VELCADE(tm) (bortezomib) for Injection Prescribing Information
VELCADE(tm) (bortezomib) for Injection is an antineoplastic agent available for
intravenous injection (IV) use only. Each single dose vial contains 3.5 mg of bortezomib
as a sterile lyophilized powder. Inactive ingredient: 35 mg mannitol, USP.
Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol
boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium
with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its
cyclic anhydride form as a trimeric boroxine.
The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-
[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl]boronic acid.
Bortezomib has the following chemical structure:
O
OH
H
N
N B
N
OH
H
O
N
The molecular weight is 384.24. The molecular formula is; C19H25BN4O4.The solubility
of bortezomib, as the monomeric boronic acid, in water is 3.3-3.8mg/mL in a pH range of
2-6.5.
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted
proteolysis which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in non-clinical tumor models, including multiple myeloma.
Following intravenous administration of 1.3 mg/m2 dose, the median estimated maximum plasma concentration of bortezomib was 509 ng/mL (range=109-1300 ng/mL) in eight patients with multiple myeloma and creatinine clearance values ranging from 31-169 mL/min. The mean elimination half-life of bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies. The pharmacokinetics of bortezomib as a single agent have not been fully characterized at the recommended dose in multiple myeloma patients.
Distribution
The distribution volume of bortezomib as a single agent was not assessed at the
recommended dose in patients with multiple myeloma. The binding of bortezomib to
human plasma proteins averaged 83% over the concentration range of 100-1000 ng/mL.
Metabolism
In vitro
studies with human liver microsomes and human cDNA-expressed cytochrome
P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2D6, 2C19, 2C9, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
The pathways of elimination of bortezomib have not been characterized in humans.
Special Populations
Age, Gender, and Race: The effects of age, gender, and race on the pharmacokinetics of
bortezomib have not been evaluated.
Hepatic Impairment: No pharmacokinetic studies were conducted with bortezomib in patients with hepatic impairment (see PRECAUTIONS).
Renal Impairment: No pharmacokinetic studies were conducted with bortezomib in
patients with renal impairment. Clinical studies included patients with creatinine
clearances values ranging from 13.8 to 220 mL/min (see PRECAUTIONS).
Pediatric: There are no pharmacokinetic data in pediatric patients.
No formal drug interaction studies have been conducted with bortezomib.
In vitro
studies with human liver microsomes indicate that bortezomib is a substrate of
cytochrome P450 3A4, 2D6, 2C19, 2C9, and 1A2 (see PRECAUTIONS).
Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9,
2D6, and 3A4, with IC50 values of > 30 uM (> 11.5 ug/mL). Bortezomib may inhibit
2C19 activity (IC50=18 uM, 6.9 ug/mL) and increase exposure to drugs that are
substrates for this enzyme.
Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary
cultured human hepatocytes.
Clinical Study in Relapsed and Refractory Multiple Myeloma
The safety and efficacy of VELCADE were evaluated in an open-label, single-arm, multicenter study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy. The median number of prior therapies was six. Baseline patient and disease characteristics are summarized in Table 1. An IV bolus injection of VELCADE 1.3 mg/m2/dose was administered twice weekly for 2 weeks, followed by a 10-day rest period (21 day treatment cycle) for a maximum of 8 treatment cycles. The study employed dose modifications for toxicity (see DOSAGE AND ADMINISTRATION). Patients who experienced a response to VELCADE treatment were allowed to continue VELCADE treatment in an extension study.
Median Age in Years (Range) 59 (34,84) Gender: Male/Female 60%/40% Race: Caucasian/Black/Other 81%/10%/8% Karnofsky Performance Status Score <= 70 20% Hemoglobin <100 g/L 44% Platelet count <75 x 109/L 21%
Type of myeloma (%): IgG/IgA/Light chain 60%/24%/14% Median b2-microglobulin (mg/L) 3.5 Median Creatinine Clearance (mL/min) 73.9 Abnormal Cytogenetics Chromosome 13 Deletion 35% 15%
4.0
| Any Prior Steroids, e.g., dexamethasone, VAD | 99% |
| Any Prior Alkylating Agents, e.g., MP, VBMCP | 92% |
| Any Prior Anthracyclines, e.g., VAD, mitoxantrone | 81% |
| Any Prior Thalidomide Therapy | 83% |
| Received at Least 2 of the Above | 98% |
| Received at Least 3 of the Above | 92% |
| Received All 4 of the Above | 66% |
| Any Prior Stem Cell Transplant /Other High-dose Therapy | 64% |
| Prior Experimental or Other Types of Therapy | 44% |
*Based on number of patients with baseline data available
Responses to VELCADE alone are shown in Table 2. Response rates to VELCADE alone were determined by an independent review committee (IRC) based on criteria published by Blade and others1. Complete response required < 5% plasma cells in the marrow, 100% reduction in M protein, and a negative immunofixation test (IF-). Response rates using the SWOG criteria are also shown. SWOG response required a >= 75% reduction in serum myeloma protein and/or >= 90% urine protein2. A total of 188 patients were evaluated for response; 9 patients with nonmeasurable disease could not be evaluated for response by the IRC. Five patients were excluded from the efficacy analyses because they had minimal prior therapy. Ninety-eight percent of study patients received a starting dose of 1.3 mg/m2. Twenty- eight percent of these patients received a dose of 1.3 mg/m2 throughout the study, while
33 % of patients who started at a dose of 1.3 mg/m2 had to have their dose reduced during the study. Sixty-three percent of patients had at least one dose held during the study. In general, patients who had a confirmed CR received 2 additional cycles of VELCADE treatment beyond confirmation. The mean number of cycles administered was six. The median time to response was 38 days (range 30 to 127 days). The median survival of all patients enrolled was 16 months (range <1 to 18+ months).
