Velcade

Bortezomib.

Each single use vial contains: 3.5 mg of bortezomib as a sterile lyophilized powder.
The 10 mL vial contains 38.5 mg powder for solution for injection for the 3.5 mg product.
VELCADE 3.5 mg for injection (sterile lyophilized powder) is an antineoplastic agent available for intravenous injection (IV) or subcutaneous (SC) use.
Excipients/Inactive Ingredients: 35 mg mannitol, USP/EP (IV or SC use (E421).

Pharmacology: Pharmacodynamics: Mechanism of Action: 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 nonclinical tumor models, including multiple myeloma.
Pharmacokinetics: Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to eleven patients with multiple myeloma, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m² dose and 89 to 120 ng/mL for the 1.3 mg/m² dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 - 193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 mg/m² and 1.3 mg/m², respectively.
In the PK/PD substudy in Phase 3 trial, following an IV bolus or subcutaneous (SC) injection of a 1.3 mg/m² dose to multiple myeloma patients (n = 14 for IV, n = 17 for SC), the total systemic exposure after repeat dose administration (AUC_last) was equivalent for SC and IV administration. The C_max after SC administration (20.4 ng/mL) was lower than IV (223 ng/mL). The AUC_last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% - 122.80%.
Distribution: The mean distribution volume of bortezomib ranged from 1659 liters to 3294 liters single- or repeat dose IV administration of 1.0 mg/m² or 1.3 mg/m² to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. 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, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. 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.
Elimination: The pathways of elimination of bortezomib have not been characterized in humans.
Special Populations: Age, Gender, and Race: The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m² doses to 104 pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m², volume of distribution at steady-state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
The effects of gender, and race on the pharmacokinetics of bortezomib have not been evaluated.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of IV bortezomib was assessed in 60 cancer patients at bortezomib doses ranging from 0.5 to 1.3 mg/m². When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalised bortezomib AUC. However, the dose normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely (see Table 7).
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), Mild (CrCL = 40 - 59 mL/min/1.73 m², n = 10), Moderate (CrCL = 20 - 39 mL/min/1.73 m², n = 9), and Severe (CrCL < 20 mL/min/1.73 m², n = 3). A group of dialysis patients who were dosed after dialysis was also included in the study (n = 8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and C_max) was comparable among all the groups (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.

VELCADE is indicated for the treatment of patients with multiple myeloma.
VELCADE is indicated for the treatment of patients with mantle cell lymphoma.

Important Dosing Guidelines: VELCADE is for intravenous or subcutaneous use only. Do not administer VELCADE by any other route.
Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered.
The recommended starting dose of VELCADE is 1.3 mg/m². VELCADE may be administered intravenously at a concentration of 1 mg/ml, or subcutaneously at a concentration of 2.5 mg/ml.
VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least 6 months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose.
When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection.
Dosage in Previously Untreated Multiple Myeloma: VELCADE is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1. In Cycles 1 to 4, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE. (See Table 1.)

Click on icon to see table/diagram/image

Dose Modification Guidelines for VELCADE when given in Combination with Melphalan and Prednisone: Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone: Platelet count should be at least 70 x 10⁹/L and the absolute neutrophil count (ANC) should be at least 1.0 x 10⁹/L; Nonhematological toxicities should have resolved to Grade 1 or baseline. (See Table 2.)

Click on icon to see table/diagram/image

For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided.
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy): Combination therapy with dexamethasone: VELCADE 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Four treatment cycles of this combination therapy are administered.
Combination therapy with dexamethasone and thalidomide: VELCADE 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see Table 3).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. (See Table 3.)

Click on icon to see table/diagram/image

Dosage adjustments for transplant eligible patients: For VELCADE dosage adjustments, as described under "Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma" and "Dose Modifications for Peripheral Neuropathy" should be followed.
In addition, when VELCADE is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the local package inserts.
Dosage in Previously Untreated Mantle Cell Lymphoma: VELCADE (1.3 mg/m²) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6 three week treatment cycles as shown in Table 4. VELCADE is administered first followed by rituximab. VELCADE is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21. For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of VELCADE. (See Table 4.)

