A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Velcade Side Effects, and Drug Interactions - Bortezomib
Velcade Side Effects, and Drug Interactions - Bortezomib
SIDE EFFECTS
The two studies described (see CLINICAL
STUDIES) evaluated 228 patients with multiple myeloma receiving VELCADE
1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest
period (21 day treatment cycle length) for a maximum of 8 treatment cycles.
The most commonly reported adverse events
were asthenic conditions (including fatigue, malaise and weakness) (65%), nausea
(64%), diarrhea (51%), appetite decreased (including anorexia) (43%),
constipation (43%), thrombocytopenia (43%), peripheral neuropathy (including
peripheral sensory neuropathy and peripheral neuropathy aggravated) (37%), pyrexia
(36%), vomiting (36%), and anemia (32%). Fourteen percent of patients experienced
at least one episode of grade 4 toxicity, with the most common toxicity being
thrombocytopenia (3%) and neutropenia (3%).
Serious Adverse Events (SAEs): Serious Adverse
Events are defined as any event, regardless of causality, 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 113 (50%) of the 228 patients experienced SAEs during the
studies. The most commonly reported SAEs included pyrexia (7%), pneumonia (7%),
diarrhea (6%), vomiting (5%), dehydration (5%), and nausea (4%).
Adverse events thought by the investigator to be drug-related
and leading to discontinuation occurred in 18% of patients. The reasons for
discontinuation included peripheral neuropathy (5%), thrombocytopenia (4%),
diarrhea (2%), and fatigue (2%).
Two deaths were reported and considered by the investigator
to be possibly related to study drug: one case of cardiopulmonary arrest and
one case of respiratory failure.
The most common adverse events are shown in Table 4.
All adverse events occurring at ≥ 10% are included. In the
single arm studies conducted it is often not possible to distinguish adverse
events that are drug-caused and those that reflect the patient's underlying
disease. See discussion of specific adverse reactions following Table 4.
|
Table 4: Most Commonly Reported (≥
10% Overall) Adverse Events (N = 228)
|
| |
All Patients (N = 228) [n (%)]
|
|
Adverse Event
|
All Events
|
Grade 3 Events
|
Grade 4 Events
|
|
Asthenic conditions
|
149 (65)
|
42 (18)
|
1 (<1)
|
|
Nausea
|
145 (64)
|
13 (6)
|
0
|
|
Diarrhea
|
116 (51)
|
16 (7)
|
2 (<1)
|
|
Appetite decreased
|
99 (43)
|
6 (3)
|
0
|
|
Constipation
|
97 (43)
|
5 (2)
|
0
|
|
Thrombocytopenia
|
97 (43)
|
61 (27)
|
7 (3)
|
|
Peripheral neuropathy
|
84 (37)
|
31 (14)
|
0
|
|
Pyrexia
|
82 (36)
|
9 (4)
|
0
|
|
Vomiting
|
82 (36)
|
16 (7)
|
1 (<1)
|
|
Anemia
|
74 (32)
|
21 (9)
|
0
|
|
Headache
|
63 (28)
|
8 (4)
|
0
|
|
Insomnia
|
62 (27)
|
3 (1)
|
0
|
|
Arthralgia
|
60 (26)
|
11 (5)
|
0
|
|
Pain in limb
|
59 (26)
|
16 (7)
|
0
|
|
Edema
|
58 (25)
|
3 (1)
|
0
|
|
Neutropenia
|
55 (24)
|
30 (13)
|
6 (3)
|
|
Paresthesia and dysesthesia
|
53 (23)
|
6 (3)
|
0
|
|
Dyspnea
|
50 (22)
|
7 (3)
|
1 (<1)
|
|
Dizziness (excluding vertigo)
|
48 (21)
|
3 (1)
|
0
|
|
Rash
|
47 (21)
|
1 (<1)
|
0
|
|
Dehydration
|
42 (18)
|
15 (7)
|
0
|
|
Upper respiratory tract infection
|
41 (18)
|
0
|
0
|
|
Cough
|
39 (17)
|
1 (<1)
|
0
|
|
Bone pain
|
33 (14)
|
5 (2)
|
0
|
|
Anxiety
|
32 (14)
|
0
|
0
|
|
Myalgia
|
32 (14)
|
5 (2)
|
0
|
|
Back pain
|
31 (14)
|
9 (4)
|
0
|
|
Muscle cramps
|
31 (14)
|
1 (<1)
|
0
|
|
Dyspepsia
|
30 (13)
|
0
|
0
|
|
Abdominal pain
|
29 (13)
|
5 (2)
|
0
|
|
Dysgeusia
|
29 (13)
|
1 (<1)
|
0
|
|
Hypotension
|
27 (12)
|
8 (4)
|
0
|
|
Rigors
|
27 (12)
|
1 (<1)
|
0
|
|
Herpes zoster
|
26 (11)
|
2 (<1)
|
0
|
|
Pruritus
|
26 (11)
|
0
|
0
|
|
Vision blurred
|
25 (11)
|
1 (<1)
|
0
|
|
Pneumonia
|
23 (10)
|
12 (5)
|
0
|
Asthenic conditions (fatigue, malaise, weakness)
Asthenia was reported in 65% of patients and was predominantly
reported as Grade 1 or 2. The first onset of fatigue was most often reported
during the 1st and 2nd cycles of therapy. Asthenia was
Grade 3 for 18% of patients. Two percent of patients discontinued treatment
due to fatigue.
