• NSCLC: after platinum therapy failure: 75 mg/m2 single agent ( 2.2)
`• NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2
`( 2.2)
`• HRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously ( 2.3)
`• GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only)
`followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1-5), starting
`at end of cisplatin infusion ( 2.4)
`• SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed
`by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1-5), starting at end of
`cisplatin infusion; for 4 cycles ( 2.5)
`• SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed
`by fluorouracil 1000 mg/m2 per day as a 24-hr IV (days 1-4); for 3 cycles
`( 2.5)
`Premedication Regimen ( 2.6)
`• Oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg
`twice a day) for 3 days starting 1 day before administration
`• HRPC: oral dexamethasone 8 mg, at 12, 3, and 1 hrs before treatment
`Dosage adjustments during treatment see full prescribing information ( 2.7)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`• Single dose vial 80 mg/2 mL and diluent, 20 mg/0.5 mL and diluent ( 3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`• Hypersensitivity to Taxotere or polysorbate 80 ( 4)
`• Neutrophil counts of < 1500 cells/mm3 ( 4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Acute myeloid leukemia ( 5.6)
`• Fetal harm can occur when administered to a pregnant woman. Women of
`childbearing potential should be advised not to become pregnant when
`taking TAXOTERE ( 5.7)
`• Asthenia ( 5.12)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions are infections, neutropenia, anemia, febrile
`neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia,
`dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain,
`nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia ( 6)
`
`Other adverse reactions, including serious adverse reactions have been
`reported ( 6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`sanofi-aventis U.S. LLC at 1-800-663-1610 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`------------------------------DRUG INTERACTIONS-------------------------------
`• Compounds that induce, inhibit, or are metabolized by P450-3A4 ( 7)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`
`Revised: 09/28/07
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TAXOTERE safely and effectively. See full prescribing information for
`TAXOTERE.
`
`TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion
`(IV). Initial U.S. Approval: 1996
`
`WARNING
`See full prescribing information for complete boxed warning
`• Treatment-related mortality increases with abnormal liver function, at
`higher doses, and in patients with NSCLC and prior platinum-based therapy
`receiving TAXOTERE at 100 mg/m2 ( 5.1)
`• Should not be given if bilirubin > ULN, or if SGOT and/or SGPT > 1.5 x
`ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations
`increase risk of severe or life-threatening complications. Obtain LFTs before
`each treatment cycle ( 8.6)
`• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain
`frequent blood counts to monitor for neutropenia ( 4)
`• Severe hypersensitivity, including very rare fatal anaphylaxis, has been
`reported in patients who received dexamethasone premedication. Severe
`reactions require immediate discontinuation of TAXOTERE and
`administration of appropriate therapy ( 5.3)
`• Contraindicated if history of severe hypersensitivity reactions to
`TAXOTERE or to drugs formulated with polysorbate 80 ( 4)
`• Severe fluid retention may occur despite dexamethasone ( 5.10)
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and usage ( 1), dosage and administration ( 2), warnings and
`precautions ( 5), adverse reactions( 6), 09/28/07
`
`----------------------------INDICATIONS AND USAGE---------------------------
`Taxotere is a microtubule inhibitor used for:
`Breast Cancer (BC): single agent for locally advanced or metastatic BC after
`chemotherapy failure; and with doxorubicin and cyclophosphamide as
`adjuvant treatment of operable node-positive BC ( 1.1)
`Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced
`or metastatic NSCLC after platinum therapy failure; and with cisplatin for
`unresectable, locally advanced or metastatic untreated NSCLC ( 1.2)
`Hormone Refractory Prostate Cancer (HRPC): with prednisone in
`androgen independent (hormone refractory) metastatic prostate cancer ( 1.3)
`Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated,
`advanced GC, including the gastroesophageal junction ( 1.4)
`Squamous Cell Carcinoma of the Head and Neck Cancer (SCCHN): with
`cisplatin and fluorouracil for induction treatment of locally advanced SCCHN
`( 1.5)
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`Administer under supervision of qualified physicians experienced in using
`antineoplastic agents. Facilities to manage possible complications must be
`available.
`Administer IV over 1 hr every 3 weeks. PVC equipment is not recommended.