Click on icon to see table/diagram/image

Dose Modification Guidelines for VELCADE When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone: Prior to the first day of each cycle (other than Cycle 1): Platelet count should be at least 100 x 10⁹/L and absolute neutrophil count (ANC) should be at least 1.5 x 10⁹/L; Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L); Non-hematologic toxicity should have recovered to Grade 1 or baseline.
Interrupt VELCADE treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy (see Table 6 and Precautions). For dose adjustments, see Table 5 as follows. (See Table 5.)

Click on icon to see table/diagram/image

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information.
Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma: VELCADE (1.3 mg/m²/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten-day rest period (Days 12 to 21). For extended therapy of more than eight cycles, VELCADE may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35). At least 72 hours should elapse between consecutive doses of VELCADE.
Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least six months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose. Retreated patients are administered VELCADE twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of VELCADE. VELCADE may be administered either as a single agent or in combination with dexamethasone.
VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows (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 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).
For dose modifications guidelines for peripheral neuropathy, see Dose Modifications for Peripheral Neuropathy as follows.
Dose Modifications for Peripheral Neuropathy: Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule.
For dose or schedule modification guidelines for patients who experience VELCADE-related neuropathic pain and/or peripheral neuropathy (see Table 6).

Click on icon to see table/diagram/image

Special Populations: Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended VELCADE dose. For patients with moderate or severe hepatic impairment, see Table 7 as follows, (also, see Pharmacology: Pharmacokinetics under Actions): (see Table 7.)

Click on icon to see table/diagram/image

Administration: VELCADE is administered intravenously or subcutaneously. When administered intravenously, VELCADE is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection. For subcutaneous administration, the reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections.
If local injection site reactions occur following VELCADE injection subcutaneously, a less concentrated VELCADE solution (1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously, or changed to IV injection.

Cardiovascular safety pharmacology studies in monkeys and dogs show that IV doses approximately two to three times the recommended clinical dose on a mg/m² basis are associated with increases in heart rate, decreases in contractility, hypotension and death. The decreased cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents. In dog studies, a slight increase in the corrected QT interval was observed at a lethal dose.
Overdosage more than twice the recommended dose in patients has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes.
There is no known specific antidote for VELCADE overdosage. In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see Precautions and Dosage & Administration).

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.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE is for IV and subcutaneous use only. DO NOT ADMINISTER VELCADE INTRATHECALLY.
Overall, the safety profile of patients treated with VELCADE in monotherapy was similar to that observed in patients treated with VELCADE in combination with melphalan and prednisone.
Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy (PN) that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have 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 peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 study comparing VELCADE IV vs SC the incidence of Grade ≥2 peripheral neuropathy events was 24% for SC and 41% for IV (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of subjects in the SC treatment group, compared with 16% in the IV treatment group (p=0.0264) (Table 11). Therefore, patients with pre-existing PN or at high risk of peripheral neuropathy may benefit from starting VELCADE subcutaneously.
Patients experiencing new or worsening peripheral neuropathy may require a change in dose schedule or route of administration to SC (see Dosage & Administration). Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the single agent phase 3 multiple myeloma study of VELCADE vs dexamethasone. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies.
The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: In phase 2 and 3 single agent multiple myeloma studies, the incidence of hypotension (postural, orthostatic, and Hypotension Not Otherwise Specified) was 11% to 12%. 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 and/or sympathomimetics (see Adverse Reactions).
Cardiac Disorders: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the single agent phase 3 multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary oedema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively.
There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Hepatic Events: Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.
Pulmonary Disorders: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately.
In a clinical trial, two patients given high-dose cytarabine (2 g/m² per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
Laboratory Tests: Complete blood counts (CBC) should be frequently monitored throughout treatment with VELCADE.
Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia (see Adverse Reactions). Platelets were lowest at Day 11 of each cycle of VELCADE treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied.
Platelet counts should be monitored prior to each dose of VELCADE. VELCADE therapy should be held when the platelet count is <25,000/uL (see Dosage & Administration and Adverse Reactions). There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusion and supportive care may be considered.
In the single-agent multiple myeloma study of VELCADE vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 8. The incidence of significant bleeding events (≥ Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. (See Table 8.)

