There were 29% of patients with high risk node-negative disease included in the study. The

benefit observed for the overall population was irrespective of the nodal status.

Disease Free Survival (Intent-to-Treat Population) according to Nodal Status

High risk node-negative patients

Node-positive patients

AC-T

n = 309

AC-TH

n = 306

TCH

n = 307

AC-T

n = 764

AC-TH

n = 768

TCH

n = 768

Stratified analysis

Hazard ratio

95% CI

p-value

Percent event

free at 3 years

(95% CI)

Absolute benefit

88.0%

(84.1- 91.9%)

0.36

(0.19-0.68)

0.0010

94.8%

(91.9-97.8%)

6.8%

0.52

(0.30-0.92)

0.0209

93.0%

(89.9-96.2%)

5.1%

78.1%

(74.9-81.3%)

0.67

(0.53-0.85)

0.0008

83.6%

(80.7-86.5%)

5.5%

0.70

(0.56-0.89)

0.0029

82.6%

(79.6-85.6%)

4.6%

AC-T=doxorubicin plus cyclophosphamide, followed by docetaxel; AC-TH=doxorubicin plus

cyclophosphamide, followed by TAXOTERE in combination with trastuzumab; TCH=

docetaxel in combination with trastuzumab and carboplatin.

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CI=confidence interval; NA=not applicable.

=Relative to AC-T. Estimated using Cox regression stratified by number of nodes and

hormonal receptor status.

=Stratified log-rank p-value.

=Absolute benefit in percent event free compared with AC-T.

Non-Small Cell Lung Cancer

Patients previously treated with chemotherapy with or without radiotherapy:

In a phase III

study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks) and

overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best

Supportive Care. The 1-year survival rate was also significantly longer in docetaxel (40%)

versus BSC (16%).

There was less use of morphinic analgesic (p<0.01), non-morphinic

analgesics (p<0.01), other disease related medications (p=0.06) and radiotherapy (p<0.01) in

patients treated with docetaxel at 75 mg/m² compared to those with BSC.

The overall response rate was 6.8% in the evaluable patients, and the median duration of

response was 26.1 weeks.

Docetaxel in combination with platinum agents in chemotherapy-naïve patients:

In a Phase

III trial, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or

greater, and who did not receive previous chemotherapy for this condition, were randomised

to either docetaxel (T) 75 mg/m

as a 1 hour infusion immediately followed by cisplatin (Cis)

75 mg/ m

over 30-60 minutes every 3 weeks, docetaxel 75 mg/ m

as a 1 hour infusion in

combination with carboplatin (AUC 6 mg/mlmin) over 30-60 minutes every 3 weeks, or

vinorelbine (V) 25 mg/ m

administered over 6-10 minutes on days 1, 8, 15, 22 followed by

cisplatin 100 mg/ m

administered on day 1 of cycles repeated every 4 weeks. Survival data,

median time to progression and response rates for two arms of the study are illustrated in the

following table:

TCis

n=408

VCis

N=404

Statistical Analysis

Overall Survival (Primary end-

point):

Median Survival (months)

11.3

10.1

Hazard Ratio: 1.122 [97.2% CI: 0.937; 1.342]*

1-year Survival (%)

Treatment difference: 5.4% [95% CI: -1.1; 12.0]

2-year Survival (%)

Treatment difference: 6.2% [95% CI: 0.2; 12.3]

Median Time to Progression

(weeks):

22.0

23.0

Hazard Ratio: 1.032 [95% CI: 0.876; 1.216]

Overall response rate (%):

31.6

24.5

Treatment difference: 7.1% [95% CI: 0.7; 13.5]

*: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease

and region of treatment), based on evaluable patient population.

Secondary end-points included change of pain, global rating of quality of life by EuroQoL-

5D, Lung Cancer Symptom Scale, and changes in Karnofsky performance status. Results on

these end-points were supportive of the primary end-points results.

For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be

proven compared to the reference treatment combination VCis.

Prostate Cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in

patients with

hormone refractory metastatic prostate cancer were evaluated in a randomized

multicentre Phase III trial.

