Docivyx Drug Information

Clinical Trials Experience Breast Cancer Monotherapy with

DOCIVYX for locally advanced or metastatic breast cancer after failure of prior chemotherapy DOCIVYX 100 mg/m 2 : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received DOCIVYX administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to DOCIVYX. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving DOCIVYX for the treatment of breast cancer and in patients with other tumor types. (See Table 3.) Table 3: Summary of Adverse Reactions in Patients Receiving DOCIVYX at 100 mg/m 2 * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ‡ Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization Adverse Reaction All Tumor Types Normal LFTs* n=2045 % All Tumor Types Elevated LFTs † n=61 % Breast Cancer Normal LFTs * n=965 % Hematologic Neutropenia <2000 cells/mm3 96 96 99 <500 cells/mm3 75 88 86 Leukopenia <4000 cells/mm3 96 98 99 <1000 cells/mm3 32 47 44 Thrombocytopenia <100,000 cells/mm3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia‡ 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any Severe 22 6 33 16 22 6 Fever in Absence of Infection Any Severe 31 2 41 8 35 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 7 33 7 Neurosensory Any Severe 49 4 34 0 58 6 Cutaneous Any Severe 48 5 54 10 47 5 Nail Changes Any Severe 31 3 23 5 41 4 Gastrointestinal Nausea Vomiting Diarrhea Severe 39 22 39 5 38 23 33 5 42 23 43 6 Stomatitis Any Severe 42 6 49 13 52 7 Alopecia 76 62 74 Asthenia Any Severe 62 13 53 25 66 15 Myalgia Any Severe 19 2 16 2 21 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic reactions Reversible marrow suppression was the major dose-limiting toxicity of DOCIVYX. The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm 3 ) was 7 days.

Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm 3 with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids. Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids.

Thrombocytopenia (<100,000 cells/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity reactions Severe hypersensitivity reactions have been reported . Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. Fluid retention Fluid retention can occur with the use of DOCIVYX. Cutaneous reactions Severe skin toxicity is discussed elsewhere in the label.

Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after DOCIVYX infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.

Neurologic reactions Neurologic reactions are discussed elsewhere in the label. Gastrointestinal reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3%–5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients.

The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular reactions Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment.

Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred. Seven of 86 (8.1%) of metastatic breast cancer patients receiving DOCIVYX 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal. Infusion site reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.

Hepatic reactions In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on DOCIVYX, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline.

Whether these changes were related to the drug or underlying disease has not been established. Hematologic and other toxicity: Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given DOCIVYX at 100 mg/m 2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given DOCIVYX at 60 mg/m 2 who had normal LFTs (see Tables 4 and 5). Table 4: Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at DOCIVYX 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ‡ Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. § Febrile Neutropenia: For 100 mg/m 2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/m 2, ANC grade 3/4 and fever >38.1°C Adverse Reaction DOCIVYX 100 mg/m 2 DOCIVYX 60 mg/m 2 Norm al L FTs * n=730 % Elevate d L FTs † n=18 % Normal LFTs * n=174 % Neutropenia Any <2000 cells/mm 3 98 100 95 Grade 4 <500 cells/mm 3 84 94 75 T hrombocytopenia Any <100,000 cells/mm 3 11 44 14 Grade 4 <20,000 cells/mm3 1 17 1 Anemia <11 g/dL 95 94 65 Infection ‡ Any Grade 3 and 4 23 7 39 33 1 0 Febrile Neutropenia § By Patient By Course 12 2 33 9 0 0 Septic Death 2 6 1 Non-Septic Death 1 11 0 Table 5: Non-hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at DOCIVYX 100 mg/m 2 with Normal or Elevated Liver Function Tests or 60 mg/m 2 with Normal Liver Function Tests * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ‡ Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m 2 dose NA = not available Adverse Reaction DOCIVYX 100 mg/m 2 DOCIVYX 60 mg/m 2 Normal LFTs * n=730 % Elevat ed L FTs † n=18 % Normal LFTs * n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any Severe 13 1 6 0 1 0 Fluid Retention ‡ Regardless of Premedication Any Severe 56 8 61 17 13 0 Neurosensory Any Severe 57 6 50 0 20 0 Myalgia 23 33 3 Cutaneous Any Severe 45 5 61 17 31 0 Asthenia Any Severe 65 17 44 22 66 0 Diarrhea Any Severe 42 6 28 11 NA Stomatitis Any Severe 53 8 67 39 19 1 In the three-arm monotherapy trial, TAX313, which compared DOCIVYX 60 mg/m 2, 75 mg/m 2 and 100 mg/m 2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with DOCIVYX 60 mg/m 2 compared to 55.3% and 65.9% treated with 75 mg/m 2 and 100 mg/m 2, respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2 versus 6.9% and 16.5% for patients treated at 75 and 100 mg/m 2, respectively.

Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 2 compared to 5.3% and 1.6% for patients treated at 75 mg/m 2 and 100 mg/m 2, respectively. The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2, 75 mg/m 2, and 100 mg/m 2, respectively), thrombocytopenia (7%, 11% and 12%, respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14%, respectively), treatment-related grade 3/4 infection (2%, 3%, and 7%, respectively) and anemia (87%, 94%, and 97%, respectively). Combination therapy with DOCIVYX in the adjuvant treatment of breast cancer The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with DOCIVYX 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 6). Table 6: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving DOCIVYX in Combination with Doxorubicin and Cyclophosphamide (TAX316) * COSTART term and grading system for events related to treatment. DOCIVYX 75 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphami de 50 0 mg/m 2 (TAC) n=744 % Fluorouracil 500 mg/m 2 + Doxorubicin 50 mg/m 2 + Cyclophosphamide 500 mg/m 2 (FAC) n=736 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 92 4 72 2 Neutropenia 71 66 82 49 Fever in absence of infection 47 1 17 0 Infection 39 4 36 2 Thrombocytopenia 39 2 28 1 Febrile neutropenia 25 N/A 3 N/A Neutropenic infection 12 N/A 6 N/A Hypersensitivity reactions 13 1 4 0 Lymphedema 4 0 1 0 Fluid Retention * Peripheral edema Weight gain 35 27 13 1 0 0 15 7 9 0 0 0 Neuropathy sensory 26 0 10 0 Neuro-cortical 5 1 6 1 Neuropathy motor 4 0 2 0 Neuro-cerebellar 2 0 2 0 Syncope 2 1 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 1 18 0 Nail disorders 19 0 14 0 Nausea 81 5 88 10 Stomatitis 69 7 53 2 Vomiting 45 4 59 7 Diarrhea 35 4 28 2 Constipation 34 1 32 1 Taste perversion 28 1 15 0 Anorexia 22 2 18 1 Abdominal Pain 11 1 5 0 Amenorrhea 62 N/A 52 N/A Cough 14 0 10 0 Cardiac dysrhythmias 8 0 6 0 Vasodilatation 27 1 21 1 Hypotension 2 0 1 0 Phlebitis 1 0 1 0 Asthenia 81 11 71 6 Myalgia 27 1 10 0 Arthralgia 19 1 9 0 Lacrimation disorder 11 0 7 0 Conjunctivitis 5 0 7 0 Of the 744 patients treated with TAC, 36.3% experienced severe treatment-emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm.

Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. Fever and infection During the treatment period, fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients.

Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC and FAC-treated patients, respectively. Infection was seen in 39.4% of TAC- treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients, respectively.

There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.

Cardiovascular reactions More cardiovascular reactions were reported in the TAC arm versus the FAC arm during the treatment period: arrhythmias, all grades (6.2% vs 4.9%), and hypotension, all grades (1.9% vs 0.8%). Twenty-six patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two patients in TAC arm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms.

Adverse reactions during the follow-up period (median follow-up time of 8 years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years). Nervous system disorders In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm. 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 (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%). Reproductive system and breast disorders In study TAX316, amenorrhea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%). General disorders and administration site conditions In study TAX316, peripheral edema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral edema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%). In study TAX316, lymphedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%). In study TAX316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%). Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients.

One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0.3%) patients who received TAC and in 1 of 736 (0.1%) patients who received FAC. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. Lung Cancer Monotherapy with DOCIVYX for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy DOCIVYX 75 mg/m 2 : Treatment-emergent adverse drug reactions are shown in Table 7. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving DOCIVYX as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy* * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization ¶ COSTART term and grading system‡ Not Applicable § Not Done Adverse Reaction DOCIVYX 75 mg/m 2 n=176 % Best Supportive Care n=49 % Vinorelbine/ Ifosfamide n=119 % Neutropenia Any Grade 3/4 84 65 14 12 83 57 Leukopenia Any Grade 3/4 84 49 6 0 89 43 Thrombocytopenia Any Grade 3/4 8 3 0 0 8 2 Anemia Any Grade 3/4 91 9 55 12 91 14 Febrile Neutropenia † 6 NA‡ 1 Infection Any 34 29 30 Grade 3/4 10 6 9 Treatment Related Mortality 3 NA‡ 3 Hypersensitivity Reactions Any Grade 3/4 6 3 0 0 1 0 Fluid Retention Any Severe 34 3 ND§ 23 3 Neurosensory Any Grade 3/4 23 2 14 6 29 5 Neuromotor Any Grade 3/4 16 5 8 6 10 3 Skin Any Grade 3/4 20 1 6 2 17 1 Gastrointestinal Nausea Any Grade 3/4 Vomiting Any Grade 3/4 Diarrhea Any Grade 3/4 34 5 22 3 23 3 31 4 27 2 6 0 31 8 22 6 12 4 Alopecia 56 35 50 Asthenia Any Severe¶ 53 18 57 39 54 23 Stomatitis Any Grade 3/4 26 2 6 0 8 1 Pulmonary Any Grade 3/4 41 21 49 29 45 19 Nail Disorder Any Severe¶ 11 1 0 0 2 0 Myalgia Any Severe¶ 6 0 0 0 3 0 Arthralgia Any Severe¶ 3 0 2 0 2 1 Taste Perversion Any Severe¶ 6 1 0 0 0 0 Combination therapy with DOCIVYX in chemotherapy-naïve advanced unresectable or metastatic NSCLC Table 8 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted. Table 8: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naive Advanced Non-small Cell Lung Cancer Patients Receiving DOCIVYX in Combination with Cisplatin * Replaces NCI term "Allergy" † COSTART term and grading system Adverse Reaction DOCIVYX 75 mg/m 2 + Cisplatin 75 mg/m 2 n=406 % Vinorelbine 25 mg/m 2 + Cisplatin 100 mg/m 2 n=396 % Neutropenia Any Grade 3/4 91 74 90 78 Febrile Neutropenia 5 5 Thrombocytopenia Any Grade 3/4 15 3 15 4 Anemia Any 89 94 Grade 3/4 7 25 Infection Any 35 37 Grade 3/4 8 8 Fever in absence of infection Any 33 29 Grade 3/4 <1 1 Hypersensitivity Reaction * Any 12 4 Grade 3/4 3 <1 Fluid Retention † Any 54 42 All severe or life- 2 23 2 34 <1 15 <1 2 22 2 18 <1 9 <1 threatening events Pleural effusion Any All severe or life- threatening events Peripheral edema Any All severe or life- threatening events Weight gain Any All severe or life- threatening events Neurosensory Any 47 42 Grade 3/4 4 4 Neuromotor Any 19 17 Grade 3/4 3 6 Skin Any 16 14 Grade 3/4 <1 1 Nausea Any 72 76 Grade 3/4 10 17 Vomiting Any 55 61 Grade 3/4 8 16 Diarrhea Any 47 25 Grade 3/4 7 3 Anorexia † Any 42 40 All severe or life- threatening events 5 5 Stomatitis Any 24 21 Grade 3/4 2 1 Alopecia Any 75 42 Grade 3 <1 0 Asthenia † Any 74 75 All severe or life- threatening events 12 14 Nail Disorder † Any 14 <1 All severe events <1 0 Myalgia † Any 18 12 All severe events <1 <1 Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm.

Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus DOCIVYX+carboplatin (which did not demonstrate a superior survival associated with DOCIVYX ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the DOCIVYX+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm. Prostate Cancer Combination therapy with DOCIVYX in patients with CRPC The following data are based on the experience of 332 patients, who were treated with DOCIVYX 75 mg/m 2 every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 9). Table 9: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer Who Received DOCIVYX in Combination with Prednisone (TAX327) * Related to treatment DOCIVYX 75 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=332 % Mitoxantrone 12 mg/m 2 every 3 weeks + prednisone 5 mg twice daily n=335 % Adverse Reaction Any Grade 3/4 Any Grade 3/4 Anemia 67 5 58 2 Neutropenia 41 32 48 22 Thrombocytopenia 3 1 8 1 Febrile neutropenia 3 N/A 2 N/A Infection 32 6 20 4 Epistaxis 6 0 2 0 Allergic Reactions 8 1 1 0 Fluid Retention * Weight Gain* Peripheral Edema * 24 8 18 1 0 0 5 3 2 0 0 0 Neuropathy Sensory 30 2 7 0 Neuropathy Motor 7 2 3 1 Rash/Desquamation 6 0 3 1 Alopecia 65 N/A 13 N/A Nail Changes 30 0 8 0 Nausea 41 3 36 2 Diarrhea 32 2 10 1 Stomatitis/Pharyngitis 20 1 8 0 Taste Disturbance 18 0 7 0 Vomiting 17 2 14 2 Anorexia 17 1 14 0 Cough 12 0 8 0 Dyspnea 15 3 9 1 Cardiac left ventricular function 10 0 22 1 Fatigue 53 5 35 5 Myalgia 15 0 13 1 Tearing 10 1 2 0 Arthralgia 8 1 5 1 Gastric Cancer Combination therapy with DOCIVYX in gastric adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with DOCIVYX 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 10). Table 10: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study Clinically important treatment-emergent adverse reactions were determined based upon frequency, severity, and clinical impact of the adverse reaction. * Related to treatment DOCIVYX 75 mg/m 2 + cisplatin 75 mg/m 2 + fluorouracil 750 mg/m 2 n=221 Cisplatin 100 mg/m 2 + fluorouracil 1000 mg/m 2 n=224 Adverse Reaction Any % Grade 3/4 % Any % Grade 3/4 % Anemia 97 18 93 26 Neutropenia 96 82 83 57 Fever in the absence of infection 36 2 23 1 Thrombocytopenia 26 8 39 14 Infection 29 16 23 10 Febrile neutropenia 16 N/A 5 N/A Neutropenic infection 16 N/A 10 N/A Allergic reactions 10 2 6 0 Fluid retention * 15 0 4 0 Edema * 13 0 3 0 Lethargy 63 21 58 18 Neurosensory 38 8 25 3 Neuromotor 9 3 8 3 Dizziness 16 5 8 2 Alopecia 67 5 41 1 Rash/itch 12 1 9 0 Nail changes 8 0 0 0 Skin desquamation 2 0 0 0 Nausea 73 16 76 19 Vomiting 67 15 73 19 Anorexia 51 13 54 12 Stomatitis 59 21 61 27 Diarrhea 78 20 50 8 Constipation 25 2 34 3 Esophagitis/dysphagia/odynophagia 16 2 14 5 Gastrointestinal pain/cramping 11 2 7 3 Cardiac dysrhythmias 5 2 2 1 Myocardial ischemia 1 0 3 2 Tearing 8 0 2 0 Altered hearing 6 0 13 2 Head and Neck Cancer Combination therapy with DOCIVYX in head and neck cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with DOCIVYX 75 mg/m 2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6. Table 11: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with DOCIVYX in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy (TAX324) Clinically important treatment-emergent adverse reactions based upon frequency, severity, and clinical impact. * Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization. † Related to treatment. ‡ Includes superficial and deep vein thrombosis and pulmonary embolism TAX323 (n=355) TAX324 (n=494) DOCIVYX arm (n=174) Comparator arm (n=181) DOCIVYX arm (n=251) Comparator arm (n=243) Adverse Reaction (by Body System) Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Any % Grade 3/4 % Neutropenia 93 76 87 53 95 84 84 56 Anemia 89 9 88 14 90 12 86 10 Thrombocytopenia 24 5 47 18 28 4 31 11 Infection 27 9 26 8 23 6 28 5 Febrile neutropenia* 5 N/A 2 N/A 12 N/A 7 N/A Neutropenic infection 14 N/A 8 N/A 12 N/A 8 N/A Cancer pain 21 5 16 3 17 9 20 11 Lethargy 41 3 38 3 61 5 56 10 Fever in the absence of infection 32 1 37 0 30 4 28 3 Myalgia 10 1 7 0 7 0 7 2 Weight loss 21 1 27 1 14 2 14 2 Allergy 6 0 3 0 2 0 0 0 Fluid retention† Edema only Weight gain only 20 13 6 0 0 0 14 7 6 1 0 0 13 12 0 1 1 0 7 6 1 2 1 0 Dizziness 2 0 5 1 16 4 15 2 Neurosensory 18 1 11 1 14 1 14 0 Altered hearing 6 0 10 3 13 1 19 3 Neuromotor 2 1 4 1 9 0 10 2 Alopecia 81 11 43 0 68 4 44 1 Rash/itch 12 0 6 0 20 0 16 1 Dry skin 6 0 2 0 5 0 3 0 Desquamation 4 1 6 0 2 0 5 0 Nausea 47 1 51 7 77 14 80 14 Stomatitis 43 4 47 11 66 21 68 27 Vomiting 26 1 39 5 56 8 63 10 Diarrhea 33 3 24 4 48 7 40 3 Constipation 17 1 16 1 27 1 38 1 Anorexia 16 1 25 3 40 12 34 12 Esophagitis/dysphagia/Odynophagia 13 1 18 3 25 13 26 10 Taste, sense of smell altered 10 0 5 0 20 0 17 1 Gastrointestinal pain/cramping 8 1 9 1 15 5 10 2 Heartburn 6 0 6 0 13 2 13 1 Gastrointestinal bleeding 4 2 0 0 5 1 2 1 Cardiac dysrhythmia 2 2 2 1 6 3 5 3 Venous‡ 3 2 6 2 4 2 5 4 Ischemia myocardial 2 2 1 0 2 1 1 1 Tearing 2 0 1 0 2 0 2 0 Conjunctivitis 1 0 1 0 1 0 0.4 0

Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.

Cardiovascular : atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia, including ventricular tachycardia, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome. Cutaneous : cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia.

Gastrointestinal : enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence of gastrointestinal events. Hearing : ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs.

Hematologic : bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure. Hepatic : hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders. Hypersensitivity : anaphylactic shock with fatal outcome in patients who received premedication.

Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel. Metabolism and nutrition disorders : electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.

Neurologic : confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug. Ophthalmologic : conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions.

Respiratory : dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant radiotherapy. Renal : renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs.

Second primary malignancies : second primary malignancies, including AML, MDS, NHL, and renal cancer. Musculoskeletal disorder : myositis.

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of DOCIVYX and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided.

In patients receiving treatment with DOCIVYX, close monitoring for toxicity and a DOCIVYX dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided. Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism.

Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, DOCIVYX can cause fetal harm when administered to a pregnant woman . Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DOCIVYX contains alcohol which can interfere with neurobehavioral development . In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations DOCIVYX contains alcohol . Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Data Animal data Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.

L/h/m 2. Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF)

at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m 2, corresponding to an AUC of 4.20±2.57 μg·h/mL. In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults .

is contraindicated in patients with: neutrophil counts of <1500 cells/mm3. a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred . Hypersensitivity to docetaxel Neutrophil counts of <1500 cells/mm 3

There is no known antidote for DOCIVYX overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: 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. In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 as 1-hour infusions.

Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident. In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 on a mg/m 2 basis); neurotoxicity associated with paralysis, non- extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.