Bortezol

Multiple Myeloma

Bortezol^® (bortezomib) is indicated for the treatment of patients with multiple myeloma.

Mantle Cell Lymphoma

Bortezol is indicated for the treatment of patients with mantle cell lymphoma.

Important Dosing Guidelines

Bortezol is for intravenous or subcutaneous use only. Bortezol should not be administered by any other route.

Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

The recommended starting dose of Bortezol is 1.3 mg/m². Bortezol may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL.

Bortezol retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezol and who have relapsed at least 6 months after completing prior Bortezol treatment. Treatment may be started at the last tolerated dose.

When administered intravenously, Bortezol is administered as a 3 to 5 second bolus intravenous injection.

Dosage In Previously Untreated Multiple Myeloma

Bortezol is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Bortezol is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezol is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezol.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma

Dose Modification Guidelines For Bortezol When Given In Combination With Melphalan And Prednisone

Prior to initiating any cycle of therapy with Bortezol 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
• Non-hematological toxicities should have resolved to Grade 1 or baseline

Table 2: Dose Modifications during Cycles of Combination Bortezol, Melphalan and Prednisone Therapy Toxicity Dose modification or delay

For information concerning melphalan and prednisone, see manufacturer's prescribing information.

Dose modifications guidelines for peripheral neuropathy are provided.

Dosage In Previously Untreated Mantle Cell Lymphoma

Bortezol (1.3 mg/m²) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for six 3-week treatment cycles as shown in Table 3. Bortezol is administered first followed by rituximab. Bortezol is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period on Days 12-21. 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 Bortezol.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma

Dose Modification Guidelines For Bortezol 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 Bortezol treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy. For dose adjustments, see Table 4 below.

Table 4: Dose Modifications on Days 4, 8, and 11 during Cycles of Combination Bortezol, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy

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

Bortezol (1.3 mg/m²/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, Bortezol may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4 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 Bortezol.

Patients with multiple myeloma who have previously responded to treatment with Bortezol (either alone or in combination) and who have relapsed at least 6 months after their prior Bortezol therapy may be started on Bortezol at the last tolerated dose. Retreated patients are administered Bortezol twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of Bortezol. Bortezol may be administered either as a single agent or in combination with dexamethasone.

Bortezol therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below. Once the symptoms of the toxicity have resolved, Bortezol 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 section 2.7.

Dose Modifications For Peripheral Neuropathy

Starting Bortezol 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 Bortezol only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during Bortezol 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 Bortezol-related neuropathic pain and/or peripheral neuropathy see Table 5.

Table 5: Recommended Dose Modification for Bortezol related Neuropathic Pain and/or PeripheralSensory or Motor Neuropathy

Dosage In Patients With Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezol dose. Patients with moderate or severe hepatic impairment should be started on Bortezol at a reduced dose of 0.7 mg/m² per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerance (see Table 6).

Table 6: Recommended Starting Dose Modification for Bortezol in Patients with Hepatic Impairment

Administration Precautions

The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.

When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

If local injection site reactions occur following Bortezol administration subcutaneously, a less concentrated Bortezol solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, the intravenous route of administration should be considered.

Bortezol is an antineoplastic. Procedures for proper handling and disposal should be considered.

Reconstitution/Preparation For Intravenous And Subcutaneous Administration

Proper aseptic technique should be used. Reconstitute only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

For each 3.5 mg single-use vial of bortezomib reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 7):

Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration

Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezol to be administered:

• Intravenous Administration [1 mg/mL concentration]

• Subcutaneous Administration [2.5 mg/mL concentration]

Stickers that indicate the route of administration are provided with each Bortezol vial. These stickers should be placed directly on the syringe of Bortezol once Bortezol is prepared to help alert practitioners of the correct route of administration for Bortezol.

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.

Stability: Unopened vials of Bortezol are stable until the date indicated on the package when stored in the original package protected from light.

Bortezol contains no antimicrobial preservative. Reconstituted Bortezol should be administered within 8 hours of preparation. When reconstituted as directed, Bortezol may be stored at 25°C (77°F). 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 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.

Bortezol is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions.