A total of 1006 patients with KPS ≥ 60 were randomized to the

following treatment groups:

docetaxel 75 mg/m

every 3 weeks for 10 cycles.

docetaxel 30 mg/m

administered weekly for the first 5 weeks in a 6 week cycle for 5

cycles.

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Mitoxantrone 12 mg/m

every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone or prednisolone 5 mg

twice daily, continuously.

Patients who received docetaxel every three weeks demonstrated significantly longer overall

survival compared to those treated with mitoxantrone. The increase in survival seen in the

docetaxel weekly arm was not statistically significant compared to the mitoxantrone control

arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the

following table:

Endpoint

Docetaxel every 3

weeks

Docetaxel every week

Mitoxantrone

every 3 weeks

Number of patients

Median survival (months)

95% CI

Hazard ratio

95% CI

p-value

18.9

(17.0-21.2)

0.761

(0.619-0.936)

0.0094

17.4

(15.7-19.0)

0.912

(0.747-1.113)

0.3624

16.5

(14.4-18.6)

Number of patients

PSA** response rate (%)

95% CI

p-value*

45.4

(39.5-51.3)

0.0005

47.9

(41.9-53.9)

< 0.0001

31.7

(26.4-37.3)

Number of patients

Pain response rate (%)

95% CI

p-value*

34.6

(27.1-42.7)

0.0107

31.2

(24.0-39.1)

0.0798

21.7

(15.5-28.9)

Number of patients

Tumour response rate (%)

95% CI

p-value*

12.1

(7.2-18.6)

0.1112

(4.2-14.2)

0.5853

(3.0-12.1)

†Stratified log rank test

*Threshold for statistical significance=0.0175

**PSA: Prostate-Specific Antigen

Given the fact that docetaxel every week presented a slightly better safety profile than

docetaxel every

3 weeks, it is possible that certain patients may benefit from docetaxel every week.

No statistical differences were observed between treatment groups for Global Quality of Life.

Ovarian Cancer

Supportive clinical data:

Docetaxel was studied in five phase II clinical trials in patients who

were diagnosed with advanced

epithelial ovarian cancer and who failed a previous treatment

with cisplatin and/or to carboplatin. These patients (n=281) received docetaxel 100mg/m²

every three weeks as a one-hour infusion.

Overall response rate was 26.7% with a 5.7% complete response rate.

The median survival ranged from 11.2 to 11.9 months.

The adverse reaction profile from these 281 patients is similar to larger populations studied

for metastatic breast cancer (see Adverse Reactions section).

Gastric Adenocarcinoma

A multicentre, open-label, randomized trial, was conducted to evaluate the safety and efficacy

docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including

adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy

for metastatic disease. A total of 445 patients with KPS>70 were treated with either docetaxel

(T) (75 mg/m

on day 1) in combination with cisplatin (C) (75 mg/m

on day 1) and 5-

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fluorouracil (F) (750 mg/m

per day for 5 days) or cisplatin (100 mg/m

on day 1) and 5-

fluorouracil (1,000 mg/m

per day for 5 days). The length of a treatment cycle was 3 weeks

for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per

patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for

the CF arm. Time to progression (TTP) was the primary endpoint. The risk reduction of

progression was 32.1% and was associated with a significantly longer TTP (p=0.0004) in

favour of the TCF arm. Overall survival was also significantly longer (p=0.0201) in favour of

the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in

the following table:

Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma

Endpoint

TCF N=221

CF N=224

Median TTP (months) (95%CI)

Hazard ratio (95%CI)

p-value *

5.6 (4.86-5.91)

3.7 (3.45-4.47)

1.473 (1.189-1.825)

0.0004

Median survival (months) (95%CI)

2-year estimate (%)

Hazard ratio (95%CI)

p-value *

(8.38-10.58)

(7.16-9.46)

18.4

1.293

(1.041-1.606)

0.0201

Overall Response Rate (CR+PR) (%)

p-value

36.7

25.4

0.0106

Progressive Disease as Best Overall Response (%)

16.7

25.9

*Unstratified log rank test

Subgroup analyses across age, gender and race consistently favoured the TCF arm compared

to the CF arm.

A survival update analysis conducted with a median follow-up time of 41.6 months no longer

showed a statistically significant difference although always in favour of the TCF regimen

and showed that the benefit of TCF over CF is clearly observed between 18 and 30 months of

follow up.

Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement

in favour of the TCF arm. Patients treated with TCF had a longer time to 5% definitive

deterioration of global health status on the QLQ-C30 questionnaire (p=0.0121) and a longer

time to definitive worsening of Karnofsky performance status (p=0.0088) compared to

patients treated with CF.

Head and neck cancer

Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell

carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicentre, open-

label, randomized trial (TAX323). In this study, 358 patients with inoperable locally

advanced SCCHN, and WHO performance status 0 or 1, received either docetaxel 75 mg/m

followed by cisplatin 75 mg/m

followed by 5-fluorouracil 750 mg/m

per day as a continuous

infusion for 5 days (TPF) or cisplatin 100 mg/m

followed by 5-fluorouracil 1,000 mg/m

(PF) per day for 5 days. These regimens were administered every three weeks for 4 cycles in

case at least a minor response (≥ 25% reduction in bidimensionally measured tumour size)

was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks

and a maximal interval of 7 weeks, patients whose disease did not progress received

radiotherapy (RT) according to institutional guidelines for 7 weeks. Locoregional therapy

with radiation was delivered either with a conventional fraction (1.8 Gy - 2.0 Gy once a day,

5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of

radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per

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week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for

hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before

or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis with

ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or

equivalent. The primary endpoint in this study, progression-free survival (PFS), was

significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4

vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median

overall survival was also significantly longer in favour of the TPF arm compared to the PF

arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p

= 0.0128. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced

SCCHN (Intent-to-Treat Analysis)

Endpoint

Docetaxel+Cis+5-FU

n=177

Cis+5-FU

n=181

Median progression free survival (months)

(95%CI)

11.4 (10.1-14.0)

8.3 (7.4-9.1)

Adjusted Hazard ratio (95%CI)

*p-value

0.70 (0.55-0.89)

0.0042

Median survival (months) (95%CI)

18.6 (15.7-24.0)

14.5 (11.6-18.7)

Hazard ratio (95%CI)

**p-value

0.72 (0.56-0.93)

0.0128

Best overall response to chemotherapy (%)

(95%CI)

67.8 (60.4-74.6)

53.6 (46.0-61.0)

***p-value

0.006

Best overall response to study treatment

[chemotherapy +/- radiotherapy] (%)

(95%CI)

72.3 (65.1-78.8)

58.6 (51.0-65.8)

***p-value

0.006

Median duration of response to

chemotherapy ± radiotherapy (months)

(95%CI)

n=128

15.7 (13.4-24.6)

n=106

11.7 (10.2-17.4)

Hazard ratio (95%CI)

**p-value

0.72 (0.52-0.99)

0.0457

A Hazard ratio of less than 1 favors docetaxel + cisplatin + 5-FU

*Cox model (adjustment for Primary tumor site, T and N clinical stages and PSWHO)

**Logrank test

*** Chi-square test

Quality of life parameters

Patients treated with TPF experienced significantly less deterioration of their Global health

score compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit parameters

The performance status scale, for head and neck (PSS-HN) subscales designed to measure

understandability of speech, ability to eat in public, and normalcy of diet, was significantly in

favour of TPF as compared to PF.

Median time to first deterioration of WHO performance status was significantly longer in the

TPF arm compared to PF. Pain intensity score improved during treatment in both groups

indicating adequate pain management.

Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of docetaxel in the induction treatment of patients with locally

advanced squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a

randomized, multicenter open-label, phase III, trial (TAX324). In this study, 501 patients,

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with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to

one of two arms. The study population comprised patients with technically unresectable

disease, patients with low probability of surgical cure and patients aiming at organ

preservation. The efficacy and safety evaluation solely addressed survival endpoints and the

success of organ preservation was not formally addressed. Patients on the docetaxel arm

received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P)

100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the

continuous intravenous infusion of 5-fluorouracil (F) 1,000 mg/m²/day from day 1 to day 4.

The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have

progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT).

Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour

intravenous infusion on day 1 followed by the continuous intravenous infusion of 5-

fluorouracil (F) 1,000 mg/m²/day from day 1 to day 5. The cycles were repeated every 3

weeks for 3 cycles. All patients who did not have progressive disease were to receive CRT as

per protocol (PF/CRT).

Patients in both treatment arms were to receive 7 weeks of CRT following induction

chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the

last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was

given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was

delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days

per week for 7 weeks, for a total dose of 70-72 Gy). Surgery on the primary site of disease

and/or neck could be considered at anytime following completion of CRT. All patients on the

docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy

endpoint in this study, overall survival (OS) was significantly longer (log-rank test, p =

0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 versus 30.1

months respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio

(HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median follow up

time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of

progression or death and a 22 month improvement in median PFS (35.5 months for TPF and

13.1 for PF).

This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test p =

0.004. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN

(Intent-to-Treat Analysis)

Endpoint

Docetaxel + Cis + 5-FU

n = 255

Cis + 5-FU

n = 246

Median overall survival (months) (95% CI)

Hazard ratio: (95% CI)

*p-value

70.6 (49.0-NA)

30.1 (20.9-51.5)

0.70 (0.54-0.90)

0.0058

Median PFS (months) (95% CI)

Hazard ratio: (95% CI)

**p-value

35.5 (19.3-NA)

13.1 (10.6 - 20.2)

0.71 (0.56 - 0.90)

0.004

Best overall response (CR + PR) to

chemotherapy (%) (95% CI)

***p-value

71.8 (65.8-77.2)

64.2 (57.9-70.2)

0.070

Best overall response (CR + PR) to study

treatment [chemotherapy +/-

chemoradiotherapy] (%) (95%CI)

***p-value

76.5 (70.8-81.5)

71.5 (65.5-77.1)

0.209

A Hazard ratio of less than 1 favors docetaxel + cisplatin + fluorouracil

*un-adjusted log-rank test

**un-adjusted log-rank test, not adjusted for multiple comparisons

***Chi square test, not adjusted for multiple comparisons

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NA-not applicable

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies

withdocetaxel in all subsets of the paediatric population in breast cancer, non-small cell lung

cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and

III less differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric

use).

5.2 Pharmacokinetic Properties

Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after

administration of 20-115 mg/m

in Phase I studies. The kinetic profile of docetaxel is dose

independent and consistent with a three compartment pharmacokinetic model with half lives

for the α, β, and γ phases of 4 min, 36 min and 11.1 h, respectively. The late phase is due, in

part, to a relatively slow efflux of docetaxel from the peripheral compartment.

Distribution: Following the administration of a 100 mg/m2 dose given as a one-hour infusion

a mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of 4.6

h.μg/ml. Mean values for total body clearance and steady-state volume of distribution were 21

l/h/m2 and 113 l, respectively. Inter individual variation in total body clearance was

approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination: A study of 14C-docetaxel has been conducted in three cancer patients.

Docetaxel was eliminated in both the urine and faeces following cytochrome P450-mediated

oxidative metabolism of the tert-butyl ester group, within seven days, the urinary and faecal

excretion accounted for about 6% and 75% of the administered radioactivity, respectively.

About 80% of the radioactivity recovered in faeces is excreted during the first 48 hours as one

major inactive metabolite and 3 minor inactive metabolites and very low amounts of

unchanged drug.

Special population

Age and gender: A population pharmacokinetic analysis has been performed with docetaxel

in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those

estimated from Phase I studies. The pharmacokinetics of docetaxel were not altered by the

age or sex of the patient.

Hepatic impairment: In a small number of patients (n=23) with clinical chemistry data

suggestive of mild to moderate liver function impairment (ALT, AST ≥1.5 times the ULN

associated with alkaline phosphatase ≥2.5 times the ULN), total clearance was lowered by

27% on average (see section 4.2).

Fluid retention: Docetaxel clearance was not modified in patients with mild to moderate fluid

retention and there are no data available in patients with severe fluid retention.

Combination therapy

Doxorubicin: When used in combination, docetaxel does not influence the clearance of

doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The

pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by

their co-administration.

Capecitabine: Phase I study evaluating the effect of capecitabine on the pharmacokinetics of

docetaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of

docetaxel (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of a relevant

capecitabine metabolite 5’-DFUR.

Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that

observed following monotherapy. The pharmacokinetic profile of cisplatin administered

shortly after Docetaxel infusion is similar to that observed with cisplatin alone.

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Cisplatin and 5-fluorouracil: The combined administration of docetaxel, cisplatin and 5-

fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of

each individual drug.

Prednisone and dexamethasone: The effect of prednisone on the pharmacokinetics of

docetaxel administered with standard dexamethasone premedication has been studied in 42

patients.

Prednisone: No effect of prednisone on the pharmacokinetics of docetaxel was observed.

5.3 Preclinical safety data

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to

reduce fertility in rats. Docetaxel has been shown to be mutagenic in the in vitro

micronucleus and chromosome aberration test in CHO-K1 cells and in the in vivo

micronucleus test in the mouse. However, it did not induce mutagenicity in the Ames test or

the CHO/HGPRT gene mutation assay. These results are consistent with the pharmacological

activity of docetaxel.

Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel

may impair male fertility.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polysorbate 80, Ethanol anhydrous, Citric Acid anhydrous, , Macrogol 300.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

6.3 Shelflife

The expiry date of the product is indicated on the packaging materials.

After dilution:

After dilution in 0.9% sodium chloride or 5% glucose chemical and physical

in-use stability has been demonstrated for 4 hours when stored below 25°C. From a

microbiological point of view, the infusion preparation should be used immediately. If not

used immediately, in-use storage times and conditions prior to use are the responsibility of the

user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken

place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store below 25ºC.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

2 ml, 8 ml or 16 ml in a vial (Type I clear glass with or without ONCO-TAIN® overwrap)

with chlorobutyl elastomeric closures and aluminium seals with plastic flip-off cap. Not all

pack sizes may be marketed.

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6.6 Special precautions for disposal

Docetaxel Hospira

is an antineoplastic agent and, as with other potentially toxic agents,

caution should be exercised during handling and preparing solutions of Docetaxel Hospira

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

requirements.

Guidelines for the safe handling and disposal of antineoplastic agents

Preparation:

Local guidelines on safe preparation and handling should be consulted.

Cytotoxic agents should only be prepared and handled by personnel trained in the safe

handling of such preparations. Pregnant personnel should not handle cytotoxic agents.

All personnel involved with handling cytotoxic agents should be adequately protected with

appropriate personal protective equipment, including protective disposable gloves, eye shield,

mask and long-sleeved gown. Preparation and manipulation of solutions should be performed

in a designated handling area.

Contamination:

In the event of skin contact, thoroughly wash the affected area with soap and

water, taking care not to abrade the skin. A bland cream may be used to treat transient

stinging of the skin. In the event of contact with the eyes, irrigate with copious amounts of

water or sodium chloride 0.9%. Seek medical evaluation.

In the event of spillage, trained personnel wearing appropriate personal protective equipment

should remove the maximum amount of material by use of a cytotoxic drug spill kit or

designated absorbent materials. The area should be rinsed with copious amounts of water. All

contaminated cleaning materials should be disposed of as described below.

Disposal:

All contaminated waste materials (including sharps, containers, absorbent

materials, unused solutions, etc.) should be placed in a designated sealed and labelled

impervious waste disposal bag or rigid waste container, and incinerated in accordance with

local procedures for destruction of hazardous waste.

Instructions for preparation:

Refer to section 6.3; Shelf Life.

Inspect visually prior to use. Only clear solutions without visible particles should be used.

MUST BE DILUTED BEFORE USE.

Inject the required volume into a 250 ml infusion bag or bottle containing either:

Sodium Chloride 9 mg/ml (0.9%)

Glucose 50 mg/ml (5%)

If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion

vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Compatibility: It is not recommended to mix docetaxel with other drugs.

Administration: For instructions on administration see section 4.2.

7. MANUFACTURER

Hospira UK Ltd., Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK.

8. LICENSE HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St, Herzliya Pituach 46725.

Docetaxel Hospira 10mg/ml LPD CC technical change 040219

2019-0047589

9.

LICENSE NUMBER

148-24-33345

The leaflet format has been determined by the Ministry of Health and the content has been

checked and approved by in May 2017

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