| Response Analyses (VELCADE monotherapy) N=188 | N (%) | (95% CI) |
| Overall Response Rate (Blade) (CR + PR) | 52 (27.7%) | (21, 35) |
| Complete Response(CR) 1 | 5 (2.7%) | (1, 6) |
| Partial Response(PR) 2 | 47 (25%) | (19, 32) |
| Clinical Remission (SWOG) 3 | 33 (17.6%) | (12, 24) |
| Kaplan-Meier Estimated Median Duration of Response (95% CI) | 365 Days | (224, NE) |
Complete response
required 100% disappearance of the original monoclonal protein from blood and urine on at least 2 determinations at least 6 weeks apart by immunofixation, and <5% plasma cells in the bone marrow on at least two determinations for a minimum of six weeks, stable bone disease and calcium.
Partial Response
requires >= 50% reduction in serum myeloma protein and >= 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and calcium.
Clinical Remission (SWOG)
required >=75% reduction in serum myeloma protein and/or >= 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and calcium.
In this study, the response rate to VELCADE was independent of the number and types of prior therapies. There was a decreased likelihood of response in patients with either >50% plasma cells or abnormal cytogenetics in the bone marrow. Responses were seen in patients with chromosome 13 abnormalities. A small dose-response study was performed in 54 patients with multiple myeloma received a 1.0 mg/m2/dose or a 1.3 mg/m2/dose twice weekly for two out of three weeks. A single complete response was seen at each dose, and there were overall (CR + PR) response rates of 30% (8/27) at 1.0 mg/m2 and 38% (10/26) at 1.3 mg/m2.
VELCADETM (bortezomib) for Injection is indicated for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The effectiveness of VELCADE is based on response rates (see CLINICAL STUDIES section). There are no controlled trials demonstrating a clinical benefit, such as an improvement in survival.
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron or mannitol.
VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.
Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m2 in the rat and 0.05 mg/kg; 0.6 mg/m2 in the rabbit) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m2 based on body surface area. Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area. No placental transfer studies have been conducted with bortezomib. There are no adequate and well-controlled studies in pregnant women. If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
Peripheral Neuropathy:
VELCADE treatment causes a peripheral neuropathy that is predominantly sensory, although cases of mixed sensori-motor neuropathy have also been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening during treatment with VELCADE. Patients should be monitored for symptoms of
neuropathy, such as a burning sensation, hyperesthesia, hypesthesia, paresthesia, discomfort or neuropathic pain. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE (see DOSAGE AND ADMINISTRATION). Limited follow-up data regarding the outcome of peripheral neuropathy are available. Of the patients who experienced treatment emergent neuropathy more than 70% had previously been treated with neurotoxic agents and more than 80% of these patients had signs or symptoms of peripheral neuropathy at baseline (Also see ADVERSE REACTIONS).
Hypotension:
VELCADE treatment can cause orthostatic/postural hypotension in about 12% of patients. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids.
Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting (see ADVERSE REACTIONS) sometimes requiring use of antiemetics and antidiarrheals. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia: Thrombocytopenia, which occurred in about 40% of patients throughout therapy, was maximal at day 11 and usually recovered by the next cycle. Complete blood counts including platelet counts should be frequently monitored throughout treatment. Onset is most common in Cycles 1 and 2 but can continue throughout therapy. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE induced thrombocytopenia. VELCADE treatment may be temporarily discontinued if patients experience Grade 4 thrombocytopenia. VELCADE may be reinitiated at a reduced dose after resolution of thrombocytopenia (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS).
Bortezomib is metabolized by liver enzymes and bortezomib's clearance may decrease in patients with hepatic impairment. These patients should be closely monitored for toxicities when treated with VELCADE.
No clinical information is available on the use of VELCADE in patients with creatinine clearance values less than 13 mL/min and patients on hemodialysis. These patients should be closely monitored for toxicities when treated with VELCADE (see CLINICAL PHARMACOLOGY/Pharmacokinetics-Special Populations). Animal Toxicity Findings:
Cardiovascular toxicity
Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12-14 hours post dose. Doses >= 1.2 mg/m2 induced dose proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.
Chronic Administration
In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1 week rest) toxicities observed included severe anemia and thrombocytopenia, gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.
Physicians are advised to discuss the following with patients to whom VELCADE will be administered.
Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability:
Since VELCADE may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension, diplopia or blurred vision, patients should be cautious when operating machinery, including automobiles.
Pregnancy/Nursing:
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast feeding during treatment with VELCADE.
Dehydration/Hypotension:
Since patients receiving VELCADE therapy may experience vomiting and/or diarrhea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Concomitant Medications:
Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, anti- virals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.
Peripheral Neuropathy: Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
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. There have been several SAE reports since filing. These reports were submitted to the IND. If the Agency feels this information is unnecessary, the language can be removed.
None known.
Carcinogenicity studies have not been conducted with bortezomib. Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses >= 0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. VELCADE could have a potential effect on either male or female fertility.
see
It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, women should be advised against breast feeding while being treated with VELCADE.
The safety and effectiveness of VELCADE in children has not been established.
Of the 202 patients enrolled, 35% were 65 years of age or older. Nineteen percent (19%) of patients aged 65 years or older experienced responses versus 32% in patients under the age of 65. Across the 256 patients analyzed for safety, the incidence of Grade 3 or 4 events reported was 74%, 80%, and 85% for patients <= 50 years, 51 to 65 years, and > 65 years, respectively.
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 3. 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 3.
US Package Insert FDA/MPI Finalized May 13, 2003
Table 3: Most Commonly Reported (>=10% Overall) Adverse Events (N=228)
| Adverse Event | All Patients (N = 228) [n (%)] | ||
| 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 |
US Package Insert FDA/MPI Finalized May 13, 2003
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 (> 38oC) 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%.
US Package Insert FDA/MPI Finalized May 13, 2003
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
US Package Insert FDA/MPI Finalized May 13, 2003
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
Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration. No cases of overdosage with VELCADE were reported during clinical trials. Single doses of up to 2.0 mg/m2 per week have been administered in adults. In the event of overdosage, patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure and body temperature (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). There is no known specific antidote for VELCADE overdosage.
The recommended dose of VELCADE is 1.3 mg/m2/dose administered as a bolus intravenous injection twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10- day rest period (days 12-21) (see CLINICAL STUDIES section for a description of dose administration during the trials). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below (see PRECAUTIONS). Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1.0 mg/m2/dose; 1.0 mg/m2/dose reduced to 0.7 mg/m2/dose). The following table contains the recommended dose modification for the management of patients who experience VELCADE-related neuropathic pain and/or peripheral sensory neuropathy (Table 4). Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk/ benefit assessment.
| Severity of Peripheral Neuropathy Signs and Symptoms | Modification of Dose and Regimen |
| Grade 1 (paresthesias and/or loss of reflexes) without pain or loss of function | No action |
| Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) | Reduce VELCADE to 1.0 mg /m 2 |
| Grade 2 with pain or Grade 3 (interfering with activities of daily living) | Withhold VELCADE therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m 2 and change treatment schedule to once per week. |
| Grade 4 (Permanent sensory loss that interferes with function) | Discontinue VELCADE |
NCI Common Toxicity Criteria website - http://ctep.info.nih.gov/reporting/ctc.html
VELCADE is an antineoplastic. Caution should be used during handling and preparation. Proper aseptic technique should be used. Use of gloves and other protective clothing to prevent skin contact is recommended. In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of VELCADE was not associated with tissue damage.
Prior to use, the contents of each vial must be reconstituted with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection, USP. The reconstituted product should be a clear and colorless solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.
VELCADE contains no antimicrobial preservative. When reconstituted as directed, VELCADE may be stored at 25oC (77oF); excursions permitted from 15 to 30oC (59 to 86oF) [see USP Controlled Room Temperature]. Reconstituted VELCADE should be administered within eight hours of preparation. The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to three hours in a syringe, however total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.
VELCADE (bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder. NDC 63020-049-01 3.5 mg single dose vial
Unopened vials may be stored at controlled room temperature 25o C (77o F); excursions permitted from 15 to 30o C (59 to 86o F) [see USP Controlled Room Temperature]. Retain in original package to protect from light.
Rx only.
U.S. Patents: 5,780,454, 6,083,903, 6,297,217
: Millennium Pharmaceuticals, Inc.
75 Sidney St. Cambridge, MA 02139 (c) 2003, Millennium Pharmaceuticals, Inc.
References
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high- dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. British Journal of Haematology 1998; 102 ( 5): 1115- 23.
Salmon SE, Haut A, Bonnet JD, Amare M, Weick JK, Durie BG et al. Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study. Journal of Clinical Oncology 1983; 1 ( 8): 453- 61.