Bortezol is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezol.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Peripheral Neuropathy

Bortezol treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor 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 Bortezol. 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 relapsed multiple myeloma trial comparing Bortezol subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting Bortezol subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during Bortezol therapy may require a decrease in the dose and/or a less dose-intense schedule. In the Bortezol versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. 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

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. 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, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Bortezol therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of Bortezol versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Bortezol and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the Bortezol group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving Bortezol. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2g/m² per day) by continuous infusion with daunorubicin and Bortezol for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

There have been reports of pulmonary hypertension associated with Bortezol administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezol until a prompt and comprehensive diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES)

Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Bortezol. 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 Bortezol. The safety of reinitiating Bortezol therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity

Bortezol treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezol for severe symptoms.

Thrombocytopenia/Neutropenia

Bortezol is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.

Monitor complete blood counts (CBC) frequently during treatment with Bortezol. Measure platelet counts prior to each dose of Bortezol. Adjust dose/schedule for thrombocytopenia. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with Bortezol. Support with transfusions and supportive care, according to published guidelines.

In the single-agent, relapsed multiple myeloma study of Bortezol versus 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 bleeding (≥ Grade 3) was 2% on the Bortezol arm and was < 1% in the dexamethasone arm.

Table 8: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezol versus Dexamethasone

In the combination study of Bortezol with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥ Grade 4) was 32% versus 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12. The incidence of bleeding events (≥ Grade 3) was 1% in the VcR-CAP arm (3 patients) and was < 1% in the R-CHOP arm (1 patient).

Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the RCHOP 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. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the RCHOP arm.

Tumor Lysis Syndrome

Tumor lysis syndrome has been reported with Bortezol therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.

Hepatic Toxicity

Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezol therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, Bortezol can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m² based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Females of reproductive potential should avoid becoming pregnant while being treated with Bortezol. Advise females and males of reproductive potential that they must use contraception during treatment with Bortezol and for 2 months following treatment. If Bortezol is used during pregnancy or if the patient becomes pregnant during Bortezol treatment, the patient should be apprised of the potential risk to the fetus.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, Bortezol can cause fetal harm when administered to a pregnant woman. There are no studies with the use of Bortezol in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

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 0.5 times the clinical dose of 1.3 mg/m² based on body surface area.

Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately 0.5 times the clinical dose of 1.3 mg/m² based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/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.

Lactation

Risk Summary

There are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from Bortezol is unknown, advise nursing women not to breastfeed during treatment with Bortezol and for 2 months after treatment.

Females And Males Of Reproductive Potential

Based on its mechanism of action and findings in animals, Bortezol can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Bortezol treatment.

Contraception

Advise patients of reproductive potential to use effective contraception during treatment with Bortezol and for at least 2 months after treatment.

Infertility

Based on the mechanism of action and findings in animals, Bortezol may have an effect on either male or female fertility.

Pediatric Use

The effectiveness of Bortezol in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL) has not been established.

The activity and safety of Bortezol in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; block 2 included cyclophosphamide, etoposide and methotrexate; block 3 included high dose cytosine arabinoside and asparaginase. Bortezol was administered at a dose of 1.3 mg/m² as a bolus intravenous injection on days 1, 4, 8, and 11 of block 1 and days 1, 4, and 8 of block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was 10 years (range 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/ Alaska Native, 1% were Pacific Islander.

The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL ≤ 21 years and relapsed < 36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without Bortezol. There was no evidence that the addition of Bortezol had any impact on the CR rate.

No new safety concerns were observed when Bortezol was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without Bortezol.

The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

Geriatric Use

Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the Bortezol arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on Bortezol compared to dexamethasone [5.5 moversus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the Bortezol arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for Bortezol patients ≤ 50, 51-64 and ≥ 65 years old, respectively.

No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving Bortezol; but greater sensitivity of some older individuals cannot be ruled out.

Patients With Renal Impairment

The pharmacokinetics of Bortezol are not influenced by the degree of renal impairment. Therefore, dosing adjustments of Bortezol are not necessary for patients with renal insufficiency. Since dialysis may reduce Bortezol concentrations, Bortezol should be administered after the dialysis procedure.

Patients With Hepatic Impairment

The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3x ULN) and severe (bilirubin > 3 x ULN) hepatic impairment. Starting dose should be reduced in those patients.

Patients With Diabetes

During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral anti-diabetic agents receiving Bortezol treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.

The following adverse reactions are also discussed in other sections of the labeling:

• Peripheral Neuropathy
• Hypotension
• Cardiac Toxicity
• Pulmonary Toxicity
• Posterior Reversible Encephalopathy Syndrome (PRES)
• Gastrointestinal Toxicity
• Thrombocytopenia/Neutropenia
• Tumor Lysis Syndrome
• Hepatic Toxicity

Clinical Trials Safety Experience

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

Summary Of Clinical Trial In Patients With Previously Untreated Multiple Myeloma

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

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

Table 9: Most Commonly Reported Adverse Reactions (≥ 10% in the Bortezol, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study

Relapsed Multiple Myeloma Randomized Study Of Bortezol Versus Dexamethasone

The safety data described below and in Table 10 reflect exposure to either Bortezol (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezol was administered intravenously at doses of 1.3 mg/m² twice weekly for 2 out of 3 weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian.

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

Serious Adverse Reactions And Adverse Reactions Leading To Treatment Discontinuation In The Relapsed Multiple Myeloma Study Of Bortezol Versus Dexamethasone

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

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

Four deaths were considered to be Bortezol-related in this relapsed multiple myeloma study: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.

Most Commonly Reported Adverse Reactions In The Relapsed Multiple Myeloma Study Of Bortezol Versus Dexamethasone

The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥ 10% in the Bortezol arm are included.

Table 10: Most Commonly Reported Adverse Reactions (≥ 10% in Bortezol arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Bortezol versus Dexamethasone (N=663)

Safety Experience From The Phase 2 Open-Label Extension Study In Relapsed Multiple Myeloma

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

Safety Experience From The Phase 3 Open-Label Study Of Bortezol Subcutaneous Versus Intravenous In Relapsed Multiple Myeloma

The safety and efficacy of Bortezol administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of Bortezol subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 11 reflect exposure to either Bortezol subcutaneous (n=147) or Bortezol intravenous (n=74).

Table 11: Most Commonly Reported Adverse Reactions (≥ 10%), with Grade 3 and ≥ 4 Intensity in theRelapsed Multiple Myeloma Study (N=221) of Bortezol Subcutaneous versus Intravenous

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

A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.

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

Serious Adverse Reactions And Adverse Reactions Leading To Treatment Discontinuation In The Relapsed Multiple Myeloma Study Of Bortezol Subcutaneous Versus Intravenous

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

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

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

Safety Experience From The Clinical Trial In Patients With Previously Untreated Mantle Cell Lymphoma

Table 12 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received Bortezol (1.3 mg/m²) administered intravenously in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (VcR-CAP) in a prospective randomized study.

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

Table 12: Most Commonly Reported Adverse Reactions (≥ 5%) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study

n (%)

n (%)

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.

The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (3 patients in the VcR-CAP arm and 1 patient in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the VcR-CAP arm.

Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; 3 patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (< 1%; 2 patients).

Integrated Summary Of Safety (Relapsed Multiple Myeloma And Relapsed Mantle Cell Lymphoma)

Safety data from phase 2 and 3 studies of single agent Bortezol 1.3 mg/m²/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Bortezol subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezol was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

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

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adver

There is no known specific antidote for Bortezol overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given.

Studies in monkeys and dogs showed that intravenous bortezomib doses as low as 2 times the recommended clinical dose on a mg/m² basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m² and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug administration.

Following twice weekly administration of 1 mg/m² and 1.3 mg/m² bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed 5 minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 and 1.3 mg/m² doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m² and 1.3 mg/m² dose regimens, respectively.

Following intravenous administration of 1 mg/m² and 1.3 mg/m² doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 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 to 193 hours after the 1 mg/m² dose and 76 to 108 hours after the 1.3mg/m² dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m², respectively.

Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m² dose to patients (n = 14 for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% -122.80%.

Distribution

The mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m² following single-or repeat-dose administration of 1 mg/m² or 1.3mg/m² to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 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 2 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.

Age

Analyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1 mg/m²and 1.3 mg/m² showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).

Gender

Mean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m² doses.

Race

The effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.

Hepatic Impairment

The effect of hepatic impairment (see Table 6 for definition of hepatic impairment) on the pharmacokinetics of bortezomib was assessed in 60 patients with cancer 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-normalized 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.

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 Cmax) was comparable among all the groups.

Pediatric

See Use In Specific Populations.

Cytochrome P450

Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC₅₀ values of > 30μM (> 11.5μg/mL). Bortezomib may inhibit 2C19 activity (IC₅₀ = 18 μM, 6.9 μg/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.