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FOR THE HEALTHCARE PROFESSIONAL
Answers to
frequently
asked Questions
about velcade®
QA
&
About
Clinical trial results
VELCADE®(bortezomib)FOR
with VELCADE®
INJECTION
WHAT IS VELCADE?
HOW WAS THE EFFICACY OF VELCADE EVALUATED IN
VELCADE is a novel, first-in-class proteasome
PATIENTS WITH MULTIPLE MYELOMA?
inhibitor that acts in a different manner than other
The efficacy of VELCADE was evaluated in an open-
chemotherapies.1-4
label, single-arm, multi-center Phase II clinical trial
(SUMMIT) in 202 patients with multiple myeloma
VELCADE is indicated for the treatment of multiple
who had received at least 2 prior therapies (median =
myeloma patients who have received at least two prior
6) and were progressing on their last therapy.
therapies and have demonstrated disease progression
on the last therapy.The effectiveness of VELCADE is
VELCADE was given as a 1.3 mg/m2 IV push twice
based on response rates.There are no controlled trials
weekly for 2 weeks (administered on Days 1, 4, 8,
demonstrating a clinical benefit, such as improvement
and 11) followed by a 10-day rest period. Response
in survival.
rates were assessed by an Independent Review
Committee based on two determinations 6 weeks
The diagram below, based on nonclinical studies,
apart. Of 202 patients, 188 were considered evaluable
illustrates the unique mechanism of action of
for response.
VELCADE.1-4
Complete Response (CR) determined by criteria defined
MECHANISM OF ACTION AS SHOWN IN
by Bladé et al required 100% reduction in M protein on
(NONCLINICAL STUDIES)
at least 2 determinations at least 6 weeks apart, a
negative immunofixation test, < 5% plasma cells in the
bone marrow, stable bone disease, and normal
calcium. Partial Response (PR) required 50% reduction
Proteasome
Intracellular
Degraded
VELCADE
proteins
proteins
in M protein, 90% reduction in urine M protein on at
(signals)
tagged for
degradation
least 2 determinations at least 6 weeks apart, stable
1
Proteasomes are enzyme
bone disease, and normal calcium. Clinical remission
complexes in all cells that degrade
intracellular proteins in a
by SWOG criteria was defined as 75% reduction in M
regulated manner in both healthy
and cancerous cells1-4
protein on at least 2 determinations at least 6 weeks
apart and/or 90% reduction in urine M protein, stable
bone disease, and normal calcium.
In SUMMIT, VELCADE demonstrated an overall
response rate (CR+PR) of 27.7% (95% CI = 21, 35).
17.6% (95% CI = 12, 24) of patients achieved a clinical
remission as defined by the SWOG criteria.
2 Cancer cells depend
upon proteins regulated
3 Inhibition of the proteasome by
by the proteasome for
VELCADE prevents the
proliferation, metastasis,
degradation of intracellular
and survival1
proteins, affecting multiple
signaling cascades within cells
Please see enclosed full Prescribing Information.
4 This disruption of signaling
cascades can inhibit tumor
growth and cause cancer
cell death
2
3
side effects Profile For
VELCADE®
In single-arm studies, it is often not possible to
These response rates were independent of the number
distinguish between drug-caused adverse events and
and type of previous therapies, including steroids,
those that reflect the patient's underlying disease.
alkylators, anthracyclines, thalidomide, and stem cell
In 228 patients who were treated with VELCADE
transplant. In addition, the rate of response remained
1.3 mg/m2/dose in phase II studies, the most
consistent regardless of the patient's gender, race,
commonly reported adverse events were asthenic
body surface area, performance status, myeloma type,
conditions (65%), nausea (64%), diarrhea (51%),
2 microglobulin, or chromosome 13 deletion status.5
decreased appetite including anorexia (43%),
Predictors of decreased response were > 50% plasma
constipation (43%), thrombocytopenia (43%),
cells in the bone marrow and abnormal cytogenetics;
peripheral neuropathy (37%), pyrexia (36%), vomiting
chromosome 13 deletion status was not an
(36%), and anemia (32%). Fourteen percent of patients
independent predictor of decreased response.
experienced at least one episode of Grade 4 toxicity,
Patients maintained their response over time, with a
with the most common toxicities being
median duration of response of 12 months (95% CI =
thrombocytopenia (3%) and neutropenia (3%).
