6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label:

Bone Marrow Suppression [see Warnings and Precautions (5.1)]
Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4)]
Renal Failure [see Warnings and Precautions (5.5)]
Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6)]
Respiratory Disorders [see Warnings and Precautions (5.7)]
Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

TROPIC Trial (JEVTANA 25 mg/m2 compared to mitoxantrone)

The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared to mitoxantrone plus prednisone.

Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.

The most common (≥10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia.

The most common (≥5%) grade 3–4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.

Treatment discontinuations due to adverse reactions occurred in 18% of patients who received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients and 15% of mitoxantrone-treated patients.

Table 2: Adverse Reactions* and Hematologic Abnormalities in ≥5% of Patients in TROPIC
Adverse Reactions	JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily n=371		Mitoxantrone 12 mg/m2 every 3 weeks with prednisone 10 mg daily n=371
Adverse Reactions	Grade 1–4 %	Grade 3–4 %	Grade 1–4 %	Grade 3–4 %
* Graded using NCI CTCAE version 3. † Based on laboratory values, JEVTANA: n=369, mitoxantrone: n=370. ‡ Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. § Includes gastroesophageal reflux disease and reflux gastritis. ¶ Includes peripheral motor neuropathy and peripheral sensory neuropathy. # Includes urinary tract infection enterococcal and urinary tract infection fungal. Þ Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia, palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
Blood and Lymphatic System Disorders
Anemia†	98	11	82	5
Leukopenia†	96	69	93	42
Neutropenia†	94	82	87	58
Thrombocytopenia†	48	4	43	2
Febrile Neutropenia	7	7	1	1
Gastrointestinal Disorders
Diarrhea	47	6	11	<1
Nausea	34	2	23	<1
Vomiting	22	2	10	0
Constipation	20	1	15	<1
Abdominal Pain‡	17	2	6	0
Dyspepsia§	10	0	2	0
General Disorders and Administration Site Conditions
Fatigue	37	5	27	3
Asthenia	20	5	12	2
Pyrexia	12	1	6	<1
Peripheral Edema	9	<1	9	<1
Mucosal Inflammation	6	<1	3	<1
Pain	5	1	5	2
Renal and Urinary Tract Disorders
Hematuria	17	2	4	<1
Dysuria	7	0	1	0
Musculoskeletal and Connective Tissue Disorders
Back Pain	16	4	12	3
Arthralgia	11	1	8	1
Muscle Spasms	7	0	3	0
Metabolism and Nutrition Disorders
Anorexia	16	<1	11	<1
Dehydration	5	2	3	<1
Nervous System Disorders
Peripheral Neuropathy¶	13	<1	3	<1
Dysgeusia	11	0	4	0
Dizziness	8	0	6	<1
Headache	8	0	5	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	12	1	4	<1
Cough	11	0	6	0
Skin and Subcutaneous Tissue Disorders
Alopecia	10	0	5	0
Investigations
Weight Decreased	9	0	8	<1
Infections and Infestations
Urinary Tract Infection#	8	2	3	1
Cardiac Disorders
ArrhythmiaÞ	5	1	2	<1
Vascular Disorders
Hypotension	5	<1	2	<1

PROSELICA Trial (comparison of two doses of JEVTANA)

In a noninferiority, multicenter, randomized, open-label study (PROSELICA), 1175 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen, were treated with either JEVTANA 25 mg/m2 (n=595) or the 20 mg/m2 (n=580) dose.

Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m2 and 32 (5.4%) patients in the 25 mg/m2 arm. The most common fatal adverse reactions in JEVTANA-treated patients were related to infections, and these occurred more commonly on the 25 mg/m2 arm (n=15) than on the 20 mg/m2 arm (n=8). Other fatal adverse reactions in JEVTANA-treated patients included cerebral hemorrhage, respiratory failure, paralytic ileus, diarrhea, acute pulmonary edema, disseminated intravascular coagulation, renal failure, sudden death, cardiac arrest, ischemic stroke, diverticular perforation, and cardiorenal syndrome.

Grade 1–4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, thrombocytopenia, febrile neutropenia, decreased appetite, nausea, diarrhea, asthenia, and hematuria.

Grade 3–4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, and febrile neutropenia.

Treatment discontinuations due to adverse reactions occurred in 17% of patients in the 20 mg/m2 group and 20% of patients in the 25 mg/m2 group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m2, and 9 patients (2%) had a dose reduced from 15 to 12 mg/m2.