Gastrointestinal Events
The majority of patients experienced gastrointestinal adverse
events during the studies, including nausea, diarrhea, constipation, and vomiting.
Grade 3 or 4 gastrointestinal events occurred in 21% of patients and were considered
serious in 13% of patients. Vomiting and diarrhea each were of Grade 3 severity
in 7% of patients and were Grade 4 in <1%. Five percent of patients discontinued
due to gastrointestinal events. Appetite decreased (anorexia) was reported as
an adverse event for 43% of patients. The incidence of Grade 3 decreased appetite
was 3%.
Thrombocytopenia
Thrombocytopenia was reported during treatment with VELCADE
for 43% of patients. The thrombocytopenia was characterized by a dose related
decrease in platelet count during the VELCADE dosing period (days 1 to 11) with
a return to baseline in platelet count during the rest period (days 12 to 21)
in each treatment cycle. Thrombocytopenia was Grade 3 or 4 in intensity for
27% and 3% respectively of patients. Four percent (4%) of patients discontinued
VELCADE treatment due to thrombocytopenia of any grade.
Peripheral Sensory Neuropathy
Events reported as peripheral neuropathy, peripheral sensory
neuropathy, and peripheral neuropathy aggravated occurred in 37% of patients.
Peripheral neuropathy was Grade 3 for 14% of patients with no Grade 4 events.
New onset or worsening of existing neuropathy was noted throughout the cycles
of treatment. Six percent (6%) of patients discontinued VELCADE due to neuropathy.
More than 80% of all study patients had signs or symptoms of peripheral neuropathy
at baseline evaluation. The incidence of Grade 3 neuropathy was 5% (2 of 41
patients) in patients without baseline neuropathy. Symptoms may improve or return
to baseline in some patients upon discontinuation of VELCADE. The complete time-course
of this toxicity has not been fully characterized.
Pyrexia
Pyrexia (>38șC) was reported as an adverse event for 36%
of patients and was assessed as Grade 3 in 4% of patients.
Neutropenia
Neutropenia occurred in 24% of patients and was grade 3 in
13% and grade 4 in 3%. The incidence of febrile neutropenia was <1%.
Hypotension
Hypotension (including reports of orthostatic hypotension)
was reported in 12% of patients. Most events were Grade 1 or 2 in severity.
Grade 3 hypotension occurred in 4% of patients; no patient experienced Grade
4 hypotension. Patients developing orthostatic hypotension did not have evidence
of orthostatic hypotension at study entry; half had pre-existing hypertension
and one third had evidence of peripheral neuropathy. Doses of antihypertensive
medications may need to be adjusted in patients receiving VELCADE. Four percent
of patients experienced hypotension, including orthostatic hypotension, and
had a concurrent syncopal event.
Serious Adverse Events from Clinical Studies
In approximately 580 patients, the following serious adverse
events (not described above) were reported, considered at least possibly related
to study medication, in at least one patient treated with VELCADE administered
as monotherapy or in combination with other chemotherapeutics. These studies
were conducted in patients with hematological malignancies and in solid tumors.
Blood and lymphatic system disorders: Disseminated
intravascular coagulation
Cardiac disorders: Atrial fibrillation aggravated,
atrial flutter, cardiac amyloidosis, cardiac arrest, cardiac failure congestive,
myocardial ischemia, myocardial infarction, pericardial effusion, pulmonary
edema, ventricular tachycardia
Gastrointestinal disorders: Ascites, dysphagia,
fecal impaction, gastritis hemorrhagic, gastrointestinal hemorrhage, hematemesis,
ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction,
small intestinal obstruction, large intestinal perforation, stomatitis, melena,
pancreatitis acute
Hepatobiliary: Hyperbilirubinemia, portal vein
thrombosis
Immune system disorders: Anaphylactic reaction,
drug hypersensitivity, immune complex mediated hypersensitivity
Infections and Infestations: Bacteremia
Injury, poisoning and procedural complications:
Skeletal fracture, subdural hematoma
Metabolism and nutrition disorders: Hypocalcemia,
hyperuricemia, hypokalemia, hyponatremia, tumor lysis syndrome
Nervous system: Ataxia, coma, dizziness, dysarthria,
dysautonomia, cranial palsy, grand mal convulsion, hemorrhagic stroke, motor
dysfunction, spinal cord compression, transient ischemic attack
Psychiatric: Agitation, confusion, psychotic
disorder, suicidal ideation
Renal and urinary: Calculus renal, bilateral
hydronephrosis, bladder spasm, hematuria urinary incontinence, urinary retention,
renal failure (acute and chronic), glomerular nephritis proliferative
Respiratory, thoracic and mediastinal: Acute
respiratory distress syndrome, atelectasis, chronic obstructive airways disease
exacerbated, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis,
hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress,
respiratory failure
Vascular: Cerebrovascular accident, deep venous
thrombosis, peripheral embolism, pulmonary embolism
DRUG INTERACTIONS
No formal drug interaction studies have been conducted with
VELCADE.
In vitro studies with human liver microsomes indicate
that bortezomib is a substrate for cytochrome P450 3A4, 2D6, 2C19, 2C9, and
1A2. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors
or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities
or reduced efficacy (see CLINICAL PHARMACOLOGY/Pharmacokinetics-Drug
Interactions).
During clinical trials, hypoglycemia and hyperglycemia were
reported in diabetic patients receiving oral hypoglycemics. Patients on oral
antidiabetic agents receiving VELCADE treatment may require close monitoring
of their blood glucose levels and adjustment of the dose of their antidiabetic
medication.
top