224 days, not estimable).The median overall survival
A total of 113 (50%) of the 228 patients experienced
of all patients enrolled in SUMMIT was 16 months
Serious Adverse Events (SAEs) during the studies.The
(range <1 to 18+ months). Patients who experienced a
most commonly reported SAEs included pyrexia (7%),
CR or PR had decreased red blood cell transfusion
pneumonia (7%), diarrhea (6%), vomiting (5%),
requirements.
dehydration (5%), and nausea (4%).
VELCADE® (bortezomib) for Injection activity was
demonstrated at 1.0 mg/m2 and 1.3 mg/m2 doses in a
separate, small, open-label, multicenter, dose-ranging
study of patients with multiple myeloma who were
progressing or relapsed on or after a median of 3 prior
therapies.5 Major responses (CR + PR) were 30%
(95% CI = 14, 50) and 38% (95% CI = 20, 59) at the
1.0 mg/m2 and 1.3 mg/m2 doses, respectively.
Please see enclosed full Prescribing Information.
4
5
PrescribIng
Considerations
CONTRAINDICATIONS
Treatment emergent adverse events (25% overall)
VELCADE® is contraindicated in patients with
are illustrated in the chart that follows.
hypersensitivity to bortezomib, boron, or mannitol.
Treatment emergent adverse events (25% overall)
WARNINGS
in Phase II clinical trials at 1.3 mg/m2 dose (N=228)
VELCADE should be administered under the
supervision of a physician experienced in the use of
Adverse
Overall Grade
Grade
Grade
antineoplastic therapy.
Event
1/2*
3*
4*
Nausea
64%
58%
6%
0
Pregnancy Category D
Women of childbearing potential should avoid
Diarrhea
51%
43%
7%
<1%
becoming pregnant while being treated with VELCADE.
Decreased appetite
43%
41%
3%
0
& anorexia
PRECAUTIONS
Constipation
43%
41%
2%
0
Peripheral Neuropathy: Treatment with VELCADE may
be associated with a peripheral neuropathy that is
Vomiting
36%
29%
7%
<1%
predominantly sensory, although rare cases of mixed
Thrombocytopenia
43%
13%
27%
3%
sensorimotor neuropathy have been reported. Patients
Anemia
32%
23%
9%
0
with preexisting symptoms and/or signs of peripheral
Asthenia (fatigue,
65%
46%
18%
<1%
neuropathy may experience worsening during
malaise, weakness)
treatment with VELCADE. Patients should be monitored
Peripheral neuropathy
37%
23%
14%
0
for symptoms of neuropathy, such as numbness, a
Pyrexia
36%
32%
4%
0
burning sensation, hyperesthesia, hypoesthesia,
Headache
28%
24%
4%
0
paresthesia, discomfort, or neuropathic pain.
Insomnia
27%
26%
1%
0
Hypotension:Treatment with VELCADE may be
Arthralgia
26%
21%
5%
0
associated with orthostatic/postural hypotension
Pain in limb
26%
19%
7%
0
throughout therapy. Caution should be used when
treating patients with a history of syncope, patients
In Phase II clinical trials, the most common adverse
receiving medications known to be associated with
events leading to discontinuation of VELCADE®
hypotension, and patients who are dehydrated.
(bortezomib) for Injection were peripheral
Heart Failure: Acute development or exacerbation of
neuropathy (6%), gastrointestinal events (5%),
congestive heart failure has been seen in patients with
thrombocytopenia (4%), and fatigue (2%). Eighteen
risk factors for or existing heart disease. Such patients
percent of patients discontinued therapy due to
should be closely monitored.
drug-related adverse events.
Laboratory Tests: Complete blood counts (CBCs)
should be frequently monitored throughout treatment
* National Cancer Institute CommonToxicity Criteria (NCI, CTC, Version 2.0)6
with VELCADE.
Tumor Lysis Syndrome: Tumor lysis syndrome may
occur. Patients with high tumor burden prior to
treatment should be monitored closely and
appropriate precautions taken.
Please see enclosed full Prescribing Information.
6
7
How supplied/
dosing/administration
HOW IS VELCADE® SUPPLIED AND STORED?
Gastrointestinal Adverse Events: Nausea, diarrhea,
constipation, and vomiting may occur during
VELCADE is supplied in 10-mL single-dose vials
treatment with VELCADE® (bortezomib) for Injection.
containing 3.5 mg bortezomib as a lyophilized white
Thrombocytopenia: Platelet counts should be
to off-white cake or powder without preservative.
frequently monitored prior to each dose of VELCADE.
Each single-dose vial is intended for administration
Thrombocytopenia was maximal at Day 11 and
to one patient.
usually recovered by the next cycle and there was no
evidence of cumulative thrombocytopenia.There
have been reports of gastrointestinal and
intracerebral hemorrhage in association with
thrombocytopenia induced by VELCADE.
Patients with Hepatic or Renal Impairment
Patients with renal and hepatic impairment should
be closely monitored for toxicities.
Animal Toxicity Findings
Toxicities observed with chronic administration in
animals included severe anemia and
Store unopened vials at a controlled room
thrombocytopenia; gastrointestinal, neurological
temperature of 25°C (77°F) in the original package
and lymphoid system toxicities; and multifocal
protected from light; excursions are
hemorrhage in the brain, eye and heart. At doses
permitted from 15°C to 30°C (59°F to 86°F).
twice the recommended clinical dose, animals
experienced profound hypotension and bradycardia
HOW IS VELCADE RECONSTITUTED?
resulting in myocardial damage and death.
Reconstitute VELCADE
DRUG INTERACTIONS
with 3.5 mL of normal
No formal drug interaction studies have been
(0.9%) saline, Sodium
performed with VELCADE. In vitro studies indicate
Chloride Injection, USP.
that bortezomib is a substrate for cytochrome P450
The concentration of
3A4, 2D6, 2C19, 2C9, and 1A2. Patients who are
reconstituted solution is
concomitantly receiving VELCADE and drugs that are
1 mg/mL. Reconstituted
inhibitors or inducers of cytochrome P450 3A4
VELCADE should be
should be closely monitored for either toxicities or
administered within 8
reduced efficacy. During clinical trials, hypoglycemia
and hyperglycemia were reported in diabetic
hours of preparation.
patients receiving oral hypoglycemics. Close
Reconstituted VELCADE
monitoring of blood glucose levels and adjustment
can be stored in the
of antidiabetic medications may be required.
syringe for not more than 3 hours. Once
reconstituted, VELCADE does not need to be
protected from indoor lighting.
Please see enclosed full Prescribing Information.
8
9
ARE THERE ANY ADMINISTRATION PRECAUTIONS
HOW IS VELCADE® ADMINISTERED?
NECESSARY WITH VELCADE® (bortezomib) for Injection?
VELCADE may be injected directly into a peripheral
VELCADE is cytotoxic; therefore, caution should
line by IV push or injected into an infusion port. No
be used during handling and preparation. Proper
central line is required.5To ensure a full dose, flush
aseptic technique should be used, and gloves and
the line with normal saline. In clinical trials,
other protective clothing should be worn to prevent
extravasation of VELCADE was not associated with
skin contact. VELCADE should be reconstituted under
tissue damage. Local skin irritation was reported in
a hood.
5% of patients.
WHAT ARE THE DOSING GUIDELINES
FOR VELCADE?