Table 3: Adverse Reactions* and Hematologic Abnormalities in ≥5% of Patients in PROSELICA
Adverse Reactions	JEVTANA 20 mg/m2 every 3 weeks with prednisone 10 mg daily n=580		JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily n=595
Adverse Reactions	Grade 1–4 %	Grade 3–4 %	Grade 1–4 %	Grade 3–4 %
* Grade from NCI CTCAE version 4.03. † Based on laboratory values, JEVTANA 20 mg/m2: n=577, JEVTANA 25 mg/m2: n=590. ‡ Includes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis. § Includes neutropenic sepsis.
Blood and Lymphatic System Disorders
Anemia†	99.8	10	99.7	14
Leukopenia†	80	29	95	60
Neutropenia†	67	42	89	73
Thrombocytopenia†	35	3	43	4
Febrile Neutropenia	2	2	9	9
Gastrointestinal Disorders
Diarrhea	31	1	40	4
Nausea	25	0.7	32	1
Constipation	18	0.3	18	0.7
Vomiting	15	1.2	18	1
Abdominal pain	6	0.5	9	1
Stomatitis	5	0	5	0.3
General Disorders and Administration Site Conditions
Fatigue	25	3	27	4
Asthenia	15	2	20	2
Edema peripheral	7	0.2	9	0.2
Pyrexia	5	0.2	6	0.2
Renal and Urinary Disorders
Hematuria	14	2	21	4
Dysuria	5	0.3	4	0
Metabolism and Nutrition Disorders
Decreased appetite	13	0.7	19	1
Musculoskeletal and Connective Tissue Disorders
Back pain	11	0.9	14	1
Bone pain	8	2	8	2
Arthralgia	8	0.5	7	0.8
Pain in extremity	5	0.2	7	0.5
Nervous System Disorders
Dysgeusia	7	0	11	0
Peripheral sensory neuropathy	7	0	11	0.7
Dizziness	4	0	5	0
Headache	5	0.2	4	0.2
Infections and Infestations
Urinary tract infection‡	7	2	11	2
Neutropenic infection§	3	2	7	6
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	5	0.9	8	0.7
Cough	6	0	6	0
Investigations
Weight decreased	4	0.2	7	0
Skin and Subcutaneous Tissue Disorders
Alopecia	3	0	6.1	0
Injury, Poisoning and Procedural Complications
Wrong technique in drug usage process	0.3	0	5	0

CARD Trial (JEVTANA 25 mg/m2 + primary prophylaxis with G-CSF)

The safety of JEVTANA 25 mg/m2 in combination with prednisone/prednisolone and primary prophylaxis G-CSF was evaluated in a randomized, open-label study (CARD) in patients with metastatic castration-resistant prostate cancer who progressed after receiving prior docetaxel-containing regimens and abiraterone acetate or enzalutamide [see Clinical Studies 14.3]. This study compared JEVTANA 25 mg/m2 in combination with prednisone/prednisolone and primary prophylaxis with G-CSF to either abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily. Among patients receiving JEVTANA, 35% remained on treatment at 6 months and 4.7% remained on treatment at 12 months.

Serious adverse reactions occurred in 39% of patients receiving JEVTANA. Serious adverse reactions in ≥3% of patients included neutropenia (6%), infections (4.8%), and diarrhea, fatigue, pneumonia, and spinal cord compression (3.2% each). Deaths due to causes other than disease progression were reported in 2.4% of JEVTANA treated patients. Fatal adverse reactions in JEVTANA-treated patients were septic shock, urinary tract infection (UTI), and aspiration (0.8% each).

Treatment discontinuations due to adverse drug reactions occurred in 20% of patients who received JEVTANA and 8% of patients who received abiraterone acetate plus prednisone/prednisolone or enzalutamide. The adverse reactions leading to treatment discontinuation in >1% of patients in JEVTANA arm were nervous system disorders, infections/infestations, and gastrointestinal disorders.

Dose interruptions (alone or in combination with dose reduction) due to an adverse reaction occurred in 31% of patients receiving JEVTANA. Dose reductions were reported in 18% of JEVTANA-treated patients. The most frequent adverse reactions leading to dose interruption of JEVTANA were fatigue (7%) and hypersensitivity reaction (3.2%); the most frequent adverse reaction leading to reduction of JEVTANA were neutropenia and peripheral neuropathy (3.9% each).

Table 4 summarizes the adverse reactions and laboratory hematologic abnormalities in patients in CARD.

The most common (≥10%) adverse reactions were fatigue, diarrhea, musculoskeletal pain, nausea, infections, peripheral neuropathy, hematuria, constipation, abdominal pain, decreased appetite, vomiting, dysgeusia, edema peripheral and lower urinary tract symptoms.

The most common (≥10%) hematologic abnormalities were anemia, lymphopenia, neutropenia and thrombocytopenia.