`• BC: locally advanced or metastatic: 60-100 mg/m2 single agent ( 2.1)
`• BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2
`and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles ( 2.1)
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING
`1 INDICATIONS AND USAGE
`1.1 Breast Cancer
`1.2 Non-Small Cell Lung Cancer
`1.3 Prostate Cancer
`1.4 Gastric Adenocarcinoma
`1.5 Head and Neck Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1 Breast Cancer
`2.2 Non-Small Cell Lung Cancer
`2.3 Prostate Cancer
`2.4 Gastric Adenocarcinoma
`2.5 Head and Neck Cancer
`2.6 Premedication Regimen
`2.7 Dose Adjustments During Treatment
`2.8 Administration Precautions
`2.9 Preparation and Administration
`
`2.10 Stability
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Toxic Deaths
`5.2 Premedication Regimen
`5.3 Hypersensitivity Reactions
`5.4 Hematologic Effects
`5.5 Hepatic Impairment
`5.6 Acute Myeloid Leukemia
`5.7 Pregnancy
`5.8 General
`5.9 Cutaneous
`5.10 Fluid Retention
`5.11 Neurologic
`5.12 Asthenia
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post Marketing Experiences
`
`MYLAN - EXHIBIT 1024
`
`

`
`
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Human Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Breast Cancer
`
`14.2 Adjuvant Treatment of Breast Cancer
`14.3 Non-Small Cell Lung Cancer (NSCLC)
`14.4 Prostate Cancer
`14.5 Gastric Adenocarcinoma
`14.6 Head and Neck Cancer
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING
`The incidence of treatment-related mortality associated with TAXOTERE 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 TAXOTERE as a single agent at a dose of 100 mg/m2 [see Warnings
`and Precautions (5.1)].
`TAXOTERE should generally not be given to patients with bilirubin > upper limit of normal
`(ULN), or to patients with SGOT and/or SGPT >1.5 x ULN concomitant with alkaline
`phosphatase >2.5 x 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 x ULN also
`had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic
`death. Bilirubin, SGOT or SGPT, and alkaline phosphatase values should be obtained prior to
`each cycle of TAXOTERE therapy and reviewed by the treating physician.
`TAXOTERE therapy should not be given to patients with neutrophil counts of <1500 cells/mm3.
`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 TAXOTERE.
`Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension
`and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who
`received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions
`require immediate discontinuation of the TAXOTERE infusion and administration of appropriate
`therapy [see Warnings and Precautions (5.2)]. TAXOTERE must not be given to patients who
`have a history of severe hypersensitivity reactions to TAXOTERE or to other drugs formulated
`with polysorbate 80 [see Contraindications (4)].
`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) [see
`Warnings and Precautions (5.10)].
`
`
`2
`
`
`
`

`
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`
`1. INDICATIONS AND USAGE
`
`1.1 Breast Cancer
`•
`TAXOTERE is indicated for the treatment of patients with locally advanced or
`metastatic breast cancer after failure of prior chemotherapy.
`TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for
`the adjuvant treatment of patients with operable node-positive breast cancer.
`
`•
`
`
`1.2 Non-Small Cell Lung Cancer
`•
`TAXOTERE as a single agent is indicated for the treatment of patients with locally
`advanced or metastatic non-small cell lung cancer after failure of prior platinum-
`based chemotherapy.
`TAXOTERE in combination with cisplatin is indicated for the treatment of patients
`with unresectable, locally advanced or metastatic non-small cell lung cancer who
`have not previously received chemotherapy for this condition.
`
`•
`
`
`1.3 Prostate Cancer
`•
`TAXOTERE in combination with prednisone is indicated for the treatment of patients
`with androgen independent (hormone refractory) metastatic prostate cancer.
`
`
`1.4 Gastric Adenocarcinoma
`•
`TAXOTERE in combination with cisplatin and fluorouracil is indicated for the
`treatment of patients with
`advanced gastric
`adenocarcinoma,
`including
`adenocarcinoma of the gastroesophageal junction, who have not received prior
`chemotherapy for advanced disease.
`
`
`1.5 Head and Neck Cancer
`•
`TAXOTERE in combination with cisplatin and fluorouracil is indicated for the
`induction treatment of patients with locally advanced squamous cell carcinoma of the
`head and neck (SCCHN).
`
`2. DOSAGE AND ADMINISTRATION
`
`TAXOTERE (docetaxel) Injection Concentrate should be administered under the supervision of
`a qualified physician experienced in the use of antineoplastic agents. Appropriate management
`of complications is possible only when adequate diagnostic and treatment facilities are readily
`available.
`
`2.1 Breast Cancer
`The recommended dose of TAXOTERE is 60-100 mg/m2 administered intravenously
`•
`over 1 hour every 3 weeks.
`In the adjuvant treatment of operable node-positive breast cancer, the recommended
`TAXOTERE dose is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and
`cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses. Prophylactic G-CSF may
`
`•
`
`
`
`
`
`3
`
`
`
`

`
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`
`be used to mitigate the risk of hematological toxicities [see Dosage Adjustments
`During Treatment (2.7)].
`
`
`2.2 Non-Small Cell Lung Cancer
`•
`For treatment after failure of prior platinum-based chemotherapy, TAXOTERE was
`evaluated as monotherapy, and the recommended dose is 75 mg/m2 administered
`intravenously over 1 hour every 3 weeks. A dose of 100 mg/m2 in patients previously
`treated with chemotherapy was associated with increased hematologic toxicity,
`infection, and treatment-related mortality in randomized, controlled trials [see Boxed
`Warning, Dosage Adjustments During Treatment (2.7), Warnings and Precautions
`(5), Clinical Studies (14)].
`For chemotherapy-naïve patients, TAXOTERE was evaluated in combination with
`cisplatin. The recommended dose of TAXOTERE is 75 mg/m2 administered
`intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over
`30-60 minutes every 3 weeks [see Dosage Adjustments During Treatment (2.7)].
`
`•
`
`
`2.3 Prostate cancer
`•
`For hormone-refractory metastatic prostate cancer, the recommended dose of
`TAXOTERE is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion.
`Prednisone 5 mg orally twice daily is administered continuously [see Dosage
`Adjustments During Treatment (2.7)].
`
`
`2.4 Gastric adenocarcinoma
`For gastric adenocarcinoma, the recommended dose of TAXOTERE is 75 mg/m2 as a
`•
`1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour
`intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per
`day given as a 24-hour continuous intravenous 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 [see Dosage Adjustments During Treatment (2.7)].
`
`
`2.5 Head and Neck Cancer
`Patients must receive premedication with antiemetics, and appropriate hydration (prior to and
`after cisplatin administration). Prophylaxis for neutropenic infections should be administered.
`All patients treated on the TAXOTERE containing arms of the TAX323 and TAX324 studies
`received prophylactic antibiotics.
`
`
`•
`
`Induction chemotherapy followed by radiotherapy (TAX323)
`the
`For
`the
`induction
`treatment of
`locally advanced
`inoperable SCCHN,
`recommended dose of TAXOTERE is 75 mg/m2 as a 1 hour intravenous infusion
`followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by
`fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days.
`This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy,
`patients should receive radiotherapy. [see Dosage Adjustments During Treatment
`(2.7)].
`
`
`
`4
`
`
`
`

`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`
`
`
`•
`
`
`Induction chemotherapy followed by chemoradiotherapy (TAX324)
`For the induction treatment of patients with locally advanced (unresectable, low
`surgical cure, or organ preservation) SCCHN, the recommended dose of TAXOTERE
`is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin
`100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil
`1000 mg/m2/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 [see Dosage Adjustments During Treatment (2.7)].
`
`
`2.6 Premedication Regimen
`• All patients should be premedicated with oral corticosteroids (see below for prostate
`cancer) such as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days starting
`1 day prior to TAXOTERE administration in order to reduce the incidence and
`severity of fluid retention as well as the severity of hypersensitivity reactions [see
`Boxed Warning, Warnings and Precautions (5)].
`For hormone-refractory metastatic prostate cancer, given the concurrent use of
`prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at
`12 hours, 3 hours and 1 hour before the TAXOTERE infusion [see Warnings and
`Precautions (5)].
`
`•
`
`
`2.7 Dosage Adjustments During Treatment
`
`
`• Breast Cancer
`Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia,
`neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions
`during TAXOTERE therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If
`the patient continues to experience these reactions, the dosage should either be decreased from
`75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are
`dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils
`<500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe
`peripheral neuropathy during TAXOTERE therapy may tolerate higher doses. Patients who
`develop ≥grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued
`entirely.
`
`
`• Combination Therapy with TAXOTERE in the Adjuvant Treatment of Breast
`Cancer
`TAXOTERE in combination with doxorubicin and cyclophosphamide should be administered
`when the neutrophil count is ≥1,500 cells/mm3. Patients who experience febrile neutropenia
`should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction
`should remain on G-CSF and have their TAXOTERE dose reduced to 60 mg/m². Patients who
`experience Grade 3 or 4 stomatitis should have their TAXOTERE dose decreased to 60 mg/m².
`Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory
`signs and/or symptoms during TAXOTERE therapy should have their dosage of TAXOTERE
`
`
`
`5
`
`
`
`

`
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`
`reduced from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m²,
`treatment should be discontinued.
`
`
`• Non-Small Cell Lung Cancer
`Monotherapy with TAXOTERE for NSCLC treatment after failure of prior platinum-based
`chemotherapy
`Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia,
`neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions,
`or other grade 3/4 non-hematological toxicities during TAXOTERE treatment should have
`treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who
`develop ≥grade 3 peripheral neuropathy should have TAXOTERE treatment discontinued
`entirely.
`Combination therapy with TAXOTERE for chemotherapy-naïve NSCLC
`For patients who are dosed initially at TAXOTERE 75 mg/m2 in combination with cisplatin, and
`whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in
`patients who experience febrile neutropenia, and in patients with serious non-hematologic
`toxicities, the TAXOTERE dosage in subsequent cycles should be reduced to 65 mg/m2. In
`patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin
`dosage adjustments, see manufacturers’ prescribing information.
`
`
`• Prostate Cancer
`Combination therapy with TAXOTERE for hormone-refractory metastatic prostate
`cancer
`TAXOTERE should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients
`who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week,
`severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms
`during TAXOTERE therapy should have the dosage of TAXOTERE reduced from 75 to
`60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment
`should be discontinued.
`
`
`• Gastric or Head and Neck Cancer
`TAXOTERE in combination with cisplatin and fluorouracil in gastric cancer or head and
`neck cancer
`Patients treated with TAXOTERE in combination with cisplatin and fluorouracil must receive
`antiemetics and appropriate hydration according to current institutional guidelines. In both
`studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile
`neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days.
`If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs
`despite G-CSF use, the TAXOTERE dose should be reduced from 75 to 60 mg/m2. If
`subsequent episodes of complicated neutropenia occur the TAXOTERE dose should be reduced
`from 60 to 45 mg/m2. In case of Grade 4 thrombocytopenia the TAXOTERE dose should be
`reduced from 75 to 60 mg/m2. Patients should not be retreated with subsequent cycles of
`TAXOTERE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a
`level >100,000 cells/mm3. Discontinue treatment if these toxicities persist. [see Warnings and
`Precautions (5)].
`
`
`
`6
`
`
`
`

`
`
`
`Recommended dose modifications for toxicities in patients treated with TAXOTERE in
`combination with cisplatin and fluorouracil are shown in Table 1.
`
`
`Table 1 - Recommended Dose Modifications for Toxicities in Patients Treated with
`TAXOTERE in Combination with Cisplatin and Fluorouracil
`Toxicity
`Dosage adjustment
`Diarrhea grade 3
`First episode: reduce fluorouracil dose by 20%.
`Second episode: then reduce TAXOTERE dose by 20%.
`First episode: reduce TAXOTERE and fluorouracil doses by 20%.
`Second episode: discontinue treatment.
`First episode: reduce fluorouracil dose by 20%.
`Second episode: stop fluorouracil only, at all subsequent cycles.
`Third episode: reduce TAXOTERE dose by 20%.
`First episode: stop fluorouracil only, at all subsequent cycles.
`Second episode: reduce TAXOTERE dose by 20%.
`
`Diarrhea grade 4
`
`Stomatitis/mucositis
`grade 3
`
`Stomatitis/mucositis
`grade 4
`
`
`Liver dysfunction:
`In case of AST/ALT >2.5 to ≤5 x UNL and AP ≤2.5 x UNL, or AST/ALT >1.5 to ≤5 x UNL and
`AP >2.5 to ≤5 x UNL, TAXOTERE should be reduced by 20%.
`In case of AST/ALT >5 x UNL and/or AP >5 x UNL TAXOTERE should be stopped.
`
`The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided
`below:
`Cisplatin dose modifications and delays
`Peripheral neuropathy: A neurological examination should be performed before entry into the
`study, and then at least every 2 cycles and at the end of treatment. In the case of neurological
`signs or symptoms, more frequent examinations should be performed and the following dose
`modifications can be made according to NCIC-CTC grade:
`• Grade 2: Reduce cisplatin dose by 20%.
`• Grade 3: Discontinue treatment.
`Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.
`Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite
`adequate rehydration, CrCl should be determined before each subsequent cycle and the following
`dose reductions should be considered (see Table 2).
`For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information.
`
`
`1
`2
`3
`4
`5
`
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`
`
`
`7
`
`
`
`

`
`
`
`1
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`
`Table 2 – Dose Reductions for Evaluation of Creatinine Clearance
`Creatinine clearance result
`Cisplatin dose next cycle
` before next cycle
`CrCl ≥60 mL/min
`
`
`
`CrCl between 40 and 59 mL/min
`
`
`
`CrCl <40 mL/min
`
`Full dose of cisplatin was given. CrCl was to be repeated
`before each treatment cycle.
`Dose of cisplatin was reduced by 50% at subsequent
`cycle. If CrCl was >60 mL/min at end of cycle, full
`cisplatin dose was reinstituted at the next cycle.
`
`If no recovery was observed, then cisplatin was omitted
`from the next treatment cycle.
`Dose of cisplatin was omitted in that treatment cycle
`only.
`
`If CrCl was still <40 mL/min at the end of cycle,
`cisplatin was discontinued.
`
`If CrCl was >40 and <60 mL/min at end of cycle, a 50%
`cisplatin dose was given at the next cycle.
`
`If CrCl was >60 mL/min at end of cycle, full cisplatin
`dose was given at next cycle.
`
`
`
`CrCl = Creatinine clearance
`
`Fluorouracil dose modifications and treatment delays
`For diarrhea and stomatitis, see Table 1.
`In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until
`recovery. The fluorouracil dosage should be reduced by 20%.
`For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be
`delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade
`≤1 and then recommenced, if medically appropriate.
`For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing
`information.
`
`2.8 Administration Precautions
`TAXOTERE is a cytotoxic anticancer drug and, as with other potentially toxic compounds,
`caution should be exercised when handling and preparing TAXOTERE solutions. The use of
`gloves is recommended. Please refer to Handling and Disposal (16.3).
`If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for intravenous
`infusion should come into contact with the skin, immediately and thoroughly wash with soap and
`water. If TAXOTERE Injection Concentrate, initial diluted solution, or final dilution for
`intravenous infusion should come into contact with mucosa, immediately and thoroughly wash
`with water.
`Contact of the TAXOTERE concentrate with plasticized PVC equipment or devices used to
`prepare solutions for infusion is not recommended. In order to minimize patient exposure to the
`
`
`
`8
`
`
`
`

`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`
`
`
`plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or
`sets, the final TAXOTERE dilution for infusion should be stored in bottles (glass,
`polypropylene) or plastic bags (polypropylene, polyolefin) and administered
`through
`polyethylene-lined administration sets.
`TAXOTERE Injection Concentrate requires two dilutions prior to administration. Please follow
`the preparation instructions provided below. Note: Both the TAXOTERE Injection Concentrate
`and the diluent vials contain an overfill to compensate for liquid loss during preparation. This
`overfill ensures that after dilution with the entire contents of the accompanying diluent, there is
`an initial diluted solution containing 10 mg/mL docetaxel.
`The table below provides the fill range of the diluent, the approximate extractable volume of
`diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the
`initial diluted solution for TAXOTERE 20 mg and TAXOTERE 80 mg (see Table 3).
`
`
`Table 3 – Initial Dilution of TAXOTERE Injection Concentrate
`Product
`Diluent
`Approximate
`Concentration
`13% (w/w) ethanol
`extractable volume
`of the initial
` in water for
`of diluent when
`diluted
`injection
`entire contents are
`solution
`Fill Range
`withdrawn
`(mg/mL
`(mL)
`(mL)
`docetaxel)
`1.88 – 2.08 mL
`1.8 mL
`10 mg/mL
`
`Taxotere®
`20 mg/0.5
`mL
`Taxotere®
`80 mg/2 mL
`
`6.96 – 7.70 mL
`
`7.1 mL
`
`10 mg/mL
`
`
`2.9 Preparation and Administration
`A. Initial Diluted Solution
`1. TAXOTERE vials should be stored between 2 and 25°C (36 and 77°F). If the vials are stored
`under refrigeration, allow the appropriate number of vials of TAXOTERE Injection
`Concentrate and diluent (13% ethanol in water for injection) vials to stand at room
`temperature for approximately 5 minutes.
`2. Aseptically withdraw the entire contents of the appropriate diluent vial (approximately 1.8 mL
`for TAXOTERE 20 mg and approximately 7.1 mL for TAXOTERE 80 mg) into a syringe by
`partially inverting the vial, and transfer it to the appropriate vial of TAXOTERE Injection
`Concentrate. If the procedure is followed as described, an initial diluted solution of 10 mg
`docetaxel/mL will result.
`3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full
`mixture of the concentrate and diluent. Do not shake.
`4. The initial diluted TAXOTERE solution (10 mg docetaxel/mL) should be clear; however,
`there may be some foam on top of the solution due to the polysorbate 80. Allow the solution to
`stand for a few minutes to allow any foam to dissipate. It is not required that all foam dissipate
`prior to continuing the preparation process.
` The initial diluted solution may be used immediately or stored either in the refrigerator or at
`room temperature for a maximum of 8 hours.
`
`
`
`9
`
`
`
`

`
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`
`
`
`B. Final Dilution for Infusion
`1. Aseptically withdraw the required amount of initial diluted TAXOTERE solution (10 mg
`docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle of
`either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final
`concentration of 0.3 to 0.74 mg/mL.
`If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of the infusion
`vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded.
`2. Thoroughly mix the infusion by manual rotation.
`3. As with all parenteral products, TAXOTERE should be inspected visually for particulate
`matter or discoloration prior to administration whenever the solution and container permit. If
`the TAXOTERE initial diluted solution or final dilution for intravenous infusion is not clear or
`appears to have precipitation, these should be discarded.
`The final TAXOTERE dilution for infusion should be administered intravenously as a 1-hour
`infusion under ambient room temperature and lighting conditions.
`
`2.10 Stability
`TAXOTERE infusion solution, if stored between 2 and 25°C (36 and 77°F) is stable for 4 hours.
`Fully prepared TAXOTERE infusion solution (in either 0.9% Sodium Chloride solution or 5%
`Dextrose solution) should be used within 4 hours (including the 1 hour i.v. administration).
`
`3. DOSAGE FORMS AND STRENGTHS
`TAXOTERE 80 mg/2 mL
`
`
`TAXOTERE (docetaxel) Injection Concentrate 80 mg/2 mL: 80 mg docetaxel in 2 mL
`polysorbate 80 and Diluent for TAXOTERE 80 mg (13% (w/w) ethanol in water for injection).
`Both items are in a blister pack in one carton.
`TAXOTERE 20 mg/0.5 mL
`
`
`TAXOTERE (docetaxel) Injection Concentrate 20 mg/0.5 mL: 20 mg docetaxel in 0.5 mL
`polysorbate 80 and Diluent for TAXOTERE 20 mg (13% (w/w) ethanol in water for injection).
`Both items are in a blister pack in one carton.
`
`4. CONTRAINDICATIONS
`TAXOTERE is contraindicated in patients who have a history of severe hypersensitivity
`reactions to docetaxel or to other drugs formulated with polysorbate 80.
`TAXOTERE should not be used in patients with neutrophil counts of <1500 cells/mm3.
`
`5. WARNINGS AND PRECAUTIONS
`TAXOTERE should be administered under the supervision of a qualified physician experienced
`in the use of antineoplastic agents. Appropriate management of complications is possible only
`when adequate diagnostic and treatment facilities are readily available.
`
`5.1 Toxic Deaths
`• Breast Cancer
`TAXOTERE administered at 100 mg/m2 was associated with deaths considered possibly or
`probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both
`previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of
`
`
`
`10
`
`
`
`

`
`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43