VELCADE is administered as a 3- to 5-second IV
push followed by a standard saline flush. One cycle
consists of 2 doses given twice weekly for 2 weeks
(Days 1, 4, 8, and 11) followed by a 10-day rest period
(Days 1221). At least a 72-hour rest period between
doses is required.
Standard dosing regimen
Direct injection into a peripheral line by IV push
Day 1
Day 4
Day 8
Day 11 10-DAY REPEAT
REST
VELCADE
VELCADE
VELCADE
VELCADE
CYCLE
PERIOD
1.3 mg/m2
1.3 mg/m2
1.3 mg/m2
1.3 mg/m2
HOW IS THE NUMBER OF CYCLES
OF VELCADE DETERMINED?
In the SUMMIT trial, patients with a confirmed
complete response received 2 additional cycles of
VELCADE treatment beyond confirmation of
response. Patients who experienced a clinical benefit
were allowed to continue beyond 8 cycles on an
Injection into an infusion port
extension study.
Please see enclosed full Prescribing Information.
10
11
ARE INFUSION-RELATED REACTIONS COMMON?
IS THE ADMINISTRATION OF VELCADE® DIFFERENT IN
PATIENTS WITH RENAL IMPAIRMENT?
Infusion reactions and infusion-site reactions were
rarely reported with VELCADE in Phase II clinical
There are no pharmacokinetic data in patients with
impaired hepatic function or renal insufficiency.
trials.
Creatinine clearance in SUMMIT patients ranged
from 14 to 220 mL/min. Patients with creatinine
WHAT PREADMINISTRATION PROCEDURES SHOULD BE
clearance values < 14 mL/min and those receiving
PERFORMED WITH EACH CYCLE OF VELCADE®
hemodialysis should be closely monitored for
(bortezomib) for Injection?
toxicities during treatment with VELCADE.
The following preadministration procedures are
HOW IS AN OVERDOSE OF VELCADE MANAGED?
recommended with each cycle ofVELCADE treatment:
No cases of overdose with VELCADE were reported
Day 1
Day 4
Day 8
Day 11
Procedure/Test
during clinical trials. In the event of overdosage, the
patient's vital signs should be monitored and
Assess for symptom
XX
X
X
management (e.g., diarrhea,
appropriate supportive care given to maintain blood
vomiting, fever, etc)
pressure and body temperature.There is no known
Monitor for symptoms of
specific antidote for VELCADE overdose.
peripheral neuropathy,
XX
X
X
such as burning sensation,
hyperesthesia, hypoesthesia,
paresthesia, discomfort,
or pain
Examine for signs of dyspnea
XX
X
X
and peripheral edema
Vital signs (blood pressure,
XX
X
X
respiration rate,
temperature, pulse)
Clinical laboratory tests
Hematology (CBC and
XX
X
X
platelet count)
Electrolytes
X--
X
--
Clinical chemistries
X--
X
--
Total protein/albumin
X--
X
--
Weight (recalculate dose if
XX
X
X
weight change 8% or greater)
Please share "Information for Patients" from full
Prescribing Information with allVELCADE recipients.
Please see enclosed full Prescribing Information.
12
13
side effects
Management
At the onset of Grade 3 non-hematological toxicities
VELCADE therapy should be held when the platelet
or Grade 4 hematological toxicities, therapy with
count is <25,000/µl. Once toxicity has resolved,
VELCADE® (bortezomib) for Injection should be held.
VELCADE may be reinitiated at a 25% reduced dose
Once toxicity has resolved,VELCADE may be reinitiated
(1.3 mg/m2/dose reduced to 1.0 mg/m2/dose; 1.0
at a 25% reduced dose (1.3 mg/m2/dose reduced to
mg/m2/dose reduced to 0.7 mg/m2/dose).
1.0 mg/m2/dose; 1.0 mg/m2/dose reduced to
0.7 mg/m2/dose).These guidelines are not to be used
Platelet counts should be monitored prior to each
for the treatment of peripheral neuropathy; refer to the
dose of VELCADE. Observe patients for signs of
chart on page 16 for dose modification guidelines for
thrombocytopenia during patient visits. Platelet
neuropathic pain and/or peripheral sensory neuropathy
transfusions may be utilized in cases of
related toVELCADE.
thrombocytopenia at the physician's discretion.