Table 4: Adverse Reactions* and Hematologic Abnormalities in ≥5% of Patients in CARD Trial
Adverse Reactions	JEVTANA 25 mg/m2 + prednisone/prednisolone + G-CSF		Abiraterone + prednisone/prednisolone or Enzalutamide
	(N=126)		(N=124)
	Grade 1–4 %	Grade 3–4 %	Grade 1–4 %	Grade 3–4 %
* Grade from NCI CTC version 4.0. † Based on laboratory values - % calculated using the number of patients with at least one event(n) over the number of patients assessed for each parameter during the on-treatment period. ‡ includes asthenia, fatigue, lethargy, malaise. § includes lymphoedema, edema peripheral, peripheral swelling. ¶ includes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis. # includes abdominal pain, abdominal pain lower, abdominal pain upper, flank pain, gastrointestinal pain. Þ includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain. ß includes femoral neck fracture, pathological fracture, rib fracture, spinal compression fracture, sternal fracture, thoracic vertebral fracture. à includes bacteremia, bacteriuria, cellulitis, device related sepsis, Enterobacter sepsis, erysipelas, furuncle, influenza, influenza like illness, localized infection, oral fungal infection, perineal cellulitis, pulmonary sepsis, pyelocaliectasis, pyelonephritis, pyelonephritis acute, respiratory tract infection, respiratory tract infection viral, sepsis, septic shock, subcutaneous abscess, upper respiratory tract infection, ureteritis, urinary tract infection, urinary tract infection bacterial, urosepsis, viral infection. è includes neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy. ð includes hematuria, cystitis hemorrhagic. ø include lower urinary tract symptoms, micturition urgency, nocturia, pollakiuria, urinary incontinence, urinary retention, dysuria. ý includes acute kidney injury, blood creatinine increased, renal failure, renal impairment. £ includes aortic valve incompetence, aortic valve stenosis, atrial fibrillation, atrial flutter, atrioventricular block complete, atrioventricular block second degree, bradycardia, sinus bradycardia, tachycardia, cardiac failure, acute coronary syndrome, angina pectoris. ¥ includes lower respiratory tract infection, lung infection, lung infiltration, pneumonia. Œ includes hypertension, hypertensive crisis.
Blood and Lymphatic System Disorders
Anemia†	99	8	95	4.8
Lymphopenia†	72	27	55	17
Neutropenia†	66	45	7	3.2
Thrombocytopenia†	41	3.2	16	1.6
General Disorders and Administration Site Conditions
Fatigue‡	53	4	36	2.4
Edema peripheral§	11	0.8	10	1.6
Pyrexia	6	0	7	0
Pain	6	0	6	0.8
Gastrointestinal Disorders
Diarrhea¶	40	4.8	6	0
Nausea	23	0	23	0.8
Constipation	15	0	11	0
Abdominal pain#	14	1.6	6	0.8
Vomiting	13	0	12	1.6
Stomatitis	8	0	1.6	0
Dyspepsia	4.8	0	2.4	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painÞ	27	1.6	40	6
Pain in extremity	4.8	0	11	2.4
Bone fractureß	3.2	1.6	8	2.4
Infections and Infestations
Infectionsà	19	4	14	6
Nervous System Disorders
Peripheral neuropathyè	18	1.6	4.8	0
Dysgeusia	11	0	4	0
Polyneuropathy	6	1.6	0	0
Dizziness	0.8	0	4.8	0
Renal and Urinary Disorders
Hematuriað	16	0.8	6	1.6
Lower urinary tract symptomsø	10	0	9	0
Acute kidney injuryý	5	2.4	10	4
Metabolism and Nutrition Disorders
Decreased appetite	14	0.8	15	2.4
Hypokalemia	3.2	0	6	0
Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps)
Cancer pain	8	1.6	9	2.4
Cardiac disorders£	6	0.8	6	3.2
Respiratory, Thoracic and Mediastinal Disorders
Pneumonia¥	6	1.6	3.2	0.8
Dyspnea	6	0	2.4	0
Skin and Subcutaneous Tissue Disorders
Alopecia	6	0	0	0
Injury, Poisoning and Procedural Complications
Fall	4.8	0	0	0
Vascular Disorders
HypertensionŒ	4	2.4	8	2.4
Investigations
Weight decreased	4	0	6	0
Psychiatric Disorders
Insomnia	3.2	0	4.8	0

Clinically relevant ≥ Grade 3 adverse reactions in <5% of patients who received JEVTANA in combination with prednisone and primary prophylaxis G-CSF: febrile neutropenia (3.2%), pulmonary embolism (1.6%), and neutropenic infection (0.8%).

Hematuria

In study TROPIC, adverse reactions of hematuria, including those requiring medical intervention, were more common in JEVTANA-treated patients. The incidence of grade ≥2 hematuria was 6% in JEVTANA-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the JEVTANA arm.

In study PROSELICA, hematuria of all grades was observed in 18% of patients overall.

In CARD, hematuria of all grades was observed in 16% of patients receiving JEVTANA.

Hepatic Laboratory Abnormalities

The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤1%.

6.2 Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Gastrointestinal: Gastritis, intestinal obstruction.

Respiratory: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome.

Renal and urinary disorders: Radiation recall hemorrhagic cystitis.