Click on icon to see table/diagram/image

In the combination study of VELCADE with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia adverse events (≥ Grade 4) was 32% versus 2% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm. The incidence of bleeding adverse events (≥ Grade 3) was 1.7% (4 patients) in the VcR-CAP arm and was 1.2% (3 patients) in the R-CHOP arm.
There were no deaths due to bleeding events in either arm. There were no CNS bleeding events in the VcR-CAP arm; there was 1 bleeding event in the R-CHOP arm. Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.
The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Colony-stimulating factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.
Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting (see Adverse Reactions) sometimes requiring use of antiemetics and antidiarrheal medications. Fluid and electrolyte replacement should be administered to prevent dehydration. 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.
Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. (See Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.)
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.
Effects on Ability to Drive and Use Machines: VELCADE may cause tiredness, dizziness, fainting, or blurred vision. Patients should be advised not to drive or operate machinery if they experience these symptoms.

Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.
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.
Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast feeding during treatment with VELCADE.
Nursing Mothers: 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.

Summary of Clinical Trials of VELCADE IV in Patients with Relapsed/Refractory Multiple Myeloma: The safety and efficacy of VELCADE were evaluated in 3 studies at the recommended dose of 1.3 mg/m². These included a phase 3 randomized, comparative study, versus dexamethasone of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy (M34101-039); a phase 2 single arm, open-label, multicenter study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy (M34100-025); and a phase 2 dose-response clinical study in relapsed multiple myeloma for patients who had progressed or relapsed on or after first line therapy with VELCADE 1.0 mg/m² or 1.3 mg/m² (M34100-024). (See Table 9.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Summary of Clinical Trials of VELCADE IV vs SC in Patients with Relapsed Multiple Myeloma: The safety and efficacy of VELCADE SC were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of VELCADE IV vs SC in 222 patients with relapsed multiple myeloma. (See Table 10.)

Click on icon to see table/diagram/image

Although, in general safety data were similar for the IV and SC treatment groups, the following table highlights differences larger than 10% in the overall incidence of adverse drug reactions between the two treatment arms. (See Table 11.)

Click on icon to see table/diagram/image

Patients who received VELCADE subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment-emergent adverse drug reactions that were grade 3 or higher in toxicity (57% vs 70% respectively), and a 5% lower incidence of discontinuation of VELCADE (22% vs 27%). The overall incidence of diarrhea (24% for the SC arm vs 36% for the IV arm), gastrointestinal and abdominal pain (6% for the SC arm vs 19% for the IV arm), asthenic conditions (27% for SC arm vs 39% for IV arm), upper respiratory tract infections (14% SC arm vs 26% IV arm) and peripheral neuropathy NEC (38% SC arm vs 53% IV arm) were 12%-15% lower in the subcutaneous group than the intravenous group. In addition, the incidence of peripheral neuropathies that were grade 3 or higher in toxicity was 10% lower (6% for SC vs 16% for IV), and the discontinuation rate due to peripheral neuropathies was 8% lower for the subcutaneous group (5%) as compared to the intravenous group (12%).
Six percent of patients were reported to have had an adverse local reaction to SC administration, mostly redness. Only 2 (1%) subjects were reported as having severe reactions. These severe local reactions were 1 case of pruritus and 1 case of redness. These reactions seldom led to dose modifications and all resolved in a median of 6 days.
VELCADE Retreatment in Relapsed Multiple Myeloma: The following table describes adverse drug reactions reported for at least 10% of patients with relapsed multiple myeloma who received retreatment with VELCADE IV (Study MMY-2036). (See Table 12.)

Click on icon to see table/diagram/image

Summary of Clinical Trials of VELCADE Combination therapy in Patients with Relapsed Multiple Myeloma: The following table describe adverse drug reactions reported for at least 10% of patients with relapsed multiple myeloma who received VELCADE in combination with dexamethasone (Study MMY-2045) or VELCADE in combination with pegylated liposomal doxorubicin (Study DOXIL-MMY-3001). (See Table 13.)

Click on icon to see table/diagram/image

Summary of Clinical Trials in Patients with Previously Untreated Multiple Myeloma: The following table describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective phase 3 study. (See Table 14.)

Click on icon to see table/diagram/image

Herpes zoster virus reactivation: Physician should consider using antiviral prophylaxis in patients being treated with VELCADE. In the phase 3 study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VcMP compared with MP (14% vs 4% respectively). Antiviral prophylaxis was administered to 26% of the patients in the VcMP arm. The incidence of herpes zoster among patients in the VcMP treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
The following table describes adverse drug reactions considered by the Company to have at least a possible causal relationship to VELCADE from patients with previously untreated multiple myeloma eligible for stem cell transplantation who received VELCADE IV (1.3 mg/m²). 410 patients were treated with VELCADE in combination with doxorubicin and dexamethasone compared with 411 patients treated with vincristine, doxorubicin and dexamethasone in Study MMY-3003, 239 were treated with VELCADE in combination with dexamethasone alone compared with 239 patients treated with vincristine, doxorubicin and dexamethasone in Study IFM 2005-01, and 130 were treated with VELCADE in combination with thalidomide and dexamethasone compared with 126 patients treated with thalidomide and dexamethasone in Study MMY-3010. For these 3 studies conducted in the transplant setting (MMY3003, IFM2005-01, MMY3010), only the adverse reactions during the induction phase of treatment are considered for the table. (See Table 15.)

Click on icon to see table/diagram/image

Summary of the Clinical Trial in Patients with Relapsed Mantle Cell Lymphoma: Safety data for patients with relapsed mantle cell lymphoma were evaluated in a phase 2 study [M34103-053 (PINNACLE)], which included 155 patients treated with VELCADE at the recommended dose of 1.3 mg/m². The safety profile of VELCADE in these patients was similar to that observed in patients with multiple myeloma. Notable differences between the two patient populations were that thrombocytopenia, neutropenia, anemia, nausea, vomiting and pyrexia were reported more often in the patients with multiple myeloma than in those with mantle cell lymphoma; whereas peripheral neuropathy, rash and pruritus were higher among patients with mantle cell lymphoma compared to patients with multiple myeloma.
Summary of Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma: Table 16 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received VELCADE (1.3 mg/m²) administered IV in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (VcR-CAP) in a prospective randomized study.
The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (4 patients in the VcR-CAP arm and 3 patients in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the VcR-CAP arm.
Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the R-CHOP arm. Respiratory tract and lung infections were reported, with the predominant preferred term of pneumonia (VcR-CAP 8% versus R-CHOP 5%).
The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment. (See Table 16.)

Click on icon to see table/diagram/image

Post-Marketing Experience: Clinically significant adverse drug reactions are listed here if they have not been reported previously.
The frequencies provided as follows reflect reporting rates of adverse drug reactions from the worldwide post-marketing experience with VELCADE. The frequencies provided as follows reflect reporting rates and precise estimates of incidence cannot be made. These adverse drug reactions are ranked by frequency, using the following convention: Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000, including isolated reports). (See Table 17.)

Click on icon to see table/diagram/image

In vitro and animal ex vivo studies indicate that bortezomib is a weak inhibitor of cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of VELCADE, showed a bortezomib AUC mean increase of 35%, based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors (e.g., ketoconazole, ritonavir).
In a drug-drug interaction study assessing the effect of omeprazole, a potent inhibitor of CYP2C19, on the pharmacokinetics of VELCADE there was no significant effect on the pharmacokinetics of bortezomib, based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of VELCADE showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. The concomitant use of VELCADE with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort. In the same drug-drug interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on VELCADE showed a 17% increase in mean bortezomib AUC based on data from 21 patients. This is not considered clinically relevant.
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.
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.
Drug Laboratory Test Interactions: None known.

Incompatibilities: This product must not be mixed with other medicinal products except those mentioned in Instructions for Use and Handling and Disposal as follows.
Instructions for Use and Handling and Disposal: Administration Precautions: 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.
When administered subcutaneously, alternate sites for each injection (thigh or abdomen). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE is for IV and subcutaneous use only. DO NOT ADMINISTER VELCADE INTRATHECALLY.
Reconstitution/Preparation for Intravenous and Subcutaneous Administration: The contents of each vial should be reconstituted only with normal (0.9%) saline according to the following instructions based on route of administration: (see Table 18).

Click on icon to see table/diagram/image

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.
Procedure for Proper Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

VELCADE contains no antimicrobial preservative. When reconstituted as directed, VELCADE may be stored at 25°C. Reconstituted VELCADE should be administered within 8 hours of preparation. The reconstituted material may be stored for up to 8 hours in the original vial or in a syringe. The total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
Do not store unopened vials above 30°C. Retain in original package to protect from light.
Shelf Life: 3.5 mg: 36 months.
Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.

Targeted Cancer Therapy

L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

B