HOW IS ASTHENIA MANAGED?
HOW IS PERIPHERAL NEUROPATHY ASSOCIATED WITH
Asthenic conditions (fatigue, malaise, or weakness)
VELCADE MANAGED?
were reported in clinical trials with VELCADE. First
Treatment with VELCADE may be associated with a
onset of fatigue was reported most often during
peripheral neuropathy that is predominantly sensory,
treatment Cycles 1 and 2. Most patients are able to
although rare cases of mixed sensorimotor neuropathy
continue therapy with VELCADE despite fatigue.
have been reported. Patients with preexisting
At the onset of Grade 3 non-hematological toxicities,
symptoms and/or signs of peripheral neuropathy may
including asthenic conditions, therapy with VELCADE
experience a worsening of the condition during
should be held. Once toxicity has resolved, VELCADE
treatment. Symptoms may improve or return to
may be reinitiated at a 25% reduced dose (1.3
baseline in some patients upon discontinuation of
mg/m2/dose reduced to 1.0 mg/m2/dose;
VELCADE therapy.The complete time-course of this
1.0 mg/m2/dose reduced to 0.7 mg/m2/dose).
toxicity has not been fully characterized. Limited follow-
up data regarding the outcome of peripheral
Management of asthenic conditions may include
neuropathy are available. Patients with pre-existing
appropriate supportive care at the physician's discretion.
severe neuropathy should be treated with VELCADE
only after careful risk/benefit assessment.
HOW IS THROMBOCYTOPENIA MANAGED?
Transient thrombocytopenia may occur withVELCADE
treatment. Generally, platelet counts will drop during the
dosing period (Days 1-11), with a return to baseline
during the rest period (Days 12-21).There is no evidence
of cumulative thrombocytopenia. There have been
reports of gastrointestinal and intracerebral hemorrhage
in association with thrombocytopenia induced by
VELCADE.
Please see enclosed full Prescribing Information.
14
15
Since peripheral neuropathy can be a dose-limiting
At the onset of Grade 3 non-hematological toxicities,
side effect, patients should be frequently monitored
including gastrointestinal events, therapy with
for symptoms of neuropathy during VELCADE®
VELCADE® should be held. Once toxicity has
(bortezomib) for Injection treatment, such as
resolved, VELCADE may be reinitiated at a 25%
numbness, a burning sensation, hyperesthesia,
reduced dose (1.3 mg/m2/dose reduced to 1.0
hypoesthesia, paresthesia, discomfort or neuropathic
mg/m2/dose; 1.0 mg/m2/dose reduced to 0.7
pain. Early detection and appropriate dose/schedule
mg/m2/dose).
modification may prevent the progression of
neuropathy. Supportive care may be used at the
Management of gastrointestinal events associated
physician's discretion.
with VELCADE treatment may include the
administration of antiemetics and antidiarrheals.
Recommended dose modification for neuropathic
If the patient becomes dehydrated, administration
pain and/or peripheral sensory neuropathy
of fluids and electrolytes is recommended.
Severity of peripheral
Modification of dose and
neuropathy signs and
regimen
DOES HYPOTENSION OCCUR WITH VELCADE?
symptoms
Orthostatic/postural hypotension may occur
Grade 1 (paresthesias and/or
No action
throughout therapy with VELCADE.
loss of reflexes) without pain or
At the onset of Grade 3 non-hematological toxicities,
loss of function
including hypotension, therapy with VELCADE
Grade 1 with pain or Grade 2
Reduce VELCADE to 1.0 mg/m2
(interfering with function but
should be held. Once toxicity has resolved, VELCADE
not with activities of daily living)
may be reinitiated at a 25% reduced dose (1.3
Grade 2 with pain or Grade 3
Withhold VELCADE therapy
mg/m2/dose reduced to 1.0 mg/m2/dose; 1.0
(interfering with activities of
until toxicity resolves. When daily
mg/m2/dose reduced to 0.7 mg/m2/dose).
living)
toxicity resolves reinitiate with a
reduced dose of VELCADE at
Caution should be used when treating patients with a
0.7 mg/m2 and change treatment
history of syncope, patients receiving medications
schedule to once per week.
known to be associated with hypotension, or
Grade 4 (permanent sensory loss
Discontinue VELCADE
patients who are dehydrated.
that interferes with function)
Patients should be advised to maintain hydration, as
HOW ARE GASTROINTESTINAL EVENTS MANAGED?
well as to seek medical advice, if they experience
Nausea, diarrhea, constipation, and vomiting may
symptoms of dizziness, light-headedness, or fainting
occur during treatment with VELCADE.The majority of
spells.They should also be cautious when operating
gastrointestinal events are generally mild to moderate.
machinery, including automobiles.
Patients should be advised to maintain hydration,
and should be instructed to seek medical advice if
they experience symptoms of dizziness, light-
headedness or fainting spells.
Please see enclosed full Prescribing Information.
16
17
Reimbursement/
support
DOES VELCADE® OFFER A PATIENT ASSISTANCE
Management of hypotension related to VELCADE®
PROGRAM?
(bortezomib) for Injection therapy may include the
The program is called the VELCADE Reimbursement
adjustment of antihypertensive medications,
Assistance Program.The program consists of coding
rehydration, and/or the administration of
and billing assistance, reimbursement information
mineralocorticoids.
and coverage assistance, denials and appeals
HOW IS NEUTROPENIA MANAGED?
assistance and a patient assistance program.
Neutropenia may occur withVELCADE.The incidence of
The program is easily accessed through
Grade 4 neutropenia was rare in clinical trials and febrile
1-866-VELCADE and is handled by Reimbursement
neutropenia was reported at < 1%.
Specialists. All registration can occur through the
telephone and facsimile. Prospective and
At the onset of Grade 4 hematological toxicities,
retrospective assistance is available.
including neutropenia, therapy with VELCADE should
be held. Once toxicity has resolved, VELCADE may
WHERE CAN I GO FOR FURTHER SUPPORT OR
be reinitiated at a 25% reduced dose
INFORMATION ON VELCADE?
(1.3 mg/m2/dose reduced to 1.0 mg/m2/dose;
TheVELCADE information line is staffed by professionals
1.0 mg/m2/dose reduced to 0.7 mg/m2/dose).
to answer all of your questions. Call toll-free:
The complete blood count (CBC) should be frequently
1-866-VELCADE, 9 AM to 8 PM EasternTime.
monitored. Use of growth factors is at the physician's
discretion.
References: 1. Adams J, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents.
Cancer Res. 1999;59:26152622. 2. Adams J, et al. Proteasome inhibition: a new strategy in cancer treatment.
Invest New Drugs. 2000;18:109121. 3. Glickman MH, et al. The ubiquitin-proteasome proteolytic pathway:
destruction for the sake of construction. Physiol Rev. 2002;82:373428. 4. Hideshima T, et al. The proteasome
inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma
cells. Cancer Res. 2001;61(7):3071-3076. 5. Data on file, Millennium Pharmaceuticals, Inc. 6. National Cancer
Institute Cancer Therapy Evaluation Program. Common Toxicity Criteria, Version 2.0, June 1, 1999.
Please see enclosed full Prescribing Information.
18
19
For more information call:
1.866.VELCADE
(1-866-835-2233)
9 AM to 8 PM Eastern Time
Please see enclosed full Prescribing Information.
Millennium Pharmaceuticals, Inc.
Cambridge, MA 02139
Copyright ©2004, Millennium Pharmaceuticals, Inc.
All rights reserved.
Printed in U.S.A.
V0063R1
04/04