Boruzu

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

describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m²) administered intravenously in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective randomized study.

The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.

	Bortezomib, Melphalan and Prednisone (n=340)			Melphalan and Prednisone (n=337)
Body System	Total	Toxicity Grade, n (%)		Total	Toxicity Grade, n (%)
Adverse Reaction	n (%)	3	≥ 4	n (%)	3	≥ 4
Blood and Lymphatic System Disorders
Thrombocytopenia	164 (48)	60 (18)	57 (17)	140 (42)	48 (14)	39 (12)
Neutropenia	160 (47)	101 (30)	33 (10)	143 (42)	77 (23)	42 (12)
Anemia	109 (32)	41 (12)	4 (1)	156 (46)	61 (18)	18 (5)
Leukopenia	108 (32)	64 (19)	8 (2)	93 (28)	53 (16)	11 (3)
Lymphopenia	78 (23)	46 (14)	17 (5)	51 (15)	26 (8)	7 (2)
Gastrointestinal Disorders
Nausea	134 (39)	10 (3)	0	70 (21)	1 (< 1)	0
Diarrhea	119 (35)	19 (6)	2 (1)	20 (6)	1 (< 1)	0
Vomiting	87 (26)	13 (4)	0	41 (12)	2 (1)	0
Constipation	77 (23)	2 (1)	0	14 (4)	0	0
Abdominal pain upper	34 (10)	1 (< 1)	0	20 (6)	0	0
Nervous System Disorders
Peripheral neuropathy*	156 (46)	42 (12)	2 (1)	4 (1)	0	0
Neuralgia	117 (34)	27 (8)	2 (1)	1 (< 1)	0	0
Paresthesia	42 (12)	6 (2)	0	4 (1)	0	0
General Disorders and Administration Site Conditions
Fatigue	85 (25)	19 (6)	2 (1)	48 (14)	4 (1)	0
Asthenia	54 (16)	18 (5)	0	23 (7)	3 (1)	0
Pyrexia	53 (16)	4 (1)	0	19 (6)	1 (< 1)	1 (< 1)
Infections and Infestations
Herpes Zoster	39 (11)	11 (3)	0	9 (3)	4 (1)	0
Metabolism and Nutrition Disorders
Anorexia	64 (19)	6 (2)	0	19 (6)	0	0
Skin and Subcutaneous Tissue Disorders
Rash	38 (11)	2 (1)	0	7 (2)	0	0
Psychiatric Disorders
Insomnia	35 (10)	1 (< 1)	0	21 (6)	0	0
*Represents High Level Term Peripheral Neuropathies NEC

The safety data described below and in

reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m²twice weekly for two out of three weeks (21 day cycle). After eight, 21 day cycles patients continued therapy for three, 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian.

Among the 331 bortezomib-treated patients, the most commonly reported (> 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.

Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).

A total of 145 patients, including 84 (25%) of 331 patients in the bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib-treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).

Four deaths were considered to be bortezomib-related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and one case of sudden death at home.

The most common adverse reactions from the relapsed multiple myeloma study are shown in

. All adverse reactions with incidence ≥ 10% in the bortezomib arm are included.

≥

Adverse Reactions	Bortezomib (N=331)			Dexamethasone (N=332)
	All	Grade 3	Grade 4	All	Grade 3	Grade 4
Any Adverse Reactions	324 (98)	193 (58)	28 (8)	297 (89)	110 (33)	29 (9)
Nausea	172 (52)	8 (2)	0	31 (9)	0	0
Diarrhea NOS	171 (52)	22 (7)	0	36 (11)	2 (< 1)	0
Fatigue	130 (39)	15 (5)	0	82 (25)	8 (2)	0
Peripheral neuropathies*	115 (35)	23 (7)	2 (< 1)	14 (4)	0	1 (< 1)
Thrombocytopenia	109 (33)	80 (24)	12 (4)	11 (3)	5 (2)	1 (< 1)
Constipation	99 (30)	6 (2)	0	27 (8)	1 (< 1)	0
Vomiting NOS	96 (29)	8 (2)	0	10 (3)	1 (< 1)	0
Anorexia	68 (21)	8 (2)	0	8 (2)	1 (< 1)	0
Pyrexia	66 (20)	2 (< 1)	0	21 (6)	3 (< 1)	1 (< 1)
Paresthesia	64 (19)	5 (2)	0	24 (7)	0	0
Anemia NOS	63 (19)	20 (6)	1 (< 1)	21 (6)	8 (2)	0
Headache NOS	62 (19)	3 (< 1)	0	23 (7)	1 (< 1)	0
Neutropenia	58 (18)	37 (11)	8 (2)	1 (< 1)	1 (< 1)	0
Rash NOS	43 (13)	3 (< 1)	0	7 (2)	0	0
Appetite decreased NOS	36 (11)	0	0	12 (4)	0	0
Dyspnea NOS	35 (11)	11 (3)	1 (< 1)	37 (11)	7 (2)	1 (< 1)
Abdominal pain NOS	35 (11)	5 (2)	0	7 (2)	0	0
Weakness	34 (10)	10 (3)	0	28 (8)	8 (2)	0
*Represents High Level Term Peripheral Neuropathies NEC

In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study

.

The safety and efficacy of bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of bortezomib subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in

reflect exposure to either bortezomib subcutaneous (N=147) or bortezomib intravenous (N=74).

	Subcutaneous			Intravenous
	(N=147)			(N=74)
Body System	Total	Toxicity Grade, n (%)		Total	Toxicity Grade, n (%)
Adverse Reaction	n (%)	3	≥ 4	n (%)	3	≥ 4
Blood and Lymphatic System Disorders
Anemia	28 (19)	8 (5)	0	17 (23)	3 (4)	0
Leukopenia	26 (18)	8 (5)	0	15 (20)	4 (5)	1 (1)
Neutropenia	34 (23)	15 (10)	4 (3)	20 (27)	10 (14)	3 (4)
Thrombocytopenia	44 (30)	7 (5)	5 (3)	25 (34)	7 (9)	5 (7)
Gastrointestinal Disorders
Diarrhea	28 (19)	1 (1)	0	21 (28)	3 (4)	0
Nausea	24 (16)	0	0	10 (14)	0	0
Vomiting	13 (9)	3 (2)	0	8 (11)	0	0
General Disorders and Administration Site Conditions
Asthenia	10 (7)	1 (1)	0	12 (16)	4 (5)	0
Fatigue	11 (7)	3 (2)	0	11 (15)	3 (4)	0
Pyrexia	18 (12)	0	0	6 (8)	0	0
Nervous System Disorders
Neuralgia	34 (23)	5 (3)	0	17 (23)	7 (9)	0
Peripheral neuropathies*	55 (37)	8 (5)	1 (1)	37 (50)	10 (14)	1 (1)
Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least one dose of study medication *Represents High Level Term Peripheral Neuropathies NEC

In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous vs 9% intravenous), peripheral neuropathies (6% subcutaneous vs 15% intravenous), neutropenia (13% subcutaneous vs 18% intravenous), and thrombocytopenia (8% subcutaneous vs 16% intravenous).

A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only two (1%) patients were reported as having severe reactions, one case of pruritus and one case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of six days.

Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).

The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group

Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

Two patients (1%) in the subcutaneous treatment group and one (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.

describes safety data from 240 patients with previously untreated mantle cell lymphoma who received bortezomib (1.3 mg/m²) administered intravenously in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (BR-CAP) in a prospective randomized study.

Infections were reported for 31% of patients in the BR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (BR-CAP 8% vs R-CHOP 5%).

	BR-CAP (n=240)			R-CHOP (n=242)
Body System Adverse Reactions	All n (%)	Toxicity Grade 3 n (%)	Toxicity Grade ≥ 4n (%)	All n (%)	Toxicity Grade 3n (%)	Toxicity Grade ≥ 4n (%)
Blood and Lymphatic System Disorders
Neutropenia	209 (87)	32 (13)	168 (70)	172 (71)	31 (13)	125 (52)
Leukopenia	116 (48)	34 (14)	69 (29)	87 (36)	39 (16)	27 (11)
Anemia	106 (44)	27 (11)	4 (2)	71 (29)	23 (10)	4 (2)
Thrombocytopenia	172 (72)	59 (25)	76 (32)	42 (17)	9 (4)	3 (1)
Febrile neutropenia	41 (17)	24 (10)	12 (5)	33 (14)	17 (7)	15 (6)
Lymphopenia	68 (28)	25 (10)	36 (15)	28 (12)	15 (6)	2 (1)
Nervous System Disorders
Peripheral neuropathy*	71 (30)	17 (7)	1 (< 1)	65 (27)	10 (4)	0
Hypoesthesia	14 (6)	3 (1)	0	13 (5)	0	0
Paresthesia	14 (6)	2 (1)	0	11 (5)	0	0
Neuralgia	25 (10)	9 (4)	0	1 (< 1)	0	0
General Disorders and Administration Site Conditions
Fatigue	43 (18)	11 (5)	1 (< 1)	38 (16)	5 (2)	0
Pyrexia	48 (20)	7 (3)	0	23 (10)	5 (2)	0
Asthenia	29 (12)	4 (2)	1 (< 1)	18 (7)	1 (< 1)	0
Edema peripheral	16 (7)	1 (< 1)	0	13 (5)	0	0
Gastrointestinal Disorders
Nausea	54 (23)	1 (< 1)	0	28 (12)	0	0
Constipation	42 (18)	1 (< 1)	0	22 (9)	2 (1)	0
Stomatitis	20 (8)	2 (1)	0	19 (8)	0	1 (< 1)
Diarrhea	59 (25)	11 (5)	0	11 (5)	3 (1)	1 (< 1)
Vomiting	24 (10)	1 (< 1)	0	8 (3)	0	0
Abdominal distension	13 (5)	0	0	4 (2)	0	0
Infections and Infestations
Pneumonia	20 (8)	8 (3)	5 (2)	11 (5)	5 (2)	3 (1)
Skin and Subcutaneous Tissue Disorders
Alopecia	31 (13)	1 (< 1)	1 (< 1)	33 (14)	4 (2)	0
Metabolism and Nutrition Disorders
Hyperglycemia	10 (4)	1 (< 1)	0	17 (7)	10 (4)	0
Decreased appetite	36 (15)	2 (1)	0	15 (6)	1 (< 1)	0
Vascular Disorders
Hypertension	15 (6)	1 (< 1)	0	3 (1)	0	0
Psychiatric Disorders
Insomnia	16 (7)	1 (< 1)	0	8 (3)	0	0
Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; BR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. *Represents High Level Term Peripheral Neuropathies NEC

The incidence of herpes zoster reactivation was 4.6% in the BR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment.

The incidences of Grade ≥ 3 bleeding events were similar between the two arms (four patients in the BR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the BR-CAP arm.

Adverse reactions leading to discontinuation occurred in 8% of patients in BR-CAP group and 6% of patients in R-CHOP group. In the BR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (< 1%; two patients).

Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m²/dose twice weekly for two weeks followed by a ten day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 open-label study of bortezomib subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

In the Phase 2 relapsed multiple myeloma clinical trials of bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage.

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each).

Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).

In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.

The most common adverse reactions are shown in

. All adverse reactions occurring at ≥ 10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient’s underlying disease. Please see the discussion of specific adverse reactions that follows.

	All Patients (N=1163)		Multiple Myeloma (N=1008)		Mantle Cell Lymphoma (N=155)
Adverse Reactions	All	≥ Grade 3	All	≥ Grade 3	All	≥ Grade 3
Nausea	567 (49)	36 (3)	511 (51)	32 (3)	56 (36)	4 (3)
Diarrhea NOS	530 (46)	83 (7)	470 (47)	72 (7)	60 (39)	11 (7)
Fatigue	477 (41)	86 (7)	396 (39)	71 (7)	81 (52)	15 (10)
Peripheral neuropathies*	443 (38)	129 (11)	359 (36)	110 (11)	84 (54)	19 (12)
Thrombocytopenia	369 (32)	295 (25)	344 (34)	283 (28)	25 (16)	12 (8)
Vomiting NOS	321 (28)	44 (4)	286 (28)	40 (4)	35 (23)	4 (3)
Constipation	296 (25)	17 (1)	244 (24)	14 (1)	52 (34)	3 (2)
Pyrexia	249 (21)	16 (1)	233 (23)	15 (1)	16 (10)	1 (< 1)
Anorexia	227 (20)	19 (2)	205 (20)	16 (2)	22 (14)	3 (2)
Anemia NOS	209 (18)	65 (6)	190 (19)	63 (6)	19 (12)	2 (1)
Headache NOS	175 (15)	8 (< 1)	160 (16)	8 (< 1)	15 (10)	0
Neutropenia	172 (15)	121 (10)	164 (16)	117 (12)	8 (5)	4 (3)
Rash NOS	156 (13)	8 (< 1)	120 (12)	4 (< 1)	36 (23)	4 (3)
Paresthesia	147 (13)	9 (< 1)	136 (13)	8 (< 1)	11 (7)	1 (< 1)
Dizziness (excl vertigo)	129 (11)	13 (1)	101 (10)	9 (< 1)	28 (18)	4 (3)
Weakness	124 (11)	31 (3)	106 (11)	28 (3)	18 (12)	3 (2)
*Represents High Level Term Peripheral Neuropathies NEC

A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥ Grade 4 adverse reactions were ≤ 1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).

Across the studies, bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (Days 1 to 11) and a return toward baseline during the ten day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥ Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients

. Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥ Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).

Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥ Grade 4 for < 1% of patients. Eight percent (8%) of patients discontinued bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%).

In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.

In the Phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one grade or more from the last dose of bortezomib.

The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥ Grade 4 in < 1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, < 1% of patients experienced hypotension associated with a syncopal reaction.

Neutrophil counts decreased during the bortezomib dosing period (Days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in < 1% of patients and < 1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥ Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).

Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.

Pyrexia (> 38^○C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in < 1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to bortezomib discontinuation in < 1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥ Grade 3 pyrexia was 1% in patients with multiple myeloma and < 1% in patients with mantle cell lymphoma.

Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).

A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in

no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥ Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥ Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).

Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%).

Two deaths considered to be bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis.

The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.

Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia

Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion,, ventricular tachycardia

Hearing impaired, vertigo

Diplopia and blurred vision, conjunctival infection, irritation

Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux

Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis

Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure

Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema

Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter-related infection

Catheter-related complication, skeletal fracture, subdural hematoma

Weight decreased

Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia

Arthralgia, back pain, bone pain, myalgia, pain in extremity

Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack

Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation

Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative

Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension

Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